introduction to the symposium on antimicrobial therapy · compromised immunity, as well as an...

EDITORIAL

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For personal use. Mass reproduce only with permission from Mayo Clinic Proceedingsa .

2009, an estimated 33.3 million people were living with HIV.8 However, the most recent global figures indicate that the epidemic is beginning to slow down and perhaps reverse its course. Both HIV incidence and HIV-related deaths have decreased by nearly 20% worldwide. This decline is attributable in part to access to antiretroviral therapy; in 2009, more than 5 million people were receiv-ing antiretroviral therapy. Globally, tuberculosis (TB) continues to account for a substantial burden of disease, with 9.4 million (11%-13% HIV-positive) incident cases, 14 million prevalent cases, and 1.7 million deaths in 2009.9 The number of cases of multidrug-resistant TB in 2008 was estimated at 440,000. By July 2010, 58 countries and territories had reported at least 1 case of extensively drug-resistant TB. Intensive ef-forts to reduce the global burden of TB are under way. The cornerstone of these efforts is access to quality diagnosis and treatment. Although little progress has been made in the development of new anti-TB drugs, the scale-up of in-tensive efforts to improve TB care and control globally has resulted in up to 6 million lives being saved.9 The introduc-tion of newer diagnostic modalities, including automated molecular tests that can be used in a resource-limited set-ting where the burden of TB is the highest, has generated great optimism and excitement. Many infections have become increasingly difficult to treat because of the emergence of resistance to commonly used antibiotics.10 Bacteria develop resistance in response to selective pressure exerted by inappropriately used an-tibiotics. Mutations that confer resistance may be passed on to other bacteria of the same species as well as those of different species and genera. Hospital-acquired antibiotic-resistant infections are estimated to cause 100,000 deaths in the United States, with substantial direct and indirect economic costs to the country.11 These antibiotic-resistant infections are caused by a variety of organisms, including methicillin-resistant , penicillin-

EDITORIAL

Address correspondence to Zelalem Temesgen, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (temesgen [email protected]).

© 2011 Mayo Foundation for Medical Education and Research

Mayo Clinic Proceedings

February 2011 Volume 86Number 2

Introduction to the Symposium on Antimicrobial Therapy

In this issue of journal readers will discover the first of 15 articles that constitute the

new Symposium on Antimicrobial Therapy.1 The articles will be published sequentially in the monthly issues of the journal, ending in mid-2012. This new symposium is pub-lished in part because of readers’ requests to once again ad-dress antimicrobial drugs, as was done in the ’ Symposium on Antimicrobial Agents, published between October 1998 and February 2000. The new 2011-2012 symposium arrives at an important time for infectious dis-ease management worldwide. The past 2 decades have seen an unprecedented wave of new and old infections thrust into the public’s attention. During that time, the number of emerging and reemerging infectious diseases has substantially increased. Emerging infections are infections that appear for the first time in a population, whereas reemerging infections are known infections that reappear after a decline in incidence or ex-tend their geographic impact. Examples include pandemic influenza A (H1N1) virus,2 avian influenza virus,3 severe acute respiratory syndrome (SARS),4 west Nile virus infec-tion,5 and ehrlichiosis.6 A feature of current emerging and reemerging infections is that disease first appearing at one geographic location traverses continents and affects mil-lions of people within a very short period. First reported from Mexico in the spring of 2009, pandemic influenza A (H1N1) virus infection was noted in almost all countries in the world by March 2010, resulting in nearly 18,000 deaths.7 In only a few months, SARS spread from China to 26 countries and affected 8098 people, causing 774 deaths.4

The human immunodeficiency virus (HIV) epidemic continues to affect communities worldwide; at the end of

See also page 156

EDITORIAL

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resistant pneumococci, vancomycin-resistant enterococci, and resistant gram-negative bacteria (eg,

, and extended-spectrum β-lactamase–producing bac-teria (eg, , species).12 Some of the reasons for this epidemic of antibiotic resistance among bacteria include poor infection control practices, injudicious use of antibiotics in human medicine, and in-judicious use of antibiotics in agriculture. The problem is further aggravated by the lack of a robust antibiotic drug–development pipeline. Advances in cancer chemotherapy and transplantation, with the resultant increase in the number of people with compromised immunity, as well as an increase in the use of invasive procedures and wide-spectrum antibiotics, have contributed to an increase in the incidence of invasive fungal infections. Although some progress has been made in the development of new diagnostic assays and new anti-fungal drugs, they remain wholly inadequate, and optimal treatment strategies for many of these invasive fungal in-fections remain to be defined.13

The ’ Editorial Board has selected 15 topics for the Symposium on Antimicrobial Therapy that we think will be of relevance and of practical value to general internists and other clinicians. In the first article, Leekha et al1 discuss general principles of antimi-crobial therapy, dispensing pearls of infectious diseases practice that are difficult to find in any other single publi-cation. Subsequent articles address a variety of infectious disease–related topics, ranging from pharmacology of an-timicrobial agents to current concepts in the management of various infections, including bacterial, fungal, viral, mycobacterial, and parasitic infections. Topics addressed in this symposium also include laboratory testing to guide antimicrobial therapy, antibiotic prophylaxis, and current concepts in outpatient antibiotic therapy. All articles are authored by experts in the subject matter. As with previous

symposia published by , once all the articles in this Symposium on Antimicrobial Therapy have appeared in the journal, they will be compiled into a book that we hope will serve as a valuable resource to the practicing clinician.

Zelalem Temesgen, MDDivision of Infectious DiseasesMayo ClinicRochester, MN

1. Leekha S, Terrell CL, Edson RS. General principles of antimicrobial therapy. Mayo Clin Proc. 2011;86(2):156-167. 2. Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans [pub-lished correction appears in 2009;361(1):102]. . 2009;360:2605-2615. 3. Webster RG, Govorkova EA. H5N1 Influenza– continuing evolution and spread. . 2006;355:2174-2177. 4. World Health Organization. Global Alert and Response (GAR). Sum-mary of probable SARS cases with onset of illness from November 2002 to 31 July 2003 (based on data as of the 31 December 2003). http://www.who.int/csr /sars/country/table2004_04_21/en/. Accessed January 5, 2011. 5. Hayes EB, Komar N, Nasci RS, et al. Epidemiology and transmission dy-namics of West Nile virus disease. . 2005;11(8):1167-1173. 6. Paddock CD, Childs JE. : a prototypical emerging pathogen. . 2003;16(1):37-64. 7. World Health Organization. Global Alert and Response (GAR). Pan-demic (H1N1) 2009—update 94. http://www.who.int/csr/don/2010_04_01/en /index.html. Published April 1, 2010. Accessed January 5, 2011. 8. Joint United Nations Programme on HIV/AIDS (UNAIDS). Global Re-port: UNAIDS report on the global AIDS epidemic: 2010. http://www.unaids .org/documents/20101123_GlobalReport_em.pdf. Accessed January 5, 2011. 9. World Health Organization. Global tuberculosis control 2010. http://whqlibdoc.who.int/publications/2010/9789241564069_eng.pdf. Accessed January 5, 2011. 10. Spellberg B, Guidos RJ, Gilbert DN, et al. The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infec-tious Diseases Society of America. . 2008;46:155-164. 11. Eber MR, Laxminarayan R, Perencevich EN, et al. Clinical and eco-nomic outcomes attributable to health care–associated sepsis and pneumonia.

. 2010;170(4):347-353. 12. Arias CA, Murray BE. Antibiotic-resistant bugs in the 21st century: a clinical super-challenge. . 2009;360(5):439-443. 13. Chandrasekar P. Diagnostic challenges and recent advances in the early management of invasive fungal infections. . 2010;84(4): 281-290.

GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY

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SYMPOSIUM ON ANTIMICROBIAL THERAPY

From the Department of Epidemiology, University of Maryland, Baltimore (S.L.); and Division of Infectious Diseases, Mayo Clinic, Rochester, MN (C.L.T., R.S.E.).

Address correspondence to Randall S. Edson, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (edson.randall @mayo.edu). Individual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com.


For editorial comment, see page 86

The terms , , and encompass a wide variety of pharmaceutical agents

that include antibacterial, antifungal, antiviral, and anti-parasitic drugs. Of these, antibacterial agents are by far the most commonly used and thus are the focus of this article, although similar principles apply to the other agents as well. Evidence-based practice guidelines from the Infec-tious Diseases Society of America1 can help direct appro-priate therapy for specific infectious disease syndromes as well as for infections caused by specific microorganisms.

General Principles of Antimicrobial Therapy

Surbhi Leekha, MBBS; Christine L. Terrell, MD; and Randall S. Edson, MD

Antimicrobial agents are some of the most widely, and often inju-diciously, used therapeutic drugs worldwide. Important consider-ations when prescribing antimicrobial therapy include obtaining an accurate diagnosis of infection; understanding the difference between empiric and definitive therapy; identifying opportunities to switch to narrow-spectrum, cost-effective oral agents for the shortest duration necessary; understanding drug characteristics that are peculiar to antimicrobial agents (such as pharmaco-dynamics and efficacy at the site of infection); accounting for host characteristics that influence antimicrobial activity; and in turn, recognizing the adverse effects of antimicrobial agents on the host. It is also important to understand the importance of antimicrobial stewardship, to know when to consult infectious disease specialists for guidance, and to be able to identify situa-tions when antimicrobial therapy is not needed. By following these general principles, all practicing physicians should be able to use antimicrobial agents in a responsible manner that benefits both the individual patient and the community.

Mayo Clin Proc. 2011;86(2):156-167

AST = antimicrobial susceptibility testing; CSF = cerebrospinal fluid; ESBL = extended-spectrum β-lactamase; G6PD = glucose-6-phosphate dehydrogenase; HIV = human immunodeficiency virus; MIC = minimum inhibitory concentration; MRSA = methicillin-resistant Staphylococcus aureus; OPAT = outpatient parenteral antimicrobial therapy; UTI = uri-nary tract infection

These guidelines should be applied in the context of host characteristics, response to therapy, and cost of therapy. This article discusses many such factors that should guide appropriate use of antimicrobial therapy.

SELECTING AND INITIATING AN ANTIBIOTIC REGIMEN

OBTAINING AN ACCURATE INFECTIOUS DISEASE DIAGNOSIS

An infectious disease diagnosis is reached by determining the site of infection, defining the host (eg, immunocompro-mised, diabetic, of advanced age), and establishing, when possible, a microbiological diagnosis. It is critical to isolate the specific pathogen in many serious, life-threatening infections, especially for situations that are likely to require prolonged therapy (eg, endocarditis, septic arthritis, disk space infection, and meningitis). Similarly, when a patient does not benefit from antimicrobial therapy chosen on the basis of clini-cal presentation, additional investigations are needed to determine the etiologic agent or exclude noninfectious diagnoses. To optimize an accurate microbiological diag-nosis, clinicians should ensure that diagnostic specimens are properly obtained and promptly submitted to the mi-crobiology laboratory, preferably before the institution of antimicrobial therapy. Infectious disease diagnoses also frequently rely on a detailed exposure history, as in the case of a patient with nonresolving pneumonia who has resided in or traveled to the southwestern United States where coc-cidioidomycosis is endemic. Although the microbiological diagnosis is ideally based on data such as bacterial or fun-gal culture or serologic testing, frequently the “most likely” microbiological etiology can be inferred from the clinical presentation. For example, cellulitis is most frequently as-sumed to be caused by streptococci or staphylococci, and antibacterial treatment can be administered in the absence of a positive culture. Similarly, community-acquired pneu-monia that does not warrant hospitalization can also be treated empirically—with a macrolide or fluoroquinolone antibiotic—without performing specific diagnostic test-


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ing.2 Finally, noninfectious conditions should be consid-ered in the differential diagnosis for infections, especially when the diagnosis is not clear-cut.

TIMING OF INITIATION OF ANTIMICROBIAL THERAPY

The timing of initial therapy should be guided by the urgen-cy of the situation. In critically ill patients, such as those in septic shock, febrile neutropenic patients, and patients with bacterial meningitis, empiric therapy should be initiated immediately after or concurrently with collection of diag-nostic specimens. In more stable clinical circumstances, antimicrobial therapy should be deliberately withheld until appropriate specimens have been collected and submitted to the microbiology laboratory. Important examples of this principle are subacute bacterial endocarditis and vertebral osteomyelitis/diskitis. Patients with these infections are frequently ill for a period of several days to weeks before presentation, and administration of antibiotic therapy should be delayed until multiple sets of blood cultures (in the case of endocarditis) or disk space aspirate and/or bone biopsy specimens (for osteomyelitis/diskitis) have been obtained. Premature initiation of antimicrobial therapy in these circumstances can suppress bacterial growth and preclude the opportunity to establish a microbiological diagnosis, which is critical in the management of these patients, who require several weeks to months of directed antimicrobial therapy to achieve cure.

EMPIRIC VS DEFINITIVE ANTIMICROBIAL THERAPY

Because microbiological results do not become available for 24 to 72 hours, initial therapy for infection is often empiric and guided by the clinical presentation. It has been shown that inadequate therapy for infections in critically ill, hospitalized patients is associated with poor outcomes, including greater morbidity and mortality as well as in-creased length of stay.3,4 Therefore, a common approach is to use broad-spectrum antimicrobial agents as initial em-piric therapy (sometimes with a combination of antimicro-bial agents; for further information on these combination regimens, see “Use of Antimicrobial Combinations”) with the intent to cover multiple possible pathogens commonly associated with the specific clinical syndrome. This is true for both community- and hospital-acquired infections. For example, in an otherwise healthy young adult with sus-pected bacterial meningitis who is seen in the emergency department, the most likely pathogens would be

and , and thus a combination of a third-generation cephalosporin (ceftri-axone) plus vancomycin would be recommended as em-piric therapy.5 Hospital-acquired infections are frequently related to the presence of invasive devices and procedures that result in loss of the normal barriers to infection, as is

the case with intravascular catheter–associated bacteremia, ventilator-associated pneumonia, and catheter-associated urinary tract infections (UTIs). They are commonly caused by drug-resistant organisms, both gram-positive (eg, methi-cillin-resistant [MRSA]) and gram-negative (eg, ) bacteria, which are often endemic in hospitals because of the selection pressure from antimicrobial use. In selecting empiric antimicrobial therapy for such infections, clinicians should consider the following: (1) the site of infection and the organisms most likely to be colonizing that site (eg, intravascular catheter–associated bacteremia is frequently a result of colonization and infection caused by staphylococci present on the skin); (2) prior knowledge of bacteria known to colonize a given patient (eg, a screening nasal swab [currently conducted routinely by many hospitals before admitting patients to the intensive care unit] may indicate that the patient is colo-nized with MRSA); and (3) the local bacterial resistance patterns or antibiograms that are available for important pathogens at most hospitals.6

Once microbiology results have helped to identify the etiologic pathogen and/or antimicrobial susceptibility data are available, every attempt should be made to nar-row the antibiotic spectrum. This is a critically important component of antibiotic therapy because it can reduce cost and toxicity and prevent the emergence of antimicrobial resistance in the community. Antimicrobial agents with a narrower spectrum should be directed at the most likely pathogens for the duration of therapy for infections such as community-acquired pneumonia or cellulitis in the ambu-latory setting because specific microbiological tests are not typically performed.

INTERPRETATION OF ANTIMICROBIAL SUSCEPTIBILITY TESTING RESULTS

When a pathogenic microorganism is identified in clinical cultures, the next step performed in most microbiology laboratories is antimicrobial susceptibility testing (AST). Antimicrobial susceptibility testing measures the ability of a specific organism to grow in the presence of a particular drug in vitro and is performed using guidelines established by the Clinical and Laboratory Standards Institute,7 a non-profit global organization that develops laboratory process standards through extensive testing and clinical correlation. The goal of AST is to predict the clinical success or failure of the antibiotic being tested against a particular organ-ism. Data are reported in the form of minimum inhibitory concentration (MIC), which is the lowest concentration of an antibiotic that inhibits visible growth of a microorgan-ism, and are interpreted by the laboratory as “susceptible,” “resistant,” or “intermediate,” according to Clinical and Laboratory Standards Institute criteria. A report of “sus-


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ceptible” indicates that the isolate is likely to be inhibited by the usually achievable concentration of a particular antimicrobial agent when the recommended dosage is used for the particular site of infection. For this reason, MICs of different agents for a particular organism are not directly comparable. For example, MICs of 1 (susceptible) for ciprofloxacin and 2 (susceptible) for ceftriaxone against

do not imply that ciprofloxacin is twice as active as ceftriaxone. Instead, it indicates that concen-trations achieved by giving recommended doses of both drugs are likely to be active against the organism. Although AST results are generally quite useful in narrowing the an-tibiotic regimen, AST has some limitations that should be kept in mind. First, it is important for both clinicians and laboratory personnel to be aware of the site of infection. For example, an isolate of could be reported as susceptible to cefazolin in vitro; however, if this particular isolate was obtained from the cerebrospinal fluid (CSF), cefazolin would not be an optimal therapeutic choice be-cause it does not achieve therapeutic concentrations in the CSF. Clinical laboratories may provide different AST in-terpretations for different sites of infection (eg, meningitis and nonmeningitis AST results for S ). In addi-tion, some organisms carry enzymes that, when expressed in vivo, can inactivate antimicrobial agents to which the organism shows in vitro susceptibility. Although their pres-ence is not immediately apparent from AST results, certain AST “patterns” can provide a clue to their existence. For example, extended-spectrum β-lactamases (ESBLs) in

are enzymes that mediate resistance to almost all β-lactam agents except carbapenems (eg, mero-penem or imipenem). Extended-spectrum β-lactamases can be difficult to detect because they have different levels of in vitro activity against various cephalosporins. In clinical practice, susceptibility to cephamycins (cefoxitin, cefo-tetan) but resistance to a third-generation cephalosporin (eg, cefpodoxime, cefotaxime, ceftriaxone, ceftazidime) or aztreonam should alert one to the possibility of ESBL pro-duction. The production of ESBL should also be suspected when treatment with β-lactams fails despite apparent in vitro susceptibility. This should lead to additional testing, which usually involves growing the bacteria in the presence of a third-generation cephalosporin alone and in combina-tion with clavulanic acid (a β-lactamase inhibitor); en-hanced bacterial inhibition with the addition of clavulanic acid indicates ESBL. When detected by the laboratory, these bacteria should be considered resistant to all β-lactam agents except the carbapenem class. In general, it is good practice to communicate directly with the microbiology laboratory when antimicrobial susceptibility patterns appear unusual. It is also useful to be aware of the limitations of AST at the local laboratory,

particularly in smaller hospitals (eg, testing of relatively newer agents [such as daptomycin for gram-positive cocci] might not be routinely performed or reported but could be available on request).

BACTERICIDAL VS BACTERIOSTATIC THERAPY

A commonly used distinction among antibacterial agents is that of bactericidal vs bacteriostatic agents. Bactericidal drugs, which cause death and disruption of the bacterial cell, include drugs that primarily act on the cell wall (eg, β-lactams), cell membrane (eg, daptomycin), or bacterial DNA (eg, fluoroquinolones). Bacteriostatic agents inhibit bacterial replication without killing the organism. Most bacteriostatic drugs, including sulfonamides, tetracyclines, and macrolides, act by inhibiting protein synthesis. The distinction is not absolute, and some agents that are bacte-ricidal against certain organisms may only be bacteriostatic against others and vice versa. In most cases, this distinction is not significant in vivo; however, bactericidal agents are preferred in the case of serious infections such as endo-carditis and meningitis to achieve rapid cure.

USE OF ANTIMICROBIAL COMBINATIONS

Although single-agent antimicrobial therapy is generally preferred, a combination of 2 or more antimicrobial agents is recommended in a few scenarios. When Agents Exhibit Synergistic Activity Against a Microorganism. Synergy between antimicrobial agents means that, when studied in vitro, the combined effect of the agents is greater than the sum of their independent ac-tivities when measured separately.8 For example, the com-bination of certain β-lactams and aminoglycosides exhibits synergistic activity against a variety of gram-positive and gram-negative bacteria9 and is used in the treatment of seri-ous infections, for which rapid killing is essential (eg, treat-ment of endocarditis caused by species with a combination of penicillin and gentamicin). In this setting, the addition of gentamicin to penicillin has been shown to be bactericidal, whereas penicillin alone is only bacterio-static and gentamicin alone has no significant activity. For certain streptococci, similar synergistic combinations that result in more rapid clearance of the infecting microorgan-ism can also be used to shorten the course of antimicrobial therapy (eg, for endocarditis due to viridans group strep-tococci, a combination of penicillin or ceftriaxone with gentamicin for 2 weeks can be as effective as penicillin or ceftriaxone alone for 4 weeks).10,11

When Critically Ill Patients Require Empiric Ther-apy Before Microbiological Etiology and/or Antimicro-bial Susceptibility Can Be Determined. As already dis-cussed, antibiotic combinations are used in empiric therapy for health care–associated infections that are frequently


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caused by bacteria resistant to multiple antibiotics. Combi-nation therapy is used in this setting to ensure that at least 1 of the administered antimicrobial agents will be active against the suspected organism(s). For example, when a pa-tient who has been hospitalized for several weeks develops septic shock and blood cultures are reported to be growing gram-negative bacilli, it would be appropriate to provide initial therapy with 2 agents that have activity against gram-negative bacilli, particularly P , which is both a common nosocomial pathogen and frequently resistant to multiple agents—in this case, a combination of an antipseudomonal β-lactam with a fluoroquinolone or aminoglycoside could be used. To Extend the Antimicrobial Spectrum Beyond That Achieved by Use of a Single Agent for Treatment of Poly-microbial Infections. When infections are thought to be caused by more than one organism, a combination regimen may be preferred because it would extend the antimicrobial spectrum beyond that achieved by a single agent. For ex-ample, most intra-abdominal infections are usually caused by multiple organisms with a variety of gram-positive cocci, gram-negative bacilli, and anaerobes. Antimicrobial combinations, such as a third-generation cephalosporin or a fluoroquinolone plus metronidazole, can be used as a potential treatment option in these cases and can sometimes be more cost-effective than a comparable single agent (eg, a carbapenem). To Prevent Emergence of Resistance. The emergence of resistant mutants in a bacterial population is generally the result of selective pressure from antimicrobial therapy. Provided that the mechanisms of resistance to 2 antimi-crobial agents are different, the chance of a mutant strain being resistant to both antimicrobial agents is much lower than the chance of it being resistant to either one. In other words, use of combination therapy would provide a better chance that at least one drug will be effective, thereby pre-venting the resistant mutant population from emerging as the dominant strain and causing therapeutic failure. This is why combination drug therapy is used as the standard for treatment of infections such as tuberculosis and the human immunodeficiency virus (HIV) when treatment duration is likely to be prolonged, resistance can emerge relatively easily, and therapeutic agents are limited.

HOST FACTORS TO BE CONSIDERED IN SELECTION OF ANTIMICROBIAL AGENTS

Although it is helpful for clinicians to gain familiarity with a few specific antimicrobial agents, a “one size fits all” ap-proach is not appropriate in antimicrobial selection, and several host factors must be taken into account. Published guidelines on appropriate dose adjustments for individual an-timicrobial agents are available from a variety of sources.12,13

Renal and Hepatic Function. Because the kidney and the liver are the primary organs responsible for elimination of drugs from the body, it is important to determine how well they are functioning during antimicrobial administra-tion. In most cases, one is concerned with dose reduction to prevent accumulation and toxicity in patients with reduced renal or hepatic function. However, sometimes doses might need to be increased to avoid underdosing young healthy patients with rapid renal elimination or those with rapid he-patic metabolism due to enzyme induction by concomitant use of drugs such as rifampin or phenytoin. Age. Patients at both extremes of age handle drugs differently, primarily due to differences in body size and kidney function. Most pediatric drug dosing is guided by weight. In geriatric patients, the serum creatinine level alone is not completely reflective of kidney function, and the creatinine clearance should be estimated by factoring in age and weight for these patients. Genetic Variation. Genetic susceptibility to the adverse effects of antimicrobial agents, which has been demon-strated for several antimicrobial agents, is occasionally significant enough to warrant testing for such variability before administration of certain drugs.8 For example, the antiretroviral drug abacavir, which has become part of the standard combination treatment for HIV infection, is as-sociated with a well-described and potentially fatal hyper-sensitivity reaction that can manifest with any combination of fever, rash, abdominal pain, and respiratory distress. The risk of experiencing this reaction has been shown to be significantly higher in patients with the human leukocyte antigen allele HLA-B*5701,14 and current HIV treatment guidelines recommend routine screening for the presence of this genetic susceptibility in patients before prescribing this drug. Another example is that of glucose-6-phosphate dehydrogenase (G6PD) deficiency, which can result in hemolysis in individuals when exposed to certain antimi-crobial agents, such as dapsone, primaquine, and nitro-furantoin. These drugs should be avoided in those known to be deficient in G6PD, and it is advisable to test for this predisposition in patients who might have a higher risk of G6PD deficiency (eg, African Americans) before prescrib-ing these agents. Many antimicrobial agents are handled by the hepatic cytochrome P450 system, and although varia-tion in expression of these enzymes occurs, insufficient data are available to recommend routine clinical testing to guide antimicrobial dosing. Pregnancy and Lactation. Special considerations for the use of antimicrobial agents in pregnancy relate to both the mother and the fetus. In the case of the mother, in-creases in plasma volume and renal blood flow, especially by the third trimester, can result in more rapid clearance and lower serum levels of pharmaceutical agents, includ-


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ing antimicrobial agents. However, data to support the clinical relevance of this change are sparse, and higher antimicrobial doses are not routinely recommended in the third trimester of pregnancy. Some experts recommend an increased dose of several protease inhibitors for the man-agement of HIV infection in pregnancy. In the case of the developing fetus, many antimicrobial agents can be either teratogenic or otherwise toxic to the fetus. Penicillins, cephalosporins, and macrolides have historically been the most commonly used antimicrobial agents considered safe in pregnancy, and a recent multicenter study of more than 13,000 women with pregnancies affected by birth defects found no association between adverse outcomes and these particular antimicrobial agents.15 In contrast, agents such as sulfonamides and nitrofurantoin, which were not previ-ously considered harmful in early pregnancy, were found to be associated with several birth defects in this study. Other drugs, such as tetracyclines and chloramphenicol, have well-described fetal or neonatal adverse effects and should be avoided. In general, however, human studies on the safety of many antimicrobial agents in pregnancy and lactation are limited, and antimicrobial agents should be prescribed with caution. History of Allergy or Intolerance. A history of antimi-crobial allergy or intolerance should be routinely obtained in the evaluation and management of infection (for a fuller discussion, see “Adverse Effects”). History of Recent Antimicrobial Use. Eliciting a his-tory of exposure to antimicrobial agents in the recent past (approximately 3 months) can also help in selection of antimicrobial therapy. Because the causative microorgan-ism for a current episode of infection emerged under the selective pressure of a recently used antimicrobial agent, it is likely to be resistant to that drug and/or drug class, and an alternative agent should be used.

ORAL VS INTRAVENOUS THERAPY

Patients hospitalized with infections are often treated with intravenous antimicrobial therapy because their admis-sion is often prompted by the severity of their infection. However, patients with mild to moderate infections who require hospitalization for other reasons (eg, dehydra-tion, pain control, cardiac arrhythmias) and have normal gastrointestinal function are candidates for treatment with well-absorbed oral antimicrobial agents (eg, treatment of pyelonephritis and community-acquired pneumonia with oral fluoroquinolones). Furthermore, patients initially treated with parenteral therapy can be safely switched to oral antibiotics when they become clinically stable. When using oral therapy for invasive infections (such as pneumo-nia, pyelonephritis, or abscesses), clinicians are advised to select an agent that has excellent absorption and bioavail-

ability (ie, the percentage of the oral dose that is available unchanged in the serum). Examples of antibiotics with excellent bioavailability are fluoroquinolones, linezolid, trimethoprim-sulfamethoxazole, and metronidazole. For more serious infections, such as infective endocarditis and central nervous system infections (eg, meningitis), in which high serum or CSF drug concentrations are desired, a switch to oral therapy is less reliable and not generally recommended.10

PHARMACODYNAMIC CHARACTERISTICS

Along with host factors, the pharmacodynamic properties of antimicrobial agents may also be important in estab-lishing a dosing regimen. Specifically, this relates to the concept of time-dependent vs concentration-dependent killing.11 Drugs that exhibit time-dependent activity (β-lactams and vancomycin) have relatively slow bactericidal action; therefore, it is important that the serum concentra-tion exceeds the MIC for the duration of the dosing inter-val, either via continuous infusion or frequent dosing. In contrast, drugs that exhibit concentration-dependent killing (aminoglycosides, fluoroquinolones, metronidazole, and daptomycin) have enhanced bactericidal activity as the serum concentration is increased. With these agents, the “peak” serum concentration, and not the frequency of the dosing interval, is more closely associated with efficacy. To illustrate the impact of this distinction on dosing options, we can take the example of a 70-year-old woman with a creatinine clearance estimated to be 30 mL/min who is be-ing treated with ciprofloxacin for pyelonephritis caused by E coli. Antimicrobial dosing guidelines suggest that a dose of either 250 mg orally every 12 hours or 500 mg every 24 hours is an acceptable modification for her reduced kidney function. However, given that ciprofloxacin exhib-its concentration-dependent killing, selection of the latter dosing schedule would be more appropriate.16 In contrast, if the same patient were being treated with intravenous am-picillin, for which the time above the MIC is more closely related to efficacy, a dose of 1 g every 4 hours would be preferable to 2 g every 8 hours.

EFFICACY AT THE SITE OF INFECTION

In addition to possessing in vitro antimicrobial activity and achieving adequate serum levels, the efficacy of an-timicrobial agents depends on their capacity to achieve a concentration equal to or greater than the MIC at the site of infection and modification of activity at certain sites. Anti-microbial concentrations attained at some sites (eg, ocular fluid, CSF, abscess cavity, prostate, and bone) are often much lower than serum levels. For example, first- and sec-ond-generation cephalosporins and macrolides do not cross the blood-brain barrier and are not recommended for cen-


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tral nervous system infections. Fluoroquinolones achieve high concentrations in the prostate and are preferred oral agents for the treatment of prostatitis.17 Daptomycin, an excellent bactericidal agent against gram-positive bacteria, is not useful for treatment of pneumonia (eg, pneumococcal pneumonia) because it is inactivated by lung surfactant.18 Many antibiotics (eg, aminoglycosides) are less active in the low-oxygen, low-pH, and high-protein environment of abscesses, and drainage of abscesses to enhance antimicro-bial efficacy is recommended when possible.8 Agents in the same class can differ from one another; for example, moxi-floxacin does not achieve significant urinary concentrations because of its low renal excretion and is therefore not suit-able for treatment of UTIs; in contrast, both levofloxacin and ciprofloxacin are excellent choices for UTIs caused by susceptible bacteria. The presence of foreign bodies at the site of infection also affects antimicrobial activity (see “Antimicrobial Therapy for Foreign Body–Associated Infections”).

SELECTION OF ANTIMICROBIAL AGENTS FOR OUTPATIENT PARENTERAL ANTIMICROBIAL THERAPY

To decrease cost, and with the help of advances both in antimicrobial agents and in technology to assist antimi-crobial administration, prolonged treatment of serious infections with intravenous or parenteral antimicrobial agents has increasingly shifted away from the hospital to the outpatient setting, and guidelines to assist with delivery of high-quality outpatient parenteral antimicrobial therapy (OPAT) have been developed.19 Therapy can be provided via one of several types of indwelling central venous ac-cess catheters (a peripherally inserted central catheter is most frequently used) and can be delivered at an infusion center, by a home-visiting nurse, by self-administration, or in a nursing home.6 In addition to the general principles for selection of antimicrobial agents that have already been discussed, OPAT requires some further considerations. First, other things being equal, an agent that requires less frequent administration is preferred. For example, for the treatment of osteomyelitis or other serious infections caused by methicillin- or oxacillin-sensitive , cefazolin is frequently used in favor of nafcillin or oxacil-lin because it allows administration every 8 hours. Its use makes treatment outside the hospital setting much more feasible than the administration every 4 hours required for the other drugs. Agents with once- or twice-daily dosing have gained popularity for OPAT and include ceftriaxone, ertapenem, vancomycin, and daptomycin. An alternative for most β-lactams, which require frequent dosing, is use of a continuous infusion pump; however, such a device can frequently be cost-prohibitive. Second, the agent must pos-sess chemical stability and should last for about 24 hours

after mixing to allow enough time for delivery and admin-istration. As an important illustration of the principle, the use of intravenous ampicillin for OPAT via self-adminis-tration or continuous infusion is often precluded because of a short (approximately 8-hour) stability period at room temperature. Ampicillin or penicillin (in combination with an aminoglycoside) is the drug of choice for endocarditis caused by penicillin-sensitive enterococci; therefore, OPAT for this type of infection usually necessitates either nursing home stay or investment in a continuous infusion device (for penicillin only). Third, agents with minimal toxicity or predictable toxicity amenable to monitoring are preferred as OPAT is generally used in the context of longer-term antimicrobial therapy. Finally, when possible, provided adherence can be expected, consideration should be given to using oral agents (as discussed in “Oral vs Intravenous Therapy”) in the outpatient setting.

USE OF THERAPEUTIC DRUG MONITORING

Monitoring serum concentrations for drugs is most useful for medications that have a fairly narrow therapeutic index, which is the ratio of the toxic to the therapeutic dose. For-tunately, most antimicrobial agents have a wide therapeutic index,20 allowing standard doses to be used, with predict-able modifications on the basis of age, weight, and renal and hepatic function. However, certain antimicrobial agents require monitoring of serum levels because the therapeutic window is narrow. This could be due primarily to toxicity at high levels (eg, aminoglycosides)21 or therapeutic failure at low drug levels (eg, vancomycin)22,23 but is usually a combination of both (eg, voriconazole).24 In some cases, the use of serum drug level monitoring is supported by its beneficial effect on clinical outcomes (eg, voriconazole in the treatment of invasive fungal infections).24

CONSIDERATIONS FOR CONTINUING ANTIBIOTIC THERAPY

DURATION OF ANTIMICROBIAL THERAPY

The duration of therapy for many infections has long been based on anecdotal data and expert opinion. In view of the deleterious effects of prolonged courses of antimicro-bial agents, including the potential for adverse reactions, problems with adherence, selection of antibiotic-resistant organisms, and high cost, a number of studies have tried to define the optimal duration of therapy, with an emphasis on shorter courses of therapy. For example, evidence sup-ports limiting treatment of uncomplicated UTI in women to 3 days,25 community-acquired pneumonia to 5 days,26 and ventilator-associated pneumonia to 8 days.27 How-ever, when administering abbreviated treatment courses, it is important for clinicians to ensure that their patients fit


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the profile of the study population and carefully monitor high-risk patients for improvement. For example, in the study of short-course treatment for ventilator-associated pneumonia,27 the 8-day course was not sufficient for the treatment of infections due to or in im-munocompromised patients. In other situations, a longer duration of therapy is clearly warranted (eg, 4-6 weeks for endocarditis, osteomyelitis, and intra-abdominal abscesses, and weeks to months for invasive fungal infections) to achieve cure and prevent relapse. In many such infections, treatment duration has to be carefully individualized on the basis of clinical and radiologic response and may require the guidance of an expert in infectious diseases.

ASSESSMENT OF RESPONSE TO TREATMENT

Response to treatment of an infection can be assessed using both clinical and microbiological parameters. Clinical pa-rameters of improvement include symptoms and signs (eg, a decrease in fever, tachycardia, or confusion), laboratory values (eg, decreasing leukocyte count), and radiologic findings (eg, decrease in the size of an abscess). Although radiologic criteria are commonly used in assessing re-sponse to infectious disease therapy, radiologic improve-ment can frequently lag behind clinical improvement, and routine radiographic follow-up of all infections is not al-ways necessary. For example, in a study of clinical and ra-diographic follow-up of patients with community-acquired pneumonia,28 clinical cure was observed in 93% of patients after 10 days of follow-up, whereas radiographic resolution was noted in only 31% of patients. In fact, several weeks or even months may be required before chest radiography or computed tomography shows complete resolution of an infiltrate. Bacteremia is the most common scenario in which microbiological response is closely assessed because clearance of the bloodstream is as important as clinical improvement. Persistent bacteremia can often be the only clue to the presence of an inadequately treated source or to the existence or development of endovascular infection (such as endocarditis or an intravascular device infection).

Persistent bacteremia can also be associated with the emer-gence of antimicrobial resistance and should always be investigated.29

ADVERSE EFFECTS

Although the term is frequently used synonymously with or , allergic reactions constitute only one subset of adverse reactions to antimicrobial agents (see the Table for a useful classification of antimicrobial adverse effects). Allergic or hypersensitivity reactions can be either im-mediate (IgE-mediated) or delayed and usually manifest as a rash; anaphylaxis is the most severe manifestation of IgE-mediated allergy. In a recent national study of the prevalence of adverse drug effects, antibiotics were impli-cated in 19% of all emergency department visits for drug-related adverse events, and 79% of all antibiotic-associated adverse events were classified as allergic reactions.30 Al-though a history of serious allergic reaction should be care-fully documented to avoid inadvertent administration of the same drug or another drug in the same class, self-report of antibiotic allergies can be quite unreliable—it has been shown that only 10% to 20% of patients reporting a history of penicillin allergy were truly allergic when assessed by skin testing.31 Historical details should be elicited to help distinguish allergic from nonallergic reactions and IgE-mediated from delayed reactions because failure to do so can result in unnecessary avoidance of the most effective, narrow-spectrum, and cost-effective antimicrobial agent (eg, use of vancomycin in place of a β-lactam). Although no single test or clinical finding leads to a diagnosis of an-tibiotic allergy, a negative skin test (best described for peni-cillin) can reliably exclude the possibility of developing an IgE-mediated reaction (such as anaphylaxis) and help opti-mize antibiotic use.32-34 Both clinicians and patients should understand that a negative skin test does not mean that a patient is not at risk for developing a non–IgE-mediated delayed allergic reaction, but that in many circumstances the benefit of receiving a more appropriate antibiotic would outweigh the risk of a less significant allergic reaction. If an ongoing reaction is attributed to an antimicrobial drug al-lergy, this usually requires discontinuation of the offending agent. Related drugs (eg, cephalosporins in patients with a history of penicillin allergy) can be used under careful observation, provided that the reaction is not severe or the skin test is negative. In some cases, if the offending agent is the only or highly preferred agent, desensitization may be necessary. Desensitization involves administration of the drug in progressively increasing doses given by mouth; protocols are available for certain agents, such as β-lactams and sulfonamides, and should be guided by experts in al-lergic diseases.

TABLE. Classification of the Adverse Effects of Antimicrobial Drugs

Direct Allergy Toxicity Drug-drug interaction Therapeutic failure Indirect Effects on commensal flora Human infection Animal Increased chance of infection with drug-resistant pathogens Effects on environmental flora

}


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Nonallergic drug toxicity is usually, but not always, associated with higher doses and/or prolonged use and is particularly noted in patients with poor kidney or liver function that results in impaired clearance. Examples in-clude nephrotoxicity with aminoglycosides, neurotoxicity of penicillins, and peripheral neuropathy with prolonged use of metronidazole; these potential adverse effects need to be discussed with patients before initiation of therapy. For patients receiving prolonged systemic antimicrobial therapy, periodic clinical and laboratory monitoring is also recommended,19 particularly for those drugs that cause predictable toxicity with increasing duration of use (eg, monitoring complete blood cell count, including white blood cell differential, with β-lactams, trimethoprim-sulfamethoxazole, and linezolid; creatine kinase level with daptomycin; and creatinine level with aminoglycoside and β-lactams). In addition, drug doses should be adjusted in response to changes in creatinine level to avoid toxicity and attain optimal serum concentrations. Many antimicrobial agents interact with other drugs to increase or decrease their serum levels and effects. This is frequently the case with antimicrobial agents that are metabolized by and/or affect the cytochrome P450 enzyme system (eg, rifampin is a powerful inducer, whereas mac-rolides and azole antifungal agents are inhibitors of cyto-chrome P450 enzymes). Clinicians should always remain alert to the possibility of such interactions of antimicrobial agents with other drugs, and it is advisable to review a patient’s medication list when prescribing antimicrobial agents. Certain drug combinations can also cause additive toxicity, as exemplified by the concomitant use of amphot-ericin and gentamicin, which can significantly increase the risk of nephrotoxicity.

SPECIAL SITUATIONS IN INFECTIOUS DISEASE THERAPY

ANTIMICROBIAL THERAPY FOR FOREIGN BODY–ASSOCIATED INFECTIONS

Prosthetic implants and devices are increasingly being used in modern medical treatment. An unfortunate consequence of this increased use is the emergence of infections associ-ated with the placement of such devices, involving both temporary (eg, urinary catheter, central venous catheter) and permanent (eg, prosthetic joint, artificial heart valve) implants. One of the important characteristics of device-related infection is the formation of biofilms, which have been described as “a structured community of bacterial cells enclosed in a self-produced polymeric matrix and adherent to an inert or living surface.”35 Bacteria growing in biofilms have been shown to be relatively protected from the effects of antimicrobial therapy, probably as a result of

alteration of their metabolic state.36 Primary care physi-cians should be aware of this because prolonged antibiotic treatment for these infections can be ineffective, associated with adverse effects, and result in the emergence of resis-tant strains of organisms.37 Certain agents (eg, rifampin38 and fluoroquinolones39) have better activity against staphy-lococci in biofilms and are recommended in the manage-ment of infections of prosthetic valves10 and joints40 caused by these organisms. However, because of the difficulty of eradicating infections with antimicrobial therapy alone, removal of the implant is often necessary for cure. As an alternative, for patients unable to tolerate implant removal, long-term suppressive antimicrobial therapy is sometimes used, with variable success. It is advisable to involve an infectious diseases expert in the management of infections associated with implanted foreign bodies.

USE OF ANTIMICROBIAL AGENTS AS PROPHYLACTIC OR SUPPRESSIVE THERAPY

In an ideal scenario for use of an antimicrobial agent as prophylactic treatment, the infection would occur predict-ably in a certain setting and would be well known to be associated with a specific organism or organisms, and an effective antimicrobial agent would be available with no or limited long-term toxicity and with little likelihood of leading to the emergence of resistance.6 Not surprisingly, such scenarios are relatively rare. However, antimicrobial prophylaxis is appropriate in some instances, a discussion of which follows. Presurgical Antimicrobial Prophylaxis. Antimicro-bial prophylaxis is used to reduce the incidence of postop-erative surgical site infections. Patients undergoing proce-dures associated with high infection rates, those involving implantation of prosthetic material, and those in which the consequences of infection are serious should receive perioperative antibiotics. The antibiotic(s) should cover the most likely organisms and be present in the tissues when the initial incision is made, and adequate serum concentra-tions should be maintained during the procedure. A single dose of a cephalosporin (such as cefazolin) administered within 1 hour before the initial incision is appropriate for most surgical procedures; this practice targets the most likely organisms (ie, skin flora), while avoiding unneces-sary broad-spectrum antimicrobial therapy. Duration of prophylaxis for surgical site infection should not exceed 24 hours in most cases.41

Antimicrobial Prophylaxis in Immunocompromised Patients. Immunocompromised patients, particularly those with HIV infection/AIDS, those who are undergoing che-motherapy for cancer, or those who are receiving immuno-suppressive therapy after organ transplant, are at increased risk of infection. These infections are caused by predictable


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organisms at an increased frequency and/or associated with high mortality (eg, invasive aspergillosis associated with prolonged neutropenia, pneumonia in the setting of impaired cell-mediated immunity [eg, AIDS, organ transplant]). In these specific settings, evidence sup-ports the use of prolonged antimicrobial prophylaxis until immune markers are restored (eg, trimethoprim-sulfameth-oxazole to prevent pneumonia42). Antimicrobial Prophylaxis to Prevent Transmission of Communicable Pathogens to Susceptible Contacts.Antimicrobial agents can be prescribed prophylactically to prevent transmission of pathogens to susceptible contacts; for example, antiviral agents can be used to limit the spread of influenza in nursing home residents, ciprofloxacin can be given to close contacts of a patient with meningitis caused by N , and macrolides can be prescribed to reduce transmission of pertussis. Antimicrobial Prophylaxis Before Dental and Other Invasive Procedures in Patients Susceptible to Bacterial Endocarditis. It should be noted that guidelines recom-mending antimicrobial prophylaxis in this setting have recently been updated and limit such use to only a few very high-risk scenarios—prosthetic valves, prior endocarditis, or congenital heart disease before surgical correction.43

Traumatic Injuries With a High Probability of In-fectious Complications. Certain types of injuries pose a particularly high risk of infection because of disruption of normal barriers and/or delivery of a high inoculum of pathogenic organisms (eg, antibiotic prophylaxis has been shown to be of some benefit and is recommended for certain types of animal bites44 and after penetrating brain injury45). An example of inappropriate antimicrobial “pro-phylaxis” is prolonged antimicrobial use in those with open but not infected wounds, including surgical wounds. No consensus has yet been reached on the use of antimicrobial prophylaxis in some other settings, such as before invasive procedures in patients with prosthetic joints.

NONANTIMICROBIAL THERAPY FOR INFECTIONS

Antimicrobial therapy is usually, but not always, the most important therapy for infectious diseases. The best-recognized example of nonantimicrobial therapy in the treatment of infections is the use of operative drainage or débridement. This procedure is useful when the organism burden is very high or in the management of abscesses, for which the penetration and activity of antimicrobial agents are often inadequate. Other therapies used in the treatment of infectious diseases involve modulating the host inflam-matory response to infection. Systemic corticosteroids, thought to act by decreasing the deleterious effects of the host inflammatory response, have been found beneficial when used in conjunction with antimicrobial therapy for

the treatment of bacterial meningitis,46 tuberculous men-ingitis,47 and pneumonia in patients with AIDS.48 Temporary discontinuation or dose reduction of immunosuppressive agents is often required for successful treatment of infections, such as cytomegalovirus disease in organ transplant recipients or patients with rheumatologic disorders. Similarly, granulocyte colony–stimulating factor is sometimes administered to patients with prolonged neu-tropenia who develop invasive infections with filamentous fungi. Intravenous immunoglobulin therapy, which acts to neutralize toxin produced by the bacteria, can be used in addition to surgical débridement and antimicrobial therapy in the treatment of necrotizing fasciitis caused by group A streptococci.49 Probiotics (such as and

species) are occasionally used in the man-agement of colitis caused by , with the hope of restoring the normal flora that has been altered by antimicrobial administration.50 Some of these interventions lack a strong evidence base but are often recommended by experts on the basis of clinical experience.

JUDICIOUS USE OF ANTIMICROBIAL AGENTS

COST CONSIDERATIONS IN ANTIBIOTIC SELECTION AND ANTIMICROBIAL STEWARDSHIP

The “cost” of an antimicrobial agent is dependent on many factors in addition to the purchase price of a particular agent and may include administration costs, prolonged hospitalization as a consequence of adverse effects, the cost of serum concentration monitoring, and clinical ef-ficacy. One strategy that can significantly reduce cost is the switch from intravenous to oral therapy. Oral therapy is generally less expensive, potentially associated with fewer adverse effects, and can result in considerable cost savings by facilitating earlier dismissal and a shortened hospital stay.51 Even if the purchase price of an oral agent is greater than its parenteral equivalent, the reduction in hospital stay can result in significant cost savings. This has been demon-strated for oral linezolid when compared with intravenous vancomycin for the treatment of complicated skin and soft tissue infections caused by MRSA.52,53

Cost considerations in the selection and continuation of appropriate antimicrobial therapy in acute care hospitals are part of a broader activity that is referred to as

. Antimicrobial stewardship programs are aimed at “optimizing antimicrobial selection, dosing, route, and duration of therapy to maximize clinical cure or prevention of infection while limiting the unintended consequences, such as the emergence of resistance, ad-verse drug events, and cost.”54 These programs are usually coordinated by a team of infectious disease physician(s) and pharmacist(s) and are often computer-based. Some


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components recommended for these programs include the following: prospective audit and feedback of antimicrobial prescriptions to clinicians, formulary restriction, educa-tion, use of clinical order sets and guidelines, de-escalation of therapy, and intravenous to oral antimicrobial conversion when appropriate.54 Clinicians should make it a priority to become aware of such programs in their institutions.

PREVENTING EMERGENCE OF ANTIBIOTIC RESISTANCE

The widespread—and often inappropriate—use of an-timicrobial agents is the single most important cause of the emergence of drug resistance, both in the community and hospital settings. Prior antibiotic exposure has been shown to be the most frequent risk factor for the devel-opment of community-acquired respiratory infections caused by drug-resistant .55 This is not surprising because acute upper respiratory illnesses ac-count for the highest proportion of ambulatory antibiotic prescriptions,56 with most being dispensed in situations in which antibiotics were not even indicated.57 Clearly, the emergence of antimicrobial resistance can be prevented or delayed through judicious prescribing, which can be char-acterized as follows: avoidance of antibiotic treatment for community-acquired, mostly viral, upper respiratory tract infections; use of narrow-spectrum antibiotics when pos-sible; and use of antibiotics for the shortest duration that is effective for the treatment of a particular clinical syn-drome. In the past few years, interest has been increasing in the development of rapid and accurate diagnostic tests for detection of viral respiratory pathogens with the abil-ity to distinguish between viral and bacterial infections, such as measurement of procalcitonin levels and nucleic acid tests. Although not yet widely available in clinical practice, these tests have the potential to curtail the use of antibacterial agents for clinical syndromes that are clearly caused by viruses.

COMMON MISUSES OF ANTIBIOTICS

In some settings, the use of antibiotics is clearly inappropri-ate. A discussion follows of some of the typical scenarios in which they are contraindicated.6 Prolonged Empiric Antimicrobial Treatment Without Clear Evidence of Infection. One of the most common mistakes in antimicrobial use is continuing to add or switch antibiotics when a patient does not appear to be respond-ing to therapy, even though there is no clear evidence of an infectious disease. Many noninfectious, inflammatory, or neoplastic syndromes can present with symptoms and signs that mimic infectious diseases. Examples include adult-onset Still disease and other connective tissue disorders that can present with high fever; drug-induced fever; the fever associated with pulmonary embolism; lymphoma;

and Wegener granulomatosis, which can present with fever, cavitary pulmonary nodules, and recurrent sinusitis. Treatment of a Positive Clinical Culture in the Absence of Disease. Colonization with potentially patho-genic organisms without any associated manifestation of disease occurs frequently in certain populations (eg, colonization of the urinary tract in women of advanced age or in the presence of an indwelling urinary catheter, colonization of endotracheal tubes in mechanically ven-tilated patients, and colonization of chronic wounds). Appropriate management in these situations involves obtaining cultures from these sites only when indicated and avoiding treatment of a “positive” culture result when symptoms and signs of active infection are absent (eg, asymptomatic bacteriuria). Failure to Narrow Antimicrobial Therapy When a Causative Organism Is Identified. As already discussed, initial therapy is often empiric and relies on broad-spec-trum agents until culture or other tests help determine the microbiological etiology. Once culture and susceptibility data are available, an antibiotic with the narrowest possible spectrum should be selected for continuation of therapy. Often, however, this does not occur, particularly if the pa-tient has improved while receiving empiric therapy, and the physician is uncomfortable about changing therapy in the face of clinical improvement. Prolonged Prophylactic Therapy. As already dis-cussed, infection can be prevented in certain situations by the prophylactic use of antimicrobial agents (eg, presurgical prophylaxis). However, in most cases, guide-lines support the use of a single, preoperative dose of an antimicrobial agent. Prolonged “prophylaxis” simply sets the stage for the emergence of antimicrobial resistance. For example, the common practice of prolonging antimi-crobial therapy until the removal of surgical drains is not evidence based. Excessive Use of Certain Antimicrobial Agents. The frequent use of certain agents (or classes of antimicro-bial agents) in a hospital or other health care setting can result in selection of organisms that are resistant to that particular antibiotic. For example, the increased use of fluoroquinolones during the past decade is thought to be, in part, responsible for the epidemic of a fluoroquinolone-resistant strain of ,58 the most common cause of nosocomial infectious diarrhea. More recently, an increase in levofloxacin use as initial therapy for UTI as a result of policy change at a single institution was found to have led to a rapid increase in fluoroquinolone resistance among outpatient urinary E coli isolates at that institution.59 For this reason, those involved in antimicrobial stewardship should avoid the excessive prescribing of a single class of antibiotic.


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CONCLUSION

Appropriate use of antimicrobial agents involves obtaining an accurate diagnosis, determining the need for and timing of antimicrobial therapy, understanding how dosing affects the antimicrobial activities of different agents, tailoring treatment to host characteristics, using the narrowest spec-trum and shortest duration of therapy, and switching to oral agents as soon as possible. In addition, nonantimicrobial interventions, such as abscess drainage, are equally or more important in some cases and should be pursued diligently in comprehensive infectious disease management.

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. 2007;98(4):355-359. 33. Harris AD, Sauberman L, Kabbash L, Greineder DK, Samore MH. Penicillin skin testing: a way to optimize antibiotic utilization. . 1999;107(2):166-168. 34. Raja AS, Lindsell CJ, Bernstein JA, Codispoti CD, Moellman JJ. The use of penicillin skin testing to assess the prevalence of penicillin allergy in an emergency department setting. . 2009;54(1):72-77. 35. Costerton JW, Lewandowski Z, DeBeer D, Caldwell D, Korber D, James G. Biofilms, the customized microniche. . 1994;176(8):2137-2142. 36. Anderl JN, Franklin MJ, Stewart PS. Role of antibiotic penetration limitation in biofilm resistance to ampicillin and cipro-floxacin. . 2000;44(7):1818-1824. 37. Lynch AS, Robertson GT. Bacterial and fungal biofilm infections.

. 2008;59:415-428. 38. Zheng Z, Stewart PS. Penetration of rifampin through epidermidis biofilms. . 2002;46(3):900-903. 39. Singh R, Ray P, Das A, Sharma M. Penetration of antibiotics through

and biofilms. 2010;65(9):1955-1958.

40. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE; Foreign-Body Infection (FBI) Study Group. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial.

. 1998;279(19):1537-1541. 41. Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an ad-visory statement from the National Surgical Infection Prevention Project. Clin

. 2004;38(12):1706-1715. 42. Buskin SE, Newcomer LM, Koutsky LA, Hooton TM, Spach DH, Hop-kins SG. Effect of trimethoprim-sulfamethoxazole as pneumonia prophylaxis on bacterial illness, pneumonia,


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The Symposium on Antimicrobial Therapy will continue in the March issue.

This activity was designated for 1 AMA PRA Category 1 Credit(s).™

The contributions to the Symposium on Antimicrobial Therapy are now a CME activity. For CME credit, see the link on our Web site at mayoclinicproceedings.com.

and death in persons with AIDS. . 1999;20(2):201-206. 43. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endo-carditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. . 2007;116(15):1736-1754. 44. Fleisher GR. The management of bite wounds. . 1999;340(2):138-140. 45. Antibiotic prophylaxis for penetrating brain injury. . 2001;51(2, suppl):S34-S40. 46. van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. . 2004;4(3):139-143. 47. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. . 2004;351(17):1741-1751. 48. Gagnon S, Boota AM, Fischl MA, Baier H, Kirksey OW, La Voie L. Corticosteroids as adjunctive therapy for severe pneu-monia in the acquired immunodeficiency syndrome: a double-blind, placebo-controlled trial. . 1990;323(21):1444-1450. 49. Kaul R, McGeer A, Norrby-Teglund A, et al; The Canadian Strepto-coccal Study Group. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome—a comparative observational study. . 1999;28(4):800-807. 50. McFarland LV. Evidence-based review of probiotics for antibi-otic-associated diarrhea and infections. . 2009;15(6):274-280.

51. Amodio-Groton M, Madu A, Madu CN, et al. Sequential parenteral and oral ciprofloxacin regimen versus parenteral therapy for bacteremia: a pharma-coeconomic analysis. . 1996;30(6):596-602. 52. McCollum M, Rhew DC, Parodi S. Cost analysis of switching from i.v. vancomycin to p.o. linezolid for the management of methicillin-resistant

species. . 2003;25(12):3173-3189. 53. McCollum M, Sorensen SV, Liu LZ. A comparison of costs and hospital length of stay associated with intravenous/oral linezolid or intravenous van-comycin treatment of complicated skin and soft-tissue infections caused by suspected or confirmed methicillin-resistant in elderly US patients. . 2007;29(3):469-477. 54. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases So-ciety of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. . 2007;44(2):159-177. 55. Levine OS, Farley M, Harrison LH, Lefkowitz L, McGeer A, Schwartz B. Risk factors for invasive pneumococcal disease in children: a population-based case-control study in North America. . 1999;103(3):E28. 56. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians in the United States. . 1995;273(3):214-219. 57. Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibi-otic use for acute respiratory infections in the United States. . 2001;33(6):757-762. 58. Pepin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquino-lones as the predominant risk factor for -associated diarrhea: a cohort study during an epidemic in Quebec. . 2005;41(9):1254-1260. 59. Johnson L, Sabel A, Burman WJ, et al. Emergence of fluoroquinolone resistance in outpatient urinary isolates. . 2008;121(10):876-884.

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From the Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

Dr Kanj has received honoraria as a speaker on antimicrobial resistance for the Pfizer-sponsored Antimicrobial Practices and Executions for eXcellence Program.

Address correspondence to Souha S. Kanj, MD, Division of Infectious Dis-eases, American University of Beirut Medical Center, Cairo Street, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon ([email protected]). In-dividual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com.



Antimicrobial resistance has been shaping the field of infectious diseases since the discovery of penicillin.

Many of the advances in antimicrobial drug development have resulted from efforts to combat ever-evolving mecha-nisms of resistance that render existing agents obsolete, thus prompting the search for new molecules that promise to be more effective and more resilient. Yet, the hope for a magic all-encompassing antimicrobial agent has long passed, and the number of new antimicrobial agents in the drug devel-opment pipeline is a small fraction of what it used to be. Nowhere is the concept of antimicrobial resistance better portrayed than with the gram-negative bacilli, which have proven to be tough adversaries for clinicians and research-ers alike. Of the 6 famous ESKAPE pathogens (

, , species, , and

species) recognized as the most important emerging threats of this century, 4 are gram-negative bacilli ( , species, , and

species).1 This review will address 3 major types of multidrug-resistant (MDR) gram-negative patho-gens: extended-spectrum β-lactamase (ESBL) –producing Enterobacteriaceae, carbapenemase-producing Enterobac-teriaceae, and MDR . The resistance mecha-nisms exhibited by these organisms and the epidemiology

Current Concepts in Antimicrobial Therapy Against Resistant Gram-Negative Organisms: Extended-Spectrum β-Lactamase–Producing

Enterobacteriaceae, Carbapenem-Resistant Enterobacteriaceae, and Multidrug-Resistant Pseudomonas aeruginosa

Souha S. Kanj, MD, and Zeina A. Kanafani, MD

The development of antimicrobial resistance among gram-nega-tive pathogens has been progressive and relentless. Pathogens of particular concern include extended-spectrum β-lactamase–producing Enterobacteriaceae, carbapenem-resistant Enterobac-teriaceae, and multidrug-resistant Pseudomonas aeruginosa. Classic agents used to treat these pathogens have become out-dated. Of the few new drugs available, many have already become targets for bacterial mechanisms of resistance. This review de-scribes the current approach to infections due to these resistant organisms and elaborates on the available treatment options.

Mayo Clin Proc. 2011;86(3):250-259

ESBL = extended-spectrum β-lactamase; IV = intravenously; KPC = Klebsiella pneumoniae carbapenemase; MDR = multidrug-resistant; MIC = minimum inhibitory concentration

of the infections they cause will be discussed. Existing and emerging therapeutic approaches to each type of organism will then be surveyed.

MECHANISMS OF RESISTANCE

Production of β-lactamase is the most commonly encoun-tered mechanism of resistance of bacterial pathogens to β-lactam antibiotics. Many enzymes have been described, encoded either by chromosomal genes or by genes located on movable elements such as plasmids and transposons. Classification schemes for β-lactamases are based on mo-lecular structure (Ambler classification)2 or functional sim-ilarities (Bush-Jacoby-Medeiros classification)3 (Table 1).Extended-spectrum β-lactamase enzymes initially arose through point mutations in the genes encoding the clas-sic TEM and SHV β-lactamases, thereby generating an array of enzymes with an expanded spectrum of activity.4 The potent hydrolytic activity of CTX-M enzymes against cefotaxime was later recognized. Unlike TEM, SHV, and CTX-M ESBL enzymes that are predominantly expressed by Enterobacteriaceae, the oxacillin-hydrolyzing enzymes have been mostly isolated from , and some have evolved to exhibit the ESBL phenotype. In contrast to the plasmid-mediated ESBL enzymes, AmpC β-lactamases are predominantly chromosomally encoded.5 Their expres-sion is mostly noted in species, species, and . Although chromosomal AmpC


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enzymes are usually poorly expressed in and species, plasmid-mediated AmpC enzymes can confer β-lactam resistance similar to iso-lates. Other less commonly encountered ESBL enzymes include PER-1, VEB-1, and BES-1.6

Carbapenemases are the β-lactamases with the widest spectrum of activity. In addition to hydrolyzing carbapenems, carbapenemases are active against most other members of the β-lactam family with few exceptions. The major drive behind the emergence of carbapenemases has been the widespread use of carbapenems both in the em-pirical and directed treatment of serious infections, which placed selection pressure on bacterial pathogens. On the basis of their molecular structure, carbapenemases belong to the A, B, or D classes of β-lactamase enzymes7 (Table

2). The plasmid-borne carbapenemases (KPCs) are currently among the most prevalent and widely distributed carbapenemases. They are particularly diffi-cult to detect by microbiology laboratories because many isolates have minimum inhibitory concentrations (MICs) against imipenem or meropenem that, albeit high, remain in the susceptible range.8,9 It has been observed through in vitro studies that ertapenem may be the most appropriate substrate for detection of KPC production.8 Other clini-cally important carbapenemases include the metallo-β-lactamases and the oxacillin-hydrolyzing carbapenemases.Besides β-lactamase production, isolates can exhibit additional resistance mechanisms, such as amino-glycoside-modifying enzymes, efflux pumps, porin loss, and various target site modifications.10

TABLE 1. Classification of β-Lactamase Enzymes

Ambler Bush-Jacoby- Inhibition by class Medeiros group Active site Enzyme type clavulanate Host organisms Substrates

A 2b, 2be, 2br, Serine Broad-spectrum β-lactamases Yes, Enterobacteriaceae Ampicillin, cephalothin 2c, 2e, 2f (TEM, SHV) except 2br and nonfermenters ESBL (TEM, SHV, CTX-M) Penicillins, 3rd-generation cephalosporins Carbapenemases (KPC, GES, SME) All β-lactams

B 3 Zinc-binding Carbapenemases (VIM, IMP) No Enterobacteriaceae All β-lactams thiol group and nonfermenters

C 1 Serine AmpC cephamycinases No species Cephamycins, 3rd- (AmpC) species generation cephalosporins

D 2d Serine AmpC cephamycinases (CMY, Yes Enterobacteriaceae Cephamycins, 3rd- DHA, MOX FOX, ACC) generation cephalosporins Broad-spectrum β-lactamases Enterobacteriaceae Oxacillin, ampicillin, (OXA) and nonfermenters cephalothin ESBL (OXA) Penicillins, 3rd-generation cephalosporins Carbapenemases (OXA) All β-lactams ESBL = extended-spectrum β-lactamase; KPC = carbapenemase.

TABLE 2. Classification of Carbapenemases

Inhibition by Class Subclass Examples Substrates clavulanate

A NMC-A All β-lactams Yes IMI-1, IMI-2 All β-lactams SME-1, SME-2, SME-3 Variable hydrolysis of extended-spectrum cephalosporins KPC-1, KPC-2, KPC-3, KPC-4 All β-lactams GES-2, GES-4, GES-5, GES-6 No hydrolysis of aztreonam; variable hydrolysis of carbapenems

B B1 BcII, IMP-1, CcrA, VIM-2, SPM-1 No hydrolysis of aztreonam No B2 CphA, Sfh-1 B3 L1, FEZ-1, Gob-1, CAU-1

D OXA-23, OXA-24, OXA-48, OXA-50, No hydrolysis of aztreonam; Variable OXA-51, OXA-55, OXA-58, OXA-60, variable hydrolysis of extended-spectrum OXA-62 cephalosporins and carbapenems

KPC = carbapenemase.


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EPIDEMIOLOGY

The medical literature abounds with studies illustrating the global increase in the burden of antimicrobial resistance among gram-negative pathogens.11,12 However, wide re-gional differences exist, accentuating the need to take into account the local epidemiology (at the level of the country, the region, the hospital, and at times the individual hospital unit) when making decisions about empirical therapy for serious infections. The Study for Monitoring Antimicrobial Resistance Trends collected 6156 gram-negative isolates from patients with intra-abdominal infections in 28 countries during 2004. The overall rate of ESBL production was 17% among

and 10% among E coli isolates, with the high-est rates being in isolates from Latin America, the Middle East, Africa, and Asia and the lowest being in Europe and the United States.13 These results were confirmed by the Tigecycline Evaluation and Surveillance Trial global sur-veillance database in 2007.14 Most notable in the epidemiol-ogy of ESBL-producing organisms is the recent worldwide dissemination of CTX-M–type β-lactamases,15 particularly the CTX-M-15 enzyme.16 In a recent multinational study, CTX-M enzymes were the most frequently identified ES-BLs, accounting for 65% of all β-lactamases.17

Although chromosomally mediated carbapenemases have long been recognized in gram-negative bacilli, they were mostly species-specific with a limited potential for spread except in a clonal manner.7 Recent trends, however, have refocused attention on plasmid-mediated carbapen-emases such as KPCs. Since the first report from North Carolina in the late 1990s,18 a multitude of studies have de-

scribed the relatively rapid emergence of KPC enzymes.19 In addition to certain regions of the United States, hospi-tal outbreaks due to KPC-bearing gram-negative patho-gens have been reported from Europe,20 Asia,21 and South America.22 Other carbapenemases that have been associ-ated with recent outbreaks include IMP and VIM metallo-β-lactamases.7 In addition, 2009 witnessed the emergence of the New Delhi metallo-β-lactamase in Enterobacteri-aceae,23 which led to the hospitalization of many patients in India and Pakistan.

THERAPEUTIC APPROACHES

A summary of therapeutic approaches and challenges for 3 of the emerging gram-negative organisms of most concern follows (see also Table 3), including an inventory of exist-ing antibiotic options for each organism.

EXTENDED-SPECTRUM β-LACTAMASE–PRODUCING ENTEROBACTERIACEAE

The propensity of ESBL-producing organisms to be concom-itantly resistant to other classes of antibiotics greatly limits the choice of antibiotics that can be used for treatment.24 The genes encoding for ESBL enzymes are located on large plas-mids that can harbor resistance genes to fluoroquinolones, aminoglycosides, and trimethoprim-sulfamethoxazole. Infections with ESBL-producing pathogens are usually suspected in patients who have recently received broad-spectrum antibiotics, particularly third-generation cepha-losporins and quinolones.6 Other risk factors include age older than 60 years, comorbid conditions, recent hospital and intensive care unit admission, and invasive devices.

TABLE 3. Suggested Approach to the Management of Patients With Serious Infections Due to Multidrug-Resistant Gram-Negative Pathogensa

Organism First-line therapy Second-line therapy

Empirical therapyb Monomicrobial infection Carbapenem Piperacillin-tazobactam (low inoculum) Tigecycline (not in urinary tract infections) Colistin with or without an antipseudomonal agent Mixed gram-positive and Anti-MRSA agent plus a carbapenem Anti-MRSA agent plus piperacillin- gram-negative infection Tigecycline (not in urinary tract infections) tazobactam (low inoculum) with or without an antipseudomonal agent Anti-MRSA agent plus colistinDirected therapyc ESBL-producing Carbapenems Tigecycline (not in urinary tract infections) Enterobacteriaceae Piperacillin-tazobactam (low inoculum) Fluoroquinolone Fosfomycin (oral formulation for simple Colistin urinary tract infections) Carbapenemase-producing Tigecycline Fosfomycin (parenteral formulation) Enterobacteriaceae Colistin Multidrug resistant Antipseudomonal agent (among carbapenems, Colistin use doripenem or meropenem) Combination therapy

a ESBL = extended-spectrum β-lactamase; MRSA = methicillin-resistant .b Local susceptibility patterns should be taken into consideration before deciding on empirical therapy.c Based on available culture and susceptibility results.


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Antibiotic Options. Carbapenems. Carbapenems are considered first-line agents in treating infections caused by ESBL-producing organisms (imipenem at 500 mg intrave-nously [IV] every 6 hours up to 1 g IV every 8 hours in serious infections or meropenem at 1 g IV every 8 hours). However, no data from randomized controlled trials sup-port their use for this purpose. Most of the evidence in-stead originates from case series and retrospective studies, which compile the responses and outcomes of patients with bacteremia receiving carbapenem therapy.25 In a multinational study of 85 patients with ESBL-producing

bacteremia, carbapenem use was an inde-pendent predictor of lower mortality rate compared with the use of other antibiotic agents that exhibited in vitro activity.26 This therapeutic advantage of carbapenems has been attributed to the high inoculum effect as well as high MICs of other agents that are close to the suscep-tibility breakpoints. More recent data have shown that ertapenem at 1 g/d may be used successfully for ESBL- associated bacteremia.27 When dosed at 500 mg IV every 8 hours, doripenem, the newest addition to the carbapenem class, exhibits an activity against ESBL-producing patho-gens that is similar to that of imipenem and meropenem.28

Tigecycline. Tigecycline, the first member of the glycyl-cycline class of antibiotics, is approved by the US Food and Drug Administration for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community-acquired pneumonia when ap-propriately dosed (100-mg loading dose IV followed by 50 mg IV every 12 hours). Tigecycline is active in vitro against Enterobacteriaceae, including ESBL-producing isolates.29 Clinical data, although promising, are still limited. De-spite its excellent activity, one of the factors hindering the wider use of tigecycline for ESBL-associated infections is the fact that a large proportion of these infections are in the urinary tract, where tigecycline has a limited penetra-tion.30 Although some case reports have reported a favor-able outcome, tigecycline is not a suitable choice for the treatment of urinary tract infections. In addition, because of its rapid tissue distribution after intravenous infusion, concerns have been raised about using tigecycline for the treatment of primary bloodstream infections.30 In a recently published comparative study of tigecycline vs imipenem-cilastatin in patients with hospital-acquired pneumonia, tigecycline fared worse in the subset of patients with ven-tilator-associated pneumonia.31 It is our opinion that dose escalation needs to be considered if tigecycline is used for ventilator-associated pneumonia with MDR organisms other than species. β-Lactam/β-Lactamase Inhibitor Combinations. Clas-sic β-lactam inhibitors, such as sulbactam, clavulanate, and tazobactam, have variable inhibitory activity against ESBL

enzymes12 (Table 1). Tazobactam, which appears to be the most potent of the 3, is active against some of the TEM, SHV, and CTX-M enzymes.32 In a Spanish study from 11 centers, the cure rate of patients with cystitis treated with amoxicillin-clavulanate was 93% with susceptible ESBL-producing isolates and 56% with isolates of intermediate susceptibility and resistance, suggesting that amoxicillin-clavulanate may be successful in the treatment of simple cystitis.33 Clinical data supporting the use of piperacillin-tazobactam are mounting.34 Because it achieves high con-centrations in the urinary tract, piperacillin-tazobactam may be used successfully in the treatment of urinary tract infections35 and in other infections in which a low bacte-rial inoculum is expected.36 In a series of patients with infections due to ESBL-producing organisms, piperacil-lin-tazobactam was used successfully against susceptible isolates originating from the urinary tract as well as other sites.35 Although it was initially thought that piperacillin-tazobactam should be avoided in serious infections such as bacteremias, this notion is being challenged by emerging evidence showing that the use of piperacillin-tazobactam against susceptible isolates often results in a favorable outcome.37

Cephalosporins. Studies suggest that the use of cepha-losporins, including cephamycins and cefepime, is asso-ciated with a worse outcome compared with the use of carbapenems, despite apparent in vitro susceptibility.38 Cephalosporins are therefore not recommended in pa-tients with suspected or confirmed infections with ESBL-producing organisms. Aminoglycosides, Fluoroquinolones, and Trimetho-prim-Sulfamethoxazole. The high rates of concurrent re-sistance to these agents and the potential for emergence of resistance on treatment often preclude their use for empirical coverage. Some studies have observed a suboptimal response to quinolones vs carbapenems in ESBL-producing isolates with retained susceptibility to quinolones.25 Aminoglyco-sides, fluoroquinolones, and trimethoprim-sulfamethoxazole should be used with caution in serious infections even after documentation of in vitro activity. Clinical response should be closely monitored, and switching to carbapenems should be considered in patients who do not improve. Colistin. Colistin has been successfully used to treat ESBL-associated infections in a few case reports.39,40 In the absence of formally adopted Clinical and Laboratory Standards Institute breakpoints for susceptibility of colistin against Enterobacteriaceae, susceptibility testing by E-test and disk diffusion methods has been proposed recently.41 Colistin use is discussed in more detail in the “Multidrug-Resistant ” section. Fosfomycin. Fosfomycin inhibits bacterial cell wall synthesis, thereby exhibiting bactericidal activity against


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gram-positive and gram-negative pathogens.42 Fosfomycin is approved by the US Food and Drug Administration for the treatment of uncomplicated urinary tract infections at a single oral dose of 3 g. The emergence of resistance among gram-negative bacilli has sparked new interest in using fos-fomycin to treat infections caused by MDR isolates. In vitro studies have shown that fosfomycin remains active against ESBL-producing E coli and isolates.43 The drug appears to be useful in the oral treatment of ESBL-associated infections of the urinary tract, and initial clini-cal studies are promising.44 An intravenous formulation of fosfomycin, currently available in some European countries, could be useful in treating systemic infections.45

Other Agents. Also active in vitro against ESBL-pro-ducing organisms are the β-lactams temocillin46 and pivme-cillinam,47 the carbapenems biapenem,48 faropenem,49 and tomopenem,50 and the urinary tract agent nitrofurantoin.51

More data are needed to support their use in the clinical setting.

CARBAPENEM-RESISTANT ENTEROBACTERIACEAE

Recognizing carbapenemase expression is the key to the ap-propriate management of infections caused by carbapenem- resistant Enterobacteriaceae. Unusually elevated MICs to carbapenems should arouse suspicion for a carbapenem-resistant isolate and preclude the use of carbapenems even if the MICs do not exceed the breakpoints for resistance. As with ESBL-producing organisms, carbapenemase-pro-ducing strains are likely to exhibit simultaneous resistance to aminoglycosides and fluoroquinolones.52

Antibiotic Options. Tigecycline. Isolates may show in vitro susceptibility to tigecycline,53 but clinical experience with carbapenem-resistant strains is limited. A recent review by Hirsch and Tam54 gathered data from 15 publications on the treatment of 55 patients with KPC-related infections. A favorable outcome was achieved in 5 of 7 patients treated with tigecycline. Despite tigecycline being one of the first-line agents for use in the setting of carbapenemase-produc-ing isolates, it is worth noting that clinical failures have been reported in the literature, as exemplified by a brief report by Anthony et al,55 in which some patients with MDR gram-negative pathogens, including ESBL- and KPC-producing isolates, had a negative clinical and/or microbiological out-come with tigecycline. In addition, as discussed previously, primary bloodstream infections and urinary tract infections present a challenge for the use of tigecycline. Colistin. Although colistin retained activity against car-ba penemase-producing Enterobacteriaceae in initial stud-ies,56 more recent data suggest that resistance to colistin is emerging, and outbreaks of colistin-resistant strains have been reported.57 In the review by Hirsch and Tam,54 mono-therapy with polymyxins (n =7) was associated with poor

response rates, whereas combination therapy (n= 11) gave more promising results. Fosfomycin. The activity of fosfomycin was evaluated against 68 KPC-producing isolates, 23 of which were nonsusceptible to tigecycline and/or colistin.58 The susceptibility rates were 93% for the overall group, 87% for the group nonsusceptible to tigecycline and/or colistin, and 83% (5 of 6 isolates) for the extremely drug-resistant subgroup that was nonsusceptible to tigecycline and/or colistin. Clinical correlation of this in vitro study is needed. Rifampin. In vitro studies suggest that rifampin has a synergistic activity when used as part of a combination therapy regimen against carbapenemase-producing E coli and .59 More clinical data are needed. Agents Under Development. Agents under development include new β-lactamase inhibitors with activity against car-bapenemases, such as MK-7655,60 NXL104,61 and 6-alky-lidenepenam sulfones,62 and several bis-indole compounds,63 the mode of action of which is currently unidentified.

MULTIDRUG-RESISTANT P AERUGINOSA

For the purpose of this review, we define MDR as strains that are resistant to 2 or more classes of antibi-

otics. In recent years, the treatment of infections caused by has become a challenging task for clinicians.

The emergence of antimicrobial resistance has played a pivotal role in determining the approach to patients with

species infections. Central to this approach is the recognition that delayed therapy correlates with in-creased mortality even when a patient is considered clini-cally stable at the time of initial evaluation.64 Because the treatment of serious infections is frequently empirical until the organism is isolated and susceptibility testing performed, high resistance rates raise the likelihood of administering inappropriate initial therapy, hence con-tributing to the observed high mortality rates. Antibiotic Options. When used in the appropriate dos-age, the following agents have shown reliable activity against

isolates. Antipseudomonal Penicillins. Ticarcillin should be dosed at 3 g IV every 4 hours and piperacillin at 4 g IV every 4 hours. β-Lactam/β-Lactamase Inhibitor Combinations. Ticar - cillin-clavulanate should be dosed at 3 g of ticarcillin and 0.1 g of clavulanic acid IV every 4 hours, and piperacillin-tazobactam should be dosed at 4 g of piperacillin and 0.5 g of tazobactam IV every 6 hours or 3 g of piperacillin and 0.375 g of tazobactam IV every 4 hours. Cephalosporins. Ceftazidime should be dosed at 2 g IV every 8 hours and cefepime at 2 g IV every 8 hours. Because of their good activity and narrow spectrum com-


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pared with carbapenems, cephalosporins are still consid-ered treatments of choice if the isolate is susceptible. Monobactams. Aztreonam should be dosed at 2 g IV every 8 hours. isolates that produce metallo-β-lactamases may be susceptible to aztreonam, which dem-onstrates resistance to hydrolysis by class B β-lactamases65 (Table 2). Clinical correlation is needed. Carbapenems. Imipenem should be dosed at 500 mg IV every 6 hours up to 1 g every 8 hours for serious infections, meropenem at 1 g IV every 8 hours, and doripenem at 500 mg IV every 8 hours. The various carbapenems have differ-ent levels of activity against isolates. In vitro studies have shown that MICs were lowest with doripen-em, followed by meropenem, then imipenem.66,67 However, doripenem, like other carbapenems, has minimal activ-ity against metallo-β-lactamase–producing strains.68 In contrast, imipenem has been associated with a higher risk of selecting for resistant isolates compared with other carbapenems. Whether these in vitro differences among carbapenems translate into clinical out-come differences has not yet been determined. Carbapen-ems are usually used in the empirical treatment of suspected

species infections or when a polymicrobial infection is considered a possibility. In view of their broad spectrum of activity and the inherent risk of selecting for MDR organisms including and species, antibiotic therapy should be de-escalated when possible based on culture results. Fluoroquinolones. Ciprofloxacin should be dosed at 400 mg IV every 8 hours or 750 mg orally every 12 hours, and levofloxacin should be dosed at 750 mg orally or IV daily. Although both ciprofloxacin and levofloxacin are ac-tive against , levofloxacin use might be asso-ciated with a higher risk of isolation of quinolone-resistant

than ciprofloxacin.69

Colistin. Colistin base should be dosed daily at 2.5 to 5.0 mg/kg intramuscularly or IV in 2 to 4 divided doses. The increasing rates of MDR isolates have prompted clinicians to turn to agents such as the polymyx-ins that had for a while fallen out of use due to their adverse effect profile.70 Studies have shown that, despite the risk for nephrotoxicity in patients receiving colistin, this drug may be useful as salvage therapy when therapeutic choices are seriously limited.71 More recently, compiled data seem to indicate that colistin use is associated with a lower than expected incidence of nephrotoxicity.72 This may be due to better fluid management and critical care services. None-theless, renal function should be well monitored during therapy and dose adjustment should be performed in pa-tients with reduced creatinine clearance as follows: serum creatinine of 1.3 to 1.5 mg/dL, 2.5 to 3.8 mg/kg IV daily; serum creatinine of 1.6 to 2.5 mg/dL, 2.5 mg/kg IV daily;

and serum creatinine of 2.6 to 4.0 mg/dL, 1.5 mg/kg IV daily. It should be noted, however, that the ideal dose of co-listin has not been evaluated in randomized clinical tri-als.73 In a recent retrospective analysis of 258 episodes of MDR gram-negative infections, 68 of which were caused by , higher daily doses of colistin were in-dependently associated with better survival regardless of the pathogen.74 The average daily dose of colistin that was used was 480±200 mg IV. The nephrotoxicity rate in this series was 10% and was independent of the dose used. Other Antimicrobial Agents. Other antimicrobial agents possess activity against but are generally not recommended as monotherapy because of their high pro-pensity to induce resistance. Hence, they are mostly used in combination with other antipseudomonal agents, such as aminoglycosides (amikacin at 5.0-7.5 mg/kg of ideal body weight IV every 8 hours, gentamicin and tobramy-cin at 1.0-2.5 mg/kg of ideal body weight IV every 8-12 hours) and rifampin (at 600 mg orally or IV once daily, particularly in cases of bacteremia refractory to standard treatment).75

Combination Therapy. The use of combination ther-apy in species infections has been a con-troversial issue among specialists in infectious diseases. Whereas counterarguments include the additional costs and increased risk of adverse effects inherent in the con-current use of multiple agents, proponents of combination therapy cite the potential for synergistic efficacy as well as the potential benefit of reducing the risk of emergence of resistance. Another rationale is to ensure an initial broad spectrum of activity when the risk of MDR isolates is high by using drugs with different mechanisms of action and/or resistance. The results of clinical studies on the value of combina-tion therapy in the treatment of have been conflicting. Although older studies showed that combina-tion therapy was more effective at reducing mortality rates in patients with bacteremia than mono-therapy,76 these results could not be corroborated by other authors.77 At least 2 meta-analyses have been published without resolving the question of whether the benefits of combination therapy outweigh the risks. The first meta-analysis evaluated 64 randomized trials comparing β-lactam monotherapy with combination therapy (a β-lactam and an aminolycoside) in more than 7500 immunocompetent pa-tients with severe infections, 426 of whom were infected with .78 Combination therapy offered no sur-vival advantage but was associated with a higher risk of nephrotoxicity than was monotherapy. A second meta-anal-ysis evaluated 17 studies, only 2 of which were randomized trials, in patients with gram-negative bacteremia.79 Mortal-


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ity rates were significantly reduced in the subgroup but not in the overall population. Data from in vitro studies and clinical trials regarding the prevention of resistance emergence during treatment of infections with combination therapy are scarce and inconclusive.80 For example, one study sug-gested that the addition of levofloxacin to imipenem might hamper the emergence of resistance.81 In another study, ad-dition of an aminoglycoside to various β-lactam antibiotics did not alter the risk of selection for resistant isolates.82

The most used drug combination for species infections is an aminoglycoside with a β-lactam.83 In a more recent study, the checkerboard technique was used to test for synergistic activity of various combina -tions of anti-pseudomonal agents (ceftazidime-tobramy cin, piperacillin-tazobactam-tobramycin, imipenem-tobramy-cin, imipenem-isepamycin, imipenem-ciprofloxacin, and ciprofloxacin-tobramycin).84 Ceftazidime-tobramycin and piperacillin-tazobactam-tobramycin combinations were asso ciated with the highest ratios of synergy. Antagonism was not observed in any of the combinations. In addition, on the basis of in vitro findings, the following drug combina-tions have been found to provide enhanced activity against highly resistant : a fluoroquinolone with either ceftazidime or cefepime,85 ticarcillin with tobramycin and rifampin,86 polymyxin B with rifampin,87 ceftazidime with colistin,88 clarithromycin with tobramycin,89 and colistin with rifampin.90

These novel combinations are not meant for routine use and should be restricted to the treatment of MDR isolates because they include agents that, when used alone, may be inactive or unreliable for the treatment of species infections. Clinical data to support the use of these regimens are not yet available. In addition to the checker-board technique, the E-test is another useful tool for deter-mining MICs and testing antimicrobial combinations that can provide clinicians with potential treatment options. A novel parameter, the susceptible breakpoint index, allows ranking of the antimicrobial combinations by order of ex-pected activity.91

Empirical therapy with 2 antipseudomonal agents may be considered when the perceived risk of antimicrobial re-sistance is substantial or in the setting of neutropenic fever, severe sepsis or septic shock, or serious infections such as pneumonia, endocarditis, and meningitis. Once suscep-tibility results become available, treatment with 1 active agent is acceptable. Inhaled Antibiotics. Intermittent aerosolization of anti-biotics into the respiratory tract has been used in patients with pneumonia, particularly in the setting of cystic fibrosis. This mode of delivery is used to attain high drug levels locally in the respiratory tract without in-

creasing systemic adverse effects. Several agents have been used as inhaled therapy, including tobramycin, colistin, and β-lactams. Tobramycin is the inhaled antibiotic that has been the most widely used in the treatment of pneu-monia. The supporting evidence comes from studies that showed increased bacterial eradication with inhaled to-bramycin.92,93 However, clinical outcomes were not always consistent in different patient populations. For example, in one study, inhaled tobramycin was associated with im-proved pulmonary function and with weight gain in ado-lescent patients with cystic fibrosis during a 2-year period of long-term, intermittent use.94 In contrast, the overall clinical outcome in intubated adult patients with gram-neg-ative pneumonia did not change with inhaled tobramycin administration despite confirmed bacterial eradication.92 Inhaled colistin has also been used successfully in the management of MDR pneumonia that does not improve with IV administered therapy. In one study from Singapore, nebulized colistin was used alone in the treatment of 21 patients with pneumonia due to MDR

and .95 Overall clinical and micro-biological response rates were 57% and 86%, respectively, and nephrotoxicity was not observed. Despite these results, more data on clinical efficacy are needed, specifically regarding patient outcomes. At this point, the routine use of inhaled antibiotics is not recom-mended for pneumonia. Agents Under Development. A number of antimicro-bial agents with antipseudomonal activity are currently in various phases of development. However, clinical data re-garding efficacy are still lacking. Drugs in Phase 2 Trials. The following drugs are cur-rently in phase 2 trials: sitafloxacin (a quinolone with better activity against gyrA or parC mutants than ciprofloxacin),96 KB001 (a high-affinity antibody fragment that reduces the toxicity and pathogenicity of ),97 CXA-101 (a novel cephalosporin with potent activity against MDR strains),98 and ceftazidime/NXL104 (a cephalosporin/β-lactamase inhibitor combination meant to restore the in vitro activity of ceftazidime against class A, C, and some class D β-lactamase–producing strains).99

Drugs in Phase 1 Trials. BLI-489/piperacillin (anoth-er β-lactamase inhibitor combination)100 and CB-182,804 (a lipopeptide with apparent bactericidal activity against MDR strains) are currently in phase 1 trials (more infor-mation on CB-182,804 available at http://www.cubist .com/products/gram-negative.php). Experimental Agents. These agents have not under-gone any clinical trials and include new β-lactams, new β-lactamase inhibitors, peptides, efflux inhibitors, and vir-ulence modulators.101


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EXTENDED-INFUSION STRATEGY FOR β-LACTAMS

Because the killing activity of β-lactams is time-depen-dent, a positive correlation exists between their efficacy and the amount of time the drug concentration exceeds the MIC value during the dosing interval. To optimize dosing strategies to achieve better bacterial killing, studies have evaluated the role of administering β-lactams in extended infusions with encouraging results. Lodise et al102 com-pared the outcome of patients with infections treated with piperacillin-tazobactam in 2 dosage regimens (3.375 g IV for 30 minutes every 4-6 hours vs 3.375 g IV for 4 hours every 8 hours). Patients with Acute Physiol-ogy And Chronic Health Evaluation (APACHE) II scores of 17 or greater who received extended-infusion therapy had lower mortality rates (12.2% vs. 31.6%; P=.04) and shorter hospital stays compared with those who received intermittent-infusion therapy (21 days vs 38 days; P=.02). More recently, 3 immunocompromised patients with MDR

infections were treated successfully with continuous infusions of β-lactam antibiotics (ceftazidime in 2 patients and aztreonam in the third patient).103

Carbapenems have also been evaluated in extended-infu-sion regimens. Using a Monte Carlo simulation, lengthening meropenem infusions from 30 minutes to 3 hours was found to be advantageous with isolates of and

species with intermediate resistance.104 This benefit was not observed with Enterobacteriaceae, which usually exhibit low MICs, and with resistant isolates having very high MICs. Subsequently, doripenem was used in clinical trials in extended infusions and at lower doses compared with other carbapenems with equivalent efficacy results (doripenem infused at 500 mg during a 4-hour period every 8 hours vs imipenem infused at 500 mg during a 30-minute period every 6 hours or at 1 g during a 60-minute period ev-ery 8 hours and meropenem infused at 1 g as a 3- to 5-min-ute bolus every 8 hours).105,106 When used at higher doses in a murine model (1 g every 8 hours), an extended infusion of doripenem during a 4-hour period achieved a static antibac-terial effect on KPC-producing isolates.107

Extended-infusion strategy therefore appears to be a valuable approach in certain settings and deserves further study. The effect of this dosing regimen on the potential for selection of resistant mutants is yet to be determined.

CONCLUSION

The treatment of infections caused by MDR pathogens is complicated. Treatment options are currently limited, and it will be some time before more investigational agents become available for clinical use, if ever. Meanwhile, prevention strat-egies should go hand in hand with antimicrobial treatment. The importance of antimicrobial stewardship and infection

control policies cannot be discounted in the fight against the worldwide emergence and spread of MDR pathogens.

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CURRENT CONCEPTS IN THE MANAGEMENT OF TUBERCULOSIS

348



From the Division of Infectious Diseases (I.G.S.) and Division of Primary Care Internal Medicine (M.L.W.), Mayo Clinic, Rochester, MN.

Address correspondence to Irene G. Sia, MD, MSc, Division of Infectious Diseases, 200 First St SW, Rochester, MN 55905 ([email protected]). In-dividual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com.


Irene G. Sia, MD, MSc, and Mark L. Wieland, MD, MPH

Current Concepts in the Management of Tuberculosis

Effective medical therapy for tuberculosis (TB) has existed for more than half a century, yet TB remains

among the most pressing public health issues of our day. Tuberculosis is, in part, a disease of poverty.1 The fact that it remains the eighth leading cause of death in the world speaks to the challenges facing practitioners and public health officials as they try to control a disease that is so en-twined in the cultural and economic fabric of society. Chal-lenges to effective solutions include lack of access to diag-nosis and treatment, the frequent coexistence of epidemics of TB and human immunodeficiency virus (HIV), and the

Tuberculosis (TB) poses a serious threat to public health through-out the world but disproportionately afflicts low-income nations. Persons in close contact with a patient with active pulmonary TB and those from endemic regions of the world are at highest risk of primary infection, whereas patients with compromised immune systems are at highest risk of reactivation of latent TB infection (LTBI). Tuberculosis can affect any organ system. Clinical mani-festations vary accordingly but often include fever, night sweats, and weight loss. Positive results on either a tuberculin skin test or an interferon-γ release assay in the absence of active TB establish a diagnosis of LTBI. A combination of epidemiological, clinical, ra-diographic, microbiological, and histopathologic features is used to establish the diagnosis of active TB. Patients with suspected active pulmonary TB should submit 3 sputum specimens for acid-fast bacilli smears and culture, with nucleic acid amplification testing performed on at least 1 specimen. For patients with LTBI, treatment with isoniazid for 9 months is preferred. Patients with active TB should be treated with multiple agents to achieve bac-terial clearance, to reduce the risk of transmission, and to prevent the emergence of drug resistance. Directly observed therapy is recommended for the treatment of active TB. Health care profes-sionals should collaborate, when possible, with local and state public health departments to care for patients with TB. Patients with drug-resistant TB or coinfection with human immunodeficien-cy virus should be treated in collaboration with TB specialists. Public health measures to prevent the spread of TB include appro-priate respiratory isolation of patients with active pulmonary TB, contact investigation, and reduction of the LTBI burden.

Mayo Clin Proc. 2011;86(4):348-361

AFB = acid-fast bacilli; BCG = bacille Calmette-Guérin; CFP-10 = cul-ture filtrate protein 10; DOT = directly observed therapy; EMB = ethambutol; ESAT-6 = early-secreted antigenic target 6; HIV = human immuno deficiency virus; IFN-γ = interferon-γ; IGRA = IFN-γ release assay; INH = isoniazid; LTBI = latent TBI; MDR-TB = multidrug-resistant TB; NAA = nucleic acid amplification; PZA = pyrazinamide; RIF = rifampin; TB = tuberculosis; TBI = TB infection; TST = tuberculin skin test; XDR-TB = extensively drug-resistant TB

increasing prevalence of multidrug-resistant TB (MDR-TB).2 Although a chasm in disease burden exists between resource-rich and poor regions, an increasingly mobile and connected global community has ensured that TB remains highly relevant to practitioners throughout the world. This review highlights key principles in the management of TB. For purposes of definition, TB infection (TBI) occurs when a susceptible person inhales droplets containing

nuclei that travel through the respirato-ry tract to the alveoli. In most patients, an immune response limits propagation of TBI, resulting in an asymptomatic, noninfectious, localized infection that may remain in the body for many years. These patients have positive immuno-logic test results for and carry a diagnosis of latent TBI (LTBI). A constellation of clinical, radiographic, microbiological, and histopathologic hallmarks are used to diagnose active TB disease.3

EPIDEMIOLOGY

An estimated one-third of the world’s population is infect-ed with TB.4 Tuberculosis accounted for 1.3 million deaths in 2007, and the prevalence of active disease is estimated at 13.7 million (206 per 100,000 persons).5 Incident cases of active TB are highest (≥100 cases per 100,000 persons) in sub-Saharan Africa, India and Central Asia, parts of East-ern Europe, Southeast Asia, and Micronesia. Intermediate incidence rates (26-100 per 100,000 persons) are observed in Central and South America, China, and northern Africa. Low rates (<25 per 100,000 persons) occur in the United States, Canada, Australia, Western Europe, and Japan.5,6

While absolute numbers have been on the rise, the prevalence of TB in relationship to population has trend-ed downward during the past 15 years, and global public


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health efforts have averted an estimated 6 million deaths during this time.2 Nevertheless, the emergence of drug re-sistance coupled with the persistence of HIV and global poverty have thwarted a more substantive break in the TB epidemic. Indeed, 0.5 million cases of MDR-TB, in which the infecting organism is resistant to at least isoni-azid (INH) and rifampin (RIF), were reported in 2007, and 55 countries reported at least 1 case of extensively drug-resistant TB (XDR-TB),5 in which the organism is resistant to at least INH, RIF, fluoroquinolones, and either amino-glycosides or capreomycin, or both. The magnitude of the problem is particularly overwhelming in parts of the Rus-sian Federation and Central Asia, where the proportion of MDR-TB among incident TB cases ranged from 12% to 28% between 1994 and 2009, compared with 0% to 3% in the United States.7

As in the rest of the world, the incidence of TBI in the United States has declined during the past decade, but this decline has been much less pronounced among foreign-born Americans. More than half of active TB cases in the United States currently occur in foreign-born individuals,5,8 and most cases result from reactivation of LTBI.9,10 The ef-fect of global migration on TB has been seen throughout the developed world, most dramatically in London, where cases of active TB increased by 50% between 1999 and 2009, mostly among foreign-born individuals.11

Sociodemographic risk factors for TBI include recent residence in an endemic region of the world, low socioeco-nomic position, being a member of a racial or ethnic minor-ity (in the United States), homelessness, residency or em-ployment at high-risk facilities (eg, correctional facilities, homeless shelters, skilled nursing facilities), and employ-ment as a health care worker caring for patients with TB.

TRANSMISSION

Tuberculosis is transmitted through droplet aerosolization by an individual with active pulmonary disease. The high-est risk of transmission occurs among patients with cavi-tary or positive acid-fast bacilli (AFB) smears12; however, patients with negative smears but positive cultures may still transmit the disease.13

Host factors dramatically influence which of those ex-posed to TB are most likely to contract primary disease or progress to active disease. Those with greater susceptibility include persons with immune systems that have been com-promised through either diseases, such as HIV infection and hematologic and reticuloendothelial malignancies, or through immunosuppressive medications, such as corti-costeroids, tumor necrosis factor α inhibitors, calcineurin inhibitors, and cytotoxic chemotherapeutic agents. Fur-thermore, patients with chronic diseases, such as diabetes,

chronic kidney disease, and silicosis, are at elevated risk. Fi-nally, age younger than 4 years, long-term malnutrition, and substance abuse are independent risk factors for disease.3

CLINICAL MANIFESTATIONS

PULMONARY TB Primary Pulmonary TB. Symptoms occurring around the time of inoculation are referred to as nary TB. Symptoms are generally mild and include low-grade fever.14,15 Two-thirds of persons with primary pulmo-nary TB remain asymptomatic. Physical examination find-ings are generally unremarkable, and the most common radiographic finding is hilar adenopathy.16 Less common radiographic findings include pulmonary infiltrates in the mid and lower lung field. Reactivation TB. Approximately 90% of TB cases among adults can be attributed to reactivation TB. Symp-toms present insidiously, most commonly with fever, cough, weight loss, fatigue, and night sweats. Less com-mon symptoms include chest pain, dyspnea, and hemopty-sis. Physical examination findings are nonspecific and may include rales or signs of pleural effusion (eg, dullness to percussion). Chest radiography demonstrates infiltrates in the apical-posterior segment of the upper lobes, and up to 20% of these infiltrates are associated with cavities char-acterized by air-fluid levels. Although not specific for TB, apical computed tomographic findings may show a “tree in bud” morphology manifested by centrilobular lesions, nodules, and branching linear densities.17,18 Among the roughly 15% of patients who present without upper lung field infiltrates, a variety of radiographic findings have been described, including lower lung infiltrates (especially superior segments), nodules, effusions, and hilar adenopa-thy. Finally, up to 5% of patients with active pulmonary disease may have normal findings on chest radiography.19,20 This is particularly worth noting among patients coinfected with HIV, who are more likely to have atypical (eg, less predisposition for upper lobes) or normal findings on chest radiography.21

Endobronchial TB. Endobronchial TB develops as the direct extension of TB from a pulmonary parenchy-mal source or sputum inoculation into the bronchial tree.22 Symptoms may include barking cough with sputum pro-duction, and examination may reveal rhonchi and wheez-ing23,24; the wheezing may lead to misdiagnosis of asthma.25 Diagnosis and response to therapy may be assessed through bronchoscopy.26

EXTRAPULMONARY TBExtrapulmonary TB accounts for roughly 15% of TB cases among immunocompetent hosts27 and for 50% to


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70% of cases that occur in the context of coinfection with HIV.28-30 In low-incidence countries, immigrants from endemic countries are much more likely to present with extrapulmonary TB.31-33 As a rule, TB can present in any organ system; therefore, vigilance and examination for extrapulmonary disease are important for all persons be-ing evaluated for TBI. A summary of the most common presentations of extrapulmonary TB follows (see also Table 1). Tuberculous Lymphadenitis. Up to 40% of extrapul-monary TB cases are attributable to tuberculous lymph-adenitis.27 It presents most commonly in the cervical lymph nodes, followed by the mediastinal and axillary nodes.34,35 A typical presenting symptom is long-term, unilateral, nontender lymphadenopathy; systemic symptoms are of-ten absent.36 On examination, the node is typically matted and adherent to surrounding structures.36,37 If tuberculous lymphadenitis is clinically suspected, fine-needle aspira-tion should be pursued, followed by lymph node biopsy if the aspiration is nondiagnostic.38,39

Pleural TB. Accounting for roughly 4% of all TB cas-es, pleural TB is the second leading cause of extrapulmo-nary TB.40 In addition to constitutional symptoms, patients may present with nonproductive cough and pleuritic chest pain.41 Chest radiography typically shows a unilateral effu-sion, and pleural fluid analysis shows lymphocyte-predom-inant exudative features with low glucose levels and low pH.42 Pleural fluid culture is positive in only roughly 30% of cases, whereas the combination of histology and culture from a closed pleural biopsy specimen yields a diagnosis in most cases.43

Central Nervous System TB. A devastating manifes-tation of the disease, central nervous system TB occurs in approximately 1% of all TB cases.44 Tuberculous men-ingitis is clinically heralded by a 2- to 3-week prodrome

of malaise, headache, low-grade fever, and personality changes. This prodrome is followed first by a meningitic phase that mimics bacterial meningitis (fever, nuchal ri-gidity, altered mental status) and then by a paralytic phase characterized by rapid progression to stupor, coma, seizures, paralysis, and death.45-47 Diagnosis requires a high index of suspicion, and cerebrospinal fluid analysis demonstrates elevated protein levels (100-150 mg/dL; to convert to g/L, multiply by 10), low glucose levels (<45 mg/dL; to convert to mmol/L, multiply by 0.0555), mono-nuclear pleocytosis, and an elevated cell count (100-150 cells/μL). A less common manifestation of the disease is central nervous system tuberculoma, which is character-ized by single or multiple conglomerate caseous foci within the brain that cause focal neurologic symptoms and signs of elevated intracranial pressure. Finally, spinal tuberculous arachnoiditis represents a focal inflammatory disease producing gradual encasement of the cord with associated neurologic deficits. Tuberculous Peritonitis. The most common manifesta-tion of TB in the gastrointestinal tract is tuberculous peri-tonitis.48,49 Cirrhosis and portal hypertension are associated with an increased proclivity for tuberculous peritonitis.50,51 Patients present with insidious onset of ascites (73%), ab-dominal pain (65%), weight loss (61%), and low-grade fever (59%).52 Clinically, tuberculous peritonitis may be mistak-en for ovarian carcinoma or peritoneal carcinomatosis.53,54 Unexplained lymphocytic ascites should prompt definitive diagnostic testing for peritoneal TB. Culture of tubercles ob-tained through peritoneal biopsy remains the criterion stan-dard for diagnosis. Tuberculous Pericarditis. In the developing world, tuberculous pericarditis is likely the most common cause of pericardial effusion and constrictive pericarditis55,56; however, in high-income nations, it is rare.57 Patients can present with pericardial effusion, constrictive pericarditis, or a mixed effusive and constrictive condition.58 Symp-toms are those of effusion or constriction from any cause (dyspnea, cough, orthopnea, edema) in the context of sys-temic symptoms (night sweats, low-grade fevers, weight loss).59

Skeletal TB. Skeletal TB occurs in 1% to 5% of pa-tients with TB60 and presents most commonly in the thora-columbar spine. Patients present with localized pain over the afflicted site; systemic symptoms are often absent.61 Diagnosis is confirmed through culture of specimens ob-tained through needle aspiration or biopsy.62

Miliary TB. The lymphatic and hematogenous spread of TB is referred to as .63 Patient presenta - tion is variable, and systemic symptoms (fever, weight loss, night sweats) are common.64 When miliary TB oc-curs in the context of primary infection, patients may

TABLE 1. Diagnosis of Common Extrapulmonary TB Manifestations

Site Diagnostic procedure

Tuberculous lymphadenitis Excisional biopsy with cultureCNS TB Characteristic CSF exam (see text for details) AFB smear and culture of CSF Polymerase chain reaction for TB of CSFPleural TB Pleural biopsy with pathology and cultureTuberculous peritonitis Laparoscopic peritoneal biopsy with cultureTuberculous pericarditis Pericardiocentesis with cultureSkeletal TB Needle biopsy and cultureGenitourinary TB Biopsy and culture of masses Culture of urineMiliary (disseminated) TB Culture of involved sites

AFB = acid-fast bacilli; CNS = central nervous system; CSF = cerebrospi-nal fluid; TB = tuberculosis.


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present with septic shock and acute respiratory distress syndrome.65-67

DIAGNOSIS

The diagnosis of LTBI is established by a positive result on either a tuberculin skin test (TST) or an interferon-γ (IFN-γ) release assay (IGRA), in the absence of active TB. Active TB is diagnosed on the basis of a combination of epide-miological (eg, exposure, travel to or residence in a high prevalence area, previous TB), clinical (eg, cough lasting longer than 2-3 weeks, fever, night sweats, weight loss), radiographic (eg, infiltrates, fibrosis, cavitation), microbio-logical (eg, positive sputum smear or culture), and histo-pathologic (eg, caseating granuloma) features. Patients in whom clinical suspicion for TB infections is strong on the

basis of clinical criteria should undergo chest radiography. Patients with chest radiographic findings suggestive of pul-monary TB should submit 3 sputum specimens, preferably obtained on different days, for AFB smears and culture.68,69 At least 1 early morning sputum specimen should be sub-mitted. Patients unable to produce sputum spontaneously should undergo sputum induction, which requires inhala-tion of an aerosol of sterile hypertonic saline (3%-15%) in negative-pressure isolation rooms.70,71 Bronchoscopy with bronchoalveolar lavage may be necessary in patients un-able to produce adequate expectorated or induced sputum samples. Nucleic acid amplification (NAA) testing should be performed on at least 1 respiratory specimen.72 Confir-mation of the diagnosis of TB requires laboratory identifi-cation of by AFB smear microscopy with NAA test and/or culture (Figure).

×

FIGURE. Evaluation and initial management of suspected pulmonary tuberculosis (TB). IGRA = interferon-γ release assay; LTBI = latent TB infection; NAA = nucleic acid amplification; TST = tuberculin skin test.


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TUBERCULIN SKIN TEST The TST, also known as the Mantoux test, requires the in-tradermal injection of 0.1 mL of 5 tuberculin units of puri-fied protein derivative into the volar surface of the forearm. The TST measures cell-mediated immunity manifesting as a delayed-type hypersensitivity to tuberculin purified protein derivative, which contains a mixture of antigens shared by several species of mycobacteria.73 The test result is recorded as the diameter of transverse induration in mil-limeters 48 to 72 hours after administration. Interpretation of the TST result varies depending on the prevalence of and the risk for progression to TB in different groups. Indura-tion between 5 and 15 mm is considered positive and may be indicative of LTBI (Table 2). The size of induration has some predictive value in that persons with TBI tend to have larger indurations74,75; however, it does not correlate with risk for progression to active TB. An increase of 10 mm or more in the skin test reaction within 2 years in persons with previously negative results (conversion) is indicative of recent infection. The TST cannot dis-criminate between active TB and LTBI. Interpretation of skin-test results is the same for bacille Calmette-Guérin (BCG)–vaccinated and non-BCG–vacci-nated persons. The estimated interval between

infection and skin test reactivity (ie, skin test conversion) is 2 to 12 weeks.76,77 Therefore, those in close contact with patients who have active pulmonary TB with initial nega-tive test results should have the test repeated 8 to 12 weeks after exposure. Skin test conversion may also be due to new

delayed-type hypersensitivity after infection with nontuber-culous mycobacteria or BCG vaccination.78 The phenom-enon of reversion (ie, decrease in the size of the tuberculin reaction) may present problems in skin test interpretation when serial TSTs are performed. Therefore, TST should not be performed if a positive TST result has been documented previously or if the patient has been treated for TB. False-positive skin tests can result from BCG vaccination or infec-tion with nontuberculous mycobacteria. False-negative test results may occur because of the following technical and bi-ological limitations: presence of active TB; presence of other bacterial, fungal, and viral (eg, HIV) infections; live virus vaccination; immunosuppressive therapy; long-standing re-nal failure; malnutrition; lymphoid diseases; and age. The TST may have a booster effect on immunologic memory in patients with a history of TB, previous BCG vaccination, and exposure to nontuberculous mycobacte-ria.74,79 This results in a positive TST 1 to 4 weeks after initial negative findings on TST. Evaluation for the booster phenomenon with a second TST 1 to 4 weeks after the first test (the 2-step method) should be considered for persons from countries with a high incidence of TB, for those with a history of BCG vaccination, and (as a baseline assess-ment) for those who need periodic retesting, such as health care workers. Test interpretation is based on the induration observed with the second test. About 10% of immunocompetent persons with LTBI will develop TB disease over their lifetime, with the greatest risk for progression (5%) being in the first 2 years after infection with .80 Approximately 50% of TB cases will occur within 2 years after initial infection.81 Targeted tuber-culin testing identifies persons at high risk of developing TB who would benefit from treatment for LTBI. These include persons at risk of becoming infected with and those with clinical conditions associated with increased risk of progression of TB infection to active TB (Table 2). A joint statement from the American Thoracic Society and the Cen-ters for Disease Control and Prevention provides guidelines on testing and treatment of LTBI in the United States.76

INTERFERON-γ RELEASE ASSAY Serum IGRAs are in vitro tests of whole blood or mono-nuclear cells that are based on IFN-γ release after T-cell stimulation by –specific proteins (eg, early-secreted antigenic target 6 [ESAT-6] and culture filtrate protein 10 [CFP-10]), which are absent from BCG vaccine strains and most nontuberculous mycobacteria. The Quan-tiFERON-TB Gold In-Tube test (Cellestis Limited, Car-negie, Victoria, Australia) is an enzyme-linked immuno-sorbent assay–based whole blood assay that measures and quantifies IFN-γ (IU/mL) released from blood collected in special tubes that are coated with –specific

TABLE 2. Interpretation of TST Results for Populations at Risk of TBa

Positive TST reaction size At-risk populations (mm)

Patients with HIV infection ≥5Patients receiving immunosuppressive therapyb Abnormal findings on chest radiography consistent with previous TB infection Persons who have come in close contact with an actively contagious patient

Patients with certain chronic conditionsc ≥10Patients with certain malignanciesd

Foreign-born persons from high-incidence regions (>25/100,000) Employees and residents of high-risk facilitiese

Healthy people at low risk of TB ≥15

a HIV = human immunodeficiency virus; TB = tuberculosis; TNF = tumor necrosis factor; TST = tuberculin skin test.

b Immunosuppressive therapies include chemotherapeutic agents, TNF-α inhibitors, and glucocorticoid therapy (>15 mg/d of prednisone equiva-lent for >1 mo).

c Diabetes, dialysis-dependent renal failure, silicosis, and being under-weight.

d Leukemia, lymphoma, and cancers of the head, neck, and lung.e Health care facilities, prisons, and homeless shelters.


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antigens, including ESAT-6, CFP-10, and TB7.7(p4). The T-SPOT.TB test (Oxford Immunotec Limited, Abingdon, United Kingdom) is an enzyme-linked immunospot assay that uses peripheral blood mononuclear cells incubated with mixtures of peptides containing ESAT-6 and CFP-10 to measure the number of cells secreting IFN-γ (IFN-γ-spot–forming cells). Results of IGRA are reported both qualitatively (positive, negative, indeterminate, or border-line) and quantitatively (IU/mL or IFN-γ-spot–forming cells). Reversion of IGRA test results from positive to neg-ative has been observed, particularly in those with nega-tive results on the initial TST.82 Conversion of IGRA (ie, a change in test results from negative to positive within 2 years) has not been associated with an increased risk of subsequent progression to TB disease.83

The IGRA can be used in the same setting as TST83 but has the advantage of being able to differentiate

infection from previous BCG vaccination and most nontuberculous mycobacterial infections; it may also be able to discriminate true-negative responses from anergy. However, currently available IGRA, like TST, cannot distin-guish active TB from latent infection.73,82 Because ESAT-6 and CFP-10 proteins are present in

, , and , false-positive IGRA results are possible. As with negative

TST findings, negative findings on IGRA may not exclude TB infection in immunosuppressed persons. An IGRA is the preferred method of testing for groups of people who have low rates of returning to have their TST test results read and for those who have received BCG vaccine. The TST is pre-ferred for testing children younger than 5 years. For other groups being tested for LTBI, either TST or IGRA may be used.83 A summary of tests for TB is presented in Table 3.

CHEST RADIOGRAPHY

Chest radiography is indicated for all persons being evalu-ated for LTBI or active TB. Pulmonary TB as a result of endogenous reactivation of latent infection classically pre-sents with infiltrates in the apical and posterior segments of the right upper lobe, the apical-posterior segment of the left upper lobe, and the superior segment of the lower lobe. Cavitation, fibrosis, and/or enlargement of the hilar and mediastinal lymph nodes may be present. In some cases, pulmonary TB may present as lobar or segmental infiltrates, lung mass, scattered fibronodular lesions (“mil-iary”), or pleural effusions.

SMEAR MICROSCOPY

Smear microscopy for the detection of AFB is the most rapid and inexpensive method for TB diagnosis. Two commonly

TABLE 3. Key Features of Tests for TB

Test Strengths Limitations

Tuberculin skin test High specificity in non–BCG-vaccinated populations Training required for administration and interpretation Cost-effectiveness Return visit required in 48-72 h for test result Possible booster effect Possible false-positive and false-negative results

Interferon-γ release assay High specificity Blood withdrawal required Only 1 patient visit required Indeterminate results in those who are immunosuppressed Results available in 16-24 h and in those aged <5 y No confounding by BCG vaccination No capacity to differentiate between latent and active TB High cost

Chest radiography Ready availability Low sensitivity and specificity Capacity to differentiate latent infection from active TB Not confirmatory

Smear microscopy Ease, speed, and cost-effectiveness of the technique Low sensitivity Quantitative estimate of the number of bacilli No capacity to differentiate from nontuberculous Usefulness in determining infectiousness and in monitoring mycobacteria treatment progress

Nucleic acid High specificity Low sensitivity with smear-negative TB amplification test Higher sensitivity than smear microscopy Contamination-prone Rapid (1-2 d) diagnosis Technical skill and expertise required Capacity to differentiate TB from other mycobacteria Results may remain positive in patients who have completed treatment High cost

Culture in solid media Examination of colony morphology possible Wait of 3-8 wk for result Quantitative results

Automated liquid culture Sensitivity greater than culture in solid media Contamination-prone Faster results (1-3 wk) Stringent quality assurance systems required Expensive equipment required

BCG = bacille Calmette-Guérin; TB = tuberculosis.


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used methods for AFB staining are the carbolfuchsin meth-ods (eg, Ziehl-Neelsen and Kinyoun methods) and the fluorochrome procedure using auramine O or auramine-rhodamine dyes. The fluorochrome method with fluores-cence microscopy is preferred because it is far more sensi-tive than the carbolfuchsin methods. The finding of AFB on respiratory specimens associated with the appropriate epi-demiological, clinical, and radiographic findings is highly suggestive of TB.

NUCLEIC ACID AMPLIFICATION TEST

The NAA test is useful for the rapid detection of in respiratory specimens. The Enhanced Amplified

MTD (Mycobacterium Tuberculosis Direct) test (Gen-Probe, San Diego, CA) detects ribosomal RNA di-rectly from AFB smear–positive and AFB smear–negative respiratory specimens from patients with suspected TB. The Amplicor MTB (Mycobacterium Tuberculosis) test (Roche Diagnostic Systems, Branchburg, NJ) detects DNA in AFB smear–positive respiratory specimens. Interpretation of NAA test results should be correlated with AFB smear results.72 Positive findings on the NAA test and a positive sputum AFB smear are strongly indicative of TB.84-86 When NAA and sputum microscopy test results are discordant, physicians should exercise their clinical judgment in deciding whether to start anti-TB treatment while culture results are awaited.72 When the clinical suspicion for TB is high, a positive NAA test result in smear-negative cases can be valuable for the early detection of TB in approximately 50% to 80% of cases.87,88 Findings on the NAA test often re-main positive after cultures become negative during therapy and can remain positive even after completion of therapy89; therefore, it should not be used for assessing infectivity or response to treatment.

CULTURE

Culture remains the criterion standard for laboratory confir-mation of TB. Three types of culture media are available for the microbiological detection of : egg-based (Löwenstein-Jensen), agar-based (Middlebrook 7H10 or 7H11), and liquid (Middlebrook 7H12 and other commercial broth systems). Mycobacterial growth tends to be slightly better on the egg-based medium but more rapid on the agar medium. Growth in liquid media is faster than growth on sol-id media and allows detection in 1 to 3 weeks.90 The develop-ment of automated liquid culture systems for mycobacterial growth detection, such as BACTEC 460TB and BACTEC MGIT960 (Becton Dickinson Microbiology Systems, Sparks, MD), VersaTREK Myco (Trek Diagnostic Systems, Westlake, OH), and BacT/Alert 3D (bioMérieux, Durham, NC), which are faster and more sensitive than solid media, has clearly facilitated TB diagnosis in the past decade.

NEW TECHNOLOGY

Several recently developed tests for TB, including molecu-lar drug resistance, have the potential for providing rapid diagnosis and targeted treatment.91,92 These fully automat-ed tests provide rapid drug-resistance testing for RIF and INH; however, they require sophisticated technology and are currently available only at reference laboratories.93

OTHER CONSIDERATIONS

At the start of LTBI therapy, baseline measurements of se-rum aspartate aminotransferase, alanine aminotransferase, and bilirubin are recommended for patients who have a his-tory of liver disease (eg, hepatitis B or C, alcoholic hepati-tis, or cirrhosis), use alcohol regularly, have risk factors for chronic liver disease, are infected with HIV, are pregnant, or have given birth within the past 3 months.76 All patients diagnosed as having LTBI should be offered voluntary HIV counseling and testing. All patients with active TB should receive counseling and be tested for HIV infection. Serologic tests for hepa-titis B and C should be performed for patients with risk factors such as injection drug use, foreign birth, and HIV infection. Susceptibility testing for INH, RIF, ethambutol (EMB), and pyrazinamide (PZA) should be performed on any initial culture that is positive. Susceptibility testing to the second-line drugs should be performed on specimens from patients who have had previous therapy, are known to have resistance to first-line drugs, are contacts of patients with drug-resistant TB, or have persistently positive cul-tures 3 months or more after starting treatment. Baseline measurements of platelet count and serum aspartate amino-transferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and serum creatinine levels are recommended for all patients starting TB treatment.68

TREATMENT

LATENT TB INFECTION

Treatment for LTBI is recommended for persons deemed to be at relatively high risk of developing active TB (Table 2) and should be initiated only after active TB has been excluded by clinical and radiographic evaluations. Failure to rule out TB may result in inadequate treatment and de-velopment of drug resistance. For most patients, treatment with INH for 9 months is preferred (Table 4).76,94 Pyridox-ine supplementation (25 mg/d) to INH is recommended for patients at an increased risk of neuropathy, including those with preexisting peripheral neuropathy, nutritional deficiency, diabetes mellitus, HIV infection, renal failure, alcoholism, or thyroid disease and those who are preg-nant or breast-feeding. Intermittent treatment (ie, a twice-weekly regimen) should only be performed as directly


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TABLE 4. Treatment Regimens for Latent Tuberculosis Infection

Adult dose Interval Medication (maximum) and duration

Preferred regimen Isoniazid 5 mg/kg (300 mg) Daily for 9 moAlternative regimens Isoniazid 15 mg/kg (900 mg) Twice weekly for 9 mo Isoniazid 5 mg/kg (300 mg) Daily for 6 mo Isoniazid 15 mg/kg (900 mg) Twice weekly for 6 mo Rifampin 10 mg/kg (600 mg) Daily for 4 mo

Data from .76

observed therapy (DOT). Due to the high rates of hospi-talization and death from liver injury, the combination of RIF and PZA is no longer recommended for the treatment of LTBI.94

ACTIVE TBPatients with active TB should be treated with multiple agents to achieve bacterial clearance, to reduce the risk of transmission, and to prevent the emergence of drug re-sistance. Directly observed therapy, which involves direct observation of patients ingesting anti-TB medications, is the preferred management strategy for all patients being treated for TB. For treatment to be successful, patient-cen-tered case management and close collaboration between health care professionals and local public health programs are imperative. Medications for treating TB are classified as first- and second-line drugs (Table 5). First-line drugs are INH, RIF, EMB, and PZA. The rifamycin derivatives rifapen-tine and rifabutin are also considered among the first-line drugs. Second-line drugs include the aminoglycosides streptomycin, kanamycin, and amikacin; the polypep-tide capreomycin; p-aminosalicylic acid; cycloserine; the thioamides ethionamide and prothionamide; and several fluoroquinolones (eg, moxifloxacin, levofloxacin and gati-floxacin). The American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Dis-eases Society of America have issued a joint statement on the treatment of TB in the United States.68 An overview of this guideline and summary recommendations follow. Four treatment regimens are recommended for patients with drug-susceptible disease. Although these regimens are broadly applicable, treatment must be individualized on the basis of each patient’s clinical situation. Each of the 4 TB treatment regimens has an initial phase of 2 months followed by a continuation phase of 4 or 7 months (Table 6). Treatment in the initial phase is usually empirical be-cause susceptibility data may not be available. To guard against drug resistance and to ensure maximal effective-ness, the initial phase of treatment should include 4 drugs (INH, RIF, PZA, and EMB). If the isolate is susceptible to INH and RIF, EMB can be discontinued. Depending on the regimen chosen, medication in the initial phase may be given daily throughout treatment, daily for 2 weeks then twice weekly thereafter, or 3 times weekly throughout. Susceptibility data should direct treatment in the continu-ation phase, which lasts for 4 months in most patients. The continuation phase of treatment should be extended to 7 months for the following 3 groups of patients: those with cavitary pulmonary TB whose sputum culture remains positive after 2 months of treatment; those in whom the initial phase of treatment did not include PZA (eg, those

who have severe liver disease or are pregnant); and those being treated with once-weekly INH and rifapentine whose sputum culture remains positive after 2 months of treatment. Extending the continuation phase of treatment in these situations reduces the rate of relapse. During the continuation phase, medications may be given daily or 2 to 3 times a week with DOT. The minimum duration of treatment for culture-posi-tive TB is 6 months. If PZA is not included in the initial phase, treatment should be given for 9 months. Smear-negative, culture-negative pulmonary TB may be treated successfully with 4 months of a combination INH-RIF regimen. Completion of anti-TB treatment is determined by both the total number of doses taken and the duration of therapy.

FOLLOW-UP EVALUATION

Patients receiving treatment for TB infection or disease should be counseled about adverse effects and should have clinical evaluations at least once monthly to assess adher-ence and evaluate for possible adverse effects of anti-TB medications (Table 5). Patients receiving INH for LTBI therapy should be given no more than a 1-month drug sup-ply and should be monitored monthly for drug-induced he-patotoxicity or other adverse effects.95 Laboratory monitor-ing during treatment for LTBI is indicated only for patients with abnormal baseline liver function test results and other risks of liver disease and for evaluation of possible adverse effects during treatment.76

Patients being treated for pulmonary TB should have sputum microscopy and culture performed at least once a month until 2 consecutive negative specimens are ob-tained. Sputum culture after 2 months of treatment is par-ticularly important because a positive result is associated with increased risk of relapse96-99 and requires 7 months of continuation therapy. Platelet counts and measurements of hepatic and renal function are necessary for those with baseline abnormalities or those at increased risk of toxic-ity (eg, hepatitis B or C infection, alcohol abuse).68 When EMB is to be used, visual acuity and red-green color dis-crimination should be monitored.


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TABLE 5. Doses and Adverse Effects of Antituberculosis Medicationsa

Adult dose Use in Medication (daily maximum) Important adverse effects pregnancy Comments

First-line medications Isoniazid 5 mg/kg (300 mg) Hepatitis (risk increases with age), Safe for fetus; Should be supplemented with pyridoxine in peripheral neuropathy, rash increased pregnant patients or in patients at risk of hepatotoxicity neuropathy postpartum

Rifampin 10 mg/kg (600 mg) GI upset, hepatotoxicity, pruritus, Safe Induces hepatic microsomal enzymes, resulting orange discoloration of bodily in decreased effectiveness of some drugs; fluids use with caution in women taking oral contraceptives and advise on use of the supplement barrier method; has important interactions with antiretroviral agents

Rifapentine 10 mg/kg (600 mg) GI symptoms, hepatotoxicity, Insufficient Can be used in a once-weekly regimen; not continuation phase pruritus, orange discoloration of information recommended in patients infected with HIV; bodily fluids induces hepatic microsomal enzymes, resulting in increased metabolism of coadministered drugs

Rifabutinb 5 mg/kg Neutropenia, uveitis, polyarthralgia, Limited data; Interacts with protease inhibitors and (300 mg) rash, hepatotoxicity, and orange use with nonnucleoside reverse transcriptase discoloration of bodily fluids caution inhibitors

Ethambutol 40-55 kg: 14.5- Optic neuritis and peripheral Safe Can affect visual acuity and color vision 20.0 mg/kg (800 mg) neuropathy and so these should be monitored 56-75 kg: 16.0- 21.4 mg/kg (1200 mg) 76-90 kg: 17.8- 21.1 mg/kg (1600 mg) Pyrazinamide 40-55 kg: 18.2- Hepatotoxicity, GI symptoms, Limited data; Routine measurement of uric acid not 25.0 mg/kg (1000 mg) polyarthralgia, asymptomatic probably safe recommended 56-75 kg: 20.0- hyperuricemia, gout, rash, 26.8 mg/kg (1500 mg) dermatitis 76-90 kg: 22.2- 26.3 mg/kg (2000 mg) Second-line medications Cycloserine 10-15 mg/kg Dose-related psychosis, seizures, Crosses Use with pyridoxine for prevention and treat- (1.0 g in 2 doses) depression, and headache placenta; ment of adverse neurotoxic effects; measure may be used serum concentration and perform periodic if necessary renal, hepatic, and hematologic tests

Ethionamide 15-20 mg/kg GI effects, including metallic taste; Contraindicated Perform liver function tests, measure (1.0 g/d in 1 or 2 neurotoxicity, including peripheral thyroid-stimulating hormone monthly divided doses) and optic neuritis; endocrine effects, including hypothyroidism, gynecomastia, alopecia, and impotence; and hepatoxicity Levofloxacinb 500-1000 mg GI upset, dizziness, tremulousness, Avoid Should not be administered within 2 h of insomnia, rash, photosensitivity, antacids and other medications containing QT prolongation divalent cations Moxifloxacin/ 400 mg GI upset, dizziness, tremulousness, Avoid Should not be administered within 2 h of gatifloxacinb insomnia, rash, photosensitivity, antacids and other medications containing QT prolongation divalent cations

p-Amino- 8-12 g in 2 or 3 doses Hepatitis, often severe GI intolerance, Has been used Perform liver function and thyroid function salicylic acid malabsorption syndrome, safely tests hypothyroidism, and coagulopathy

Streptomycin 15 mg/kg/d (1 g); in Ototoxicity, neurotoxicity Contraindicated Perform audiography, vestibular testing, and those >59 y, 10 mg/kg (weakness, circumoral paresthesia), Romberg testing; measure serum creatinine (750 mg) nephrotoxicity levels; monitor serum drug concentration

Amikacin/ 15 mg/kg/d (1 g); in Ototoxicity, nephrotoxicity Contraindicated Perform audiography, vestibular testing, and kanamycinb those >59 y, 10 mg/kg Romberg testing; measure serum creatinine (750 mg) levels; monitor serum drug concentration

Capreomycin 15 mg/kg/d (1 g); in Ototoxicity, nephrotoxicity Avoid Perform audiography, Romberg testing, and those >59 y, 10 mg/kg vestibular testing; measure serum creatinine, (750 mg) potassium, and magnesium levels; monitor serum drug concentration a GI = gastrointestinal; HIV = human immunodeficiency virus.b Not approved by the Food and Drug Administration for treatment of tuberculosis.


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Follow-up chest radiography after 2 months and at the completion of treatment is optional. Expert consultation should be sought for the management of patients who de-velop substantial adverse effects and require alternative treatment regimens.100-103

TREATMENT IN SPECIAL SITUATIONS

INFECTION WITH HIVIn general, the treatment of LTBI and TB in HIV-infected adults is the same as in adults not infected with HIV, with a few exceptions. Treatment for TB can be complicated by the interaction between rifamycins, antiretroviral agents, and other anti-infective drugs prescribed for opportunistic infections. In persons receiving antiretroviral therapy, RIF should be avoided or used with caution. Rifabutin, which has fewer problematic drug interactions, may be substitut-ed for RIF. During the continuation phase of treatment, the INH-rifapentine regimen should never be used because of the high relapse rate. Concurrent initiation of anti-TB and antiretroviral therapy may cause increased adverse effects and para-doxical reactions in patients not already receiving treat-ment. The term

is used to describe this paradoxical reaction, which presents as worsening clinical (eg, high fever, weight

loss, increased lymphadenopathy) and radiographic (eg, increased pulmonary infiltrates) manifestations of TB resulting from the immune reconstitution achieved by an-tiretroviral therapy.104-107 The mechanism for these para-doxical reactions is unclear but appears to be immune me-diated: lower CD4 counts in patients with HIV infection seem to be associated with a higher risk of developing immune reconstitution inflammatory syndrome.104,108 For these reasons, antiretroviral therapy should be delayed for 2 to 8 weeks after starting anti-TB therapy.109 Treatment of HIV-related TB is complex and is best managed by those with expertise in both HIV infection and TB.

EXTRAPULMONARY TBThe same basic principles for the treatment of pulmonary TB apply to extrapulmonary TB. For TB at any site, a treat-ment course of 6 to 9 months with regimens that include INH and RIF is recommended; the single exception is men-ingitis, for which 9 to 12 months of treatment is recom-mended. The addition of corticosteroids to anti-TB treat-ment is recommended for patients with TB of the pericar-dium and central nervous system, including the meninges.

PREGNANCY AND BREAST-FEEDING

For the treatment of TB in pregnant women, the initial regi-men should be INH, RIF, and EMB for at least 9 months.

TABLE 6. Treatment Regimens for Drug-Susceptible Pulmonary Tuberculosis

Initial phase Continuation phase

Regimen Drugs Interval and doses (duration) Regimen Drugs Interval and doses (duration)

1 Isoniazid 7 d/wk for 56 doses (8 wk) or 1a Isoniazid 7 d/wk for 126 doses (18 wk) or Rifampin 5 d/wk for 40 doses (8 wk) Rifampin 5 d/wk for 90 doses (18 wk) Pyrazinamide Ethambutola

1b Isoniazid Twice weekly for 36 doses (18 wk) Rifampin 1c Isoniazid Once weekly for 18 doses (18 wk) Rifapentine 2 Isoniazid 7 d/wk for 14 doses (2 wk), 2a Isoniazid Twice weekly for 36 doses (18 wk) Rifampin then twice weekly for 12 doses (6 wk); or Rifampin Pyrazinamide 5 d/wk for 10 doses (2 wk), Ethambutola then twice weekly for 12 doses (6 wk) 2b Isoniazid Once weekly for 18 doses (18 wk) Rifapentine 3 Isoniazid 3 times weekly for 24 doses (8 wk) 3a Isoniazid 3 times weekly for 54 doses (18 wk) Rifampin Rifampin Pyrazinamide Ethambutola 4 Isoniazid 7 d/wk for 56 doses (8 wk); or 4a Isoniazid 7 d/wk for 217 doses (31 wk); or Rifampin 5 d/wk for 40 doses (8 wk) Rifampin 5 d/wk for 155 doses (31 wk) Ethambutola 4b Isoniazid Twice weekly for 62 doses (31 wk) Rifampin

a Ethambutol need not be included when the organism is known to be fully susceptible.Data from .68


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Although teratogenicity data for PZA are limited, it is probably safe to use in pregnancy. Breast-feeding should not be discouraged for women receiving anti-TB treat-ment. Pyridoxine supplementation (25 mg/d) is recom-mended for all pregnant and breast-feeding women taking INH.

DRUG-RESISTANT TBTreatment of drug-resistant TB (resistance of the organ-ism to 1 first-line drug) has become even more complex, difficult, and expensive with the emergence of MDR-TB and XDR-TB. Patients with drug-resistant TB may acquire further drug resistance and are at high risk of treatment failure.110,111 These patients should receive prompt expert consultation. General guidelines for treating patients with drug-resistant TB include using multiple (4-6) drugs, in-cluding an injectable agent to which the organism is sus-ceptible. Treatment includes second-line drugs that have many adverse effects and are more expensive and less effective than first-line drugs. Careful supervision under DOT is mandatory to ensure adherence to therapy. Treat-ment is extended to 24 months after culture conversion, with posttreatment follow-up for 24 months. Case series reveal a possible role for surgical therapy in select cases of MDR-TB and XDR-TB.112

CONTROL AND ELIMINATION

Active TB is frequently treated in the outpatient setting. Patients with active TB should be managed in conjunction with local public health offices and TB control agencies to coordinate visits and maximize adherence. When ac-tive TB is suspected, patients should wear a simple sur-gical mask when they are out of the house or near other people. Initial treatment in the hospital may be appropriate for patients who are acutely ill, those with substantial comorbid illness, or infectious patients who are nonad-herent to therapy.68 These patients should be admitted to a negative-pressure isolation room with at least 6 air ex-changes per hour.3 Health care professionals should wear a fit-tested N95 mask; those who have not been fit-tested or are unable to use an N95 mask should use a powered air-purifying respirator. Simple surgical masks are more effective than N95 masks at preventing extrusion of respi-ratory droplets; therefore, patients with TB should wear a simple surgical mask when they are not in their isola-tion room. Patients may be removed from isolation when clinical improvement is seen on effective therapy and when 3 consecutive sputum samples on separate days are AFB smear–negative.3 If patients with active pulmonary TB are medically stable for discharge but are not yet AFB

smear–negative, they may be discharged only if a defini-tive plan for outpatient therapy has been coordinated with the local TB control agency, if no children younger than 4 years or no immunocompromised persons live with them, and if they agree to leave their home only for medical appointments.3 The preferred mechanism of therapy for both inpatients and outpatients is DOT.113,114

Treatment of patients with active TB is the top public health priority for TB control, followed by contact inves-tigation of all persons who came into close contact with these patients before initiation of therapy. Such contact in-vestigation should be carried out on all patients with con-firmed active pulmonary TB and on selected patients with suspected pulmonary TB before testing is complete.115 Pa-tients with extrapulmonary TB are generally not infectious; therefore, contact investigation is not indicated. The third priority for TB elimination and control is to reduce the population-based burden of LTBI through tar-geted testing and treatment. This strategy is particularly im-portant in low-incidence nations, where most TB cases arise from reactivation of LTBI. In high-incidence, resource-poor settings, this strategy is rarely feasible. Testing for LTBI is indicated to detect patients at risk of new infection or at risk of reactivation of LTBI due to underlying medical condi-tions. Persons at risk of new infection include contacts of patients with active pulmonary TB, employees at facilities with a high risk of exposure (eg, prisons, health care facili-ties, homeless shelters), and those who have recently immi-grated (ie, within the past 5 years) from regions of the world where TB is endemic. Persons at highest risk of reactiva-tion include those taking immunosuppressive medications (ie, chemotherapy, tumor necrosis factor α inhibitors) and those with HIV infection, hematologic malignancy, silicosis, dialysis-dependent renal failure, or changes on chest radiog-raphy consistent with previous TB.76

CONCLUSION

Tuberculosis remains a devastating disease throughout the world. Efforts to eradicate it have been thwarted by pover-ty, lack of health care access, drug resistance, immunosup-pressed populations (eg, HIV-infected persons), and global migration. Effective management requires prompt recog-nition using a combination of clinical, radiographic, mi-crobiological, and histopathologic hallmarks and initiation of appropriate multidrug therapy. In addition to effective treatment of patients with active TB, public health man-agement strategies include contact investigation and testing of persons who came into close contact with patients with active TB before initiation of therapy and reduction of the population-based burden of LTBI through targeted testing and treatment.


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99. Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoni-azid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a ran-domised clinical trial. . 2002;360:528-534. 100. Francis J. Curry National Tuberculosis Center. http://www.nationaltbcenter .edu. Accessed February 22, 2011. 101. Heartland National Tuberculosis Center. http://www.heartlandntbc.org/. Accessed February 22, 2011. 102. New Jersey Medical School Global Tuberculosis Institute. http://www .umdnj.edu/globaltb/home.htm. Accessed February 22, 2011. 103. Southeastern National Tuberculosis Center. http://sntc.medicine.ufl.edu/. Accessed February 22, 2011. 104. Murdoch DM, Venter WD, Feldman C, Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. . 2008;22(5):601-610. 105. French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active an-tiretroviral therapy. . 2000;1(2):107-115. 106. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsen-ing of tuberculosis following antiretroviral therapy in patients with AIDS.

. 1998;158:157-161. 107. Wendel KA, Alwood KS, Gachuhi R, Chaisson RE, Bishai WR, Ster-ling TR. Paradoxical worsening of tuberculosis in HIV-infected persons. . 2001;120:193-197. 108. Manabe YC, Campbell JD, Sydnor E, Moore RD. Immune reconstitu-tion inflammatory syndrome: risk factors and treatment implications.

. 2007;46(4):456-462.

The Symposium on Antimicrobial Therapy will continue in the May issue.



109. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the In - fectious Diseases Society of America. 2009;58(RR-4): 1-207. 110. Shah NS, Pratt R, Armstrong L, Robison V, Castro KG, Cegielski JP. Extensively drug-resistant tuberculosis in the United States, 1993-2007.

. 2008;300:2153-2160. 111. Kwon YS, Kim YH, Suh GY, et al. Treatment outcomes for HIV-unin-fected patients with multidrug-resistant and extensively drug-resistant tubercu-losis. . 2008;47:496-502. 112. Kang MW, Kim HK, Choi YS, et al. Surgical treatment for multidrug-resistant and extensive drug-resistant tuberculosis. . 2010; 89:1597-1602. 113. Weis SE, Slocum PC, Blais FX, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis.

. 1994;330:1179-1184. 114. Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis: consensus statement of the Public Health Tuberculosis Guidelines Panel [published correction appears in . 1998;280(2):134]. . 1998;279(12):943-948. 115. National Tuberculosis Controllers Association; Centers for Disease Controll and Prevention (CDC). Guidelines for the investigation of contacts of persons with infectious tuberculosis: recommendations from the Nation-al Tuberculosis Controllers Association and CDC. . 2005;54(RR-15):1-47.

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ANTIPARASITIC THERAPY



From the Division of Infectious Diseases and Geographic Medicine (S.K., U.S., B.G.B.), Department of Internal Medicine (S.K., U.S., B.G.B.), and Center for Primary Care and Outcomes Research (S.K.), Stanford University School of Medicine, Stanford, CA.

Dr Kappagoda was supported in part by grant HS000028 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality.

Address correspondence to Brian G. Blackburn, MD, Stanford University School of Medicine, Division of Infectious Diseases and Geographic Medicine, 300 Pasteur Dr, Grant Bldg, Room S-101, Stanford, CA 94305-5107 (blackburn @stanford.edu). Individual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com.


Shanthi Kappagoda, MD, SM; Upinder Singh, MD; and Brian G. Blackburn, MD

Antiparasitic Therapy

Parasitic diseases cause substantial morbidity and mor-tality worldwide, taking the heaviest toll among the

world’s poorest people. This article reviews the treat-ment of the major protozoan and helminth infections in humans.

PROTOZOA AND THE DISEASES THEY CAUSE

Protozoa are single-celled eukaryotes that cause a diverse array of human diseases. They are generally categorized as systemic or intestinal and usually do not cause eosinophilia.

SYSTEMIC PROTOZOA

Malaria. Human malaria is caused by the mosquito-borne parasites

, and which parasitize red blood cells

and cause hemolytic anemia. Malaria kills nearly 1 mil-lion people and causes almost 300 million symptomatic illnesses annually. It is found in sub-Saharan Africa, Asia, Oceania, and Latin America. Uncomplicated malaria can manifest as fever, anemia, thrombocytopenia, myalgias, cough, and diarrhea. Severe malaria is defined in part by

Parasitic diseases affect more than 2 billion people globally and cause substantial morbidity and mortality, particularly among the world’s poorest people. This overview focuses on the treatment of the major protozoan and helminth infections in humans. Recent developments in antiparasitic therapy include the expansion of artemisinin-based therapies for malaria, new drugs for soil-trans-mitted helminths and intestinal protozoa, expansion of the indi-cations for antiparasitic drug treatment in patients with Chagas disease, and the use of combination therapy for leishmaniasis and human African trypanosomiasis.

Mayo Clin Proc. 2011;86(6):561-583

AL = artemether-lumefantrine; CBC = complete blood cell count; CL = cutaneous leishmaniasis; CNS = central nervous system; DEC = diethyl-carbamazine; G6PD = glucose-6-phosphate dehydrogenase; HAT = hu-man African trypanosomiasis; HIV = human immunodeficiency virus; LF = lymphatic filariasis; ML = mucocutaneous leishmaniasis; NCC = neurocysticercosis; STH = soil-transmitted helminth; TMP-SMX = trimethoprim-sulfamethoxazole; VL = visceral leishmaniasis; VLM = vis-ceral larva migrans

respiratory distress, renal failure, altered mental status or seizures, intolerance of oral medications, metabolic acido-sis or hypoglycemia, and parasitemia greater than 5%. The mortality rate of severe malaria is high. Treatment of Uncomplicated P falciparum Malaria. The preferred treatment for uncomplicated malaria acquired in areas with chloroquine resistance is atovaquone-proguanil, artemether-lumefantrine (AL), or oral quinine plus doxycycline.1

Atovaquone-proguanil is a well-tolerated, oral fixed-dose combination. Atovaquone inhibits parasite mito-chondrial electron transport. Proguanil inhibits the dihy-drofolate reductase step in purine synthesis and lowers the concentration of atovaquone necessary to kill species. Adverse effects include nausea, vomiting, abdomi-nal pain, and hepatitis. Artemether-lumefantrine is an oral fixed-dose combina-tion recently approved in the United States. Artemether is a semisynthetic derivative of artemisinin, a sesquiterpene lactone. Lumefantrine, a fluorene derivative, may interfere with heme metabolism. Artemether-lumefantrine is rapidly effective against all erythrocytic stages of malaria. Adverse effects include nausea, vomiting, dizziness, headache, and possibly QT prolongation.2 It should be taken with fatty foods to increase absorption. Oral quinine plus doxycycline (or plus tetracycline or clindamycin) is effective for uncomplicated malaria. Qui-nine is an aryl-amino alcohol, which may cause toxic heme accumulation in the parasite. It can cause cinchonism (nau-

562



sea, vomiting, tinnitus, high-frequency hearing loss, and dizziness). Both tetracyclines and clindamycin inhibit ex-pression of the apicoplast genome. Adverse effects include nausea, vomiting, abdominal pain, can-didiasis, and photosensitivity for doxycycline and nausea, vomiting, abdominal pain, and diarrhea for clindamycin. Mefloquine, an aryl-amino quinoline, has the same mechanism of action as quinine. Due to resistance, it is not recommended for patients infected in much of Southeast Asia. It can cause neuropsychiatric disturbances and QT prolongation at treatment doses and is a second-line agent. Chloroquine is recommended for uncomplicated

malaria acquired in areas without chloroquine re-sistance. It is a 4-aminoquinoline and may act by disrupting heme metabolism. Adverse effects include nausea, vomit-ing, diarrhea, headache, and blurred vision. Pruritis also occurs, mostly in African patients. Hydroxychloroquine is an acceptable alternative.1

Treatment of Severe Malaria. Severe malaria (usually caused by ) should be treated with parenteral medications, such as intravenous artesunate, quinine, or quinidine. Artesunate is preferred because it works faster, is more effective, and is better tolerated than quinine.3,4 In the United States, artesunate is available from the Centers for Disease Control and Prevention for severe malaria in patients who meet certain criteria.5 Artesunate is combined with atovaquone-proguanil, doxycycline, clindamycin, or mefloquine to prevent recurrent parasitemia.3 Artesunate is well tolerated, with adverse effects similar to artemether. At high doses, it may cause neutropenia.6

Quinidine gluconate, which has the same mechanism of action as quinine, is available for severe malaria in the United States. Patients should be monitored with telemetry and have blood glucose and drug levels followed up closely. Adverse effects include infusion-related hypotension, QT prolongation, torsades de pointes, and hypoglycemia. Al-though less cardiotoxic than quinidine, parenteral quinine is not available in the United States. It can cause infusion-related hypotension, hypoglycemia, and cinchonism. Both quinine and quinidine should be combined with doxycy-cline, tetracycline, or clindamycin, and patients can transi-tion to oral therapy after improvement. Treatment of Uncomplicated Non-falciparum Ma-laria. Chloroquine plus primaquine is effective for uncom-plicated P vivax and malaria in most of the world. Patients infected in areas with chloroquine-resistant P vivax and (particularly Papua New Guinea and Indonesia) should be treated with atovaquone-proguanil, mefloquine, or quinine plus doxycycline. Patients infected with P vivax or

should receive primaquine (an 8-aminoquinolone) for 14 days to prevent relapse. Because primaquine can cause hemolytic anemia in glucose-6-phosphate dehydro-

genase (G6PD)–deficient patients, G6PD levels should be measured before use. Other adverse effects include nausea and vomiting. or infections can usu-ally be treated with chloroquine.1,7

Resistance. Chloroquine resistance is widespread. Due to resistance, mefloquine is not recommended for malaria acquired in much of Southeast Asia. Parts of South America and equatorial Africa also have high mefloquine treatment failure rates.8 Atovaquone-proguanil–resistant

is rare. The World Health Organization recommends that artemisinins be used exclusively in combination regi-mens, but strains of with decreased sensitiv-ity to artemisinins have emerged along the border between Cambodia and Thailand, in part because of long-standing monotherapy practices.9 Of 22 African countries, 2 (Ghana and Burkina Faso) had failures in more than 10% of

cases treated with AL in one study.8 Treatment failure rates with AL of more than 20% have occurred only in Cam-bodia.8 Chloroquine-resistant P vivax occurs primarily in Southeast Asia and Oceania, but cases have been reported in South America, Ethiopia, and the Solomon Islands. P vivax treatment failure rates of more than 10% with AL have oc-curred in Papua New Guinea.8 The Worldwide Antimalarial Resistance Network has developed an online database of malaria resistance.10

Treatment regimens for all types of malaria are summa-rized in Table 1. New Developments. Arterolane, a synthetic trioxolane derived from artemisinins, is undergoing phase 3 clinical trials in combination with piperaquine for malaria.11 In 2 recent clinical trials, both once-daily py-ronaridine-artesunate and azithromycin plus artesunate were noninferior to AL for malaria.12,13

African Trypanosomiasis. Human African trypanoso-miasis (HAT, or sleeping sickness) is caused by 2 subspe-cies of that are endemic only to Africa and transmitted by tsetse flies. In the United States, only 1 or 2 cases occur annually (among returning travelers). T

causes a rapidly progressive disease in Eastern and Southern Africa, whereas causes a more indolent disease in West and Central Africa. Initially, patients develop fever, lymphadenopathy, hepa-tosplenomegaly, and rash. Later, a chronic meningoen-cephalitis occurs with headaches, listlessness, disordered sleep, and neuromuscular dysfunction. Drugs for HAT are toxic; however, left untreated, the disease is fatal. T b gambiense. Pentamidine and suramin are available for early-stage disease. Neither drug crosses the blood-brain barrier, and for late-stage (central nervous system [CNS]) disease, eflornithine and melarsoprol are used (Table 1).

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TABLE 1. Treatment Regimens for Protozoal Infections in Adultsa

Additional Medication Dose Adverse effects information

First-line treatment ………………………………………………………………………………………………………… Second-line treatment

Systemic protozoa Malaria—uncomplicated or species unknown

Chloroquine-resistant Atovaquone-proguanil 250 mg/100 mg, 4 adult tablets Nausea, vomiting, Should be taken area (everywhere orally every day for 3 d hepatitis with food except Central America OR Artemether-lumefantrine 20 mg/120 mg, 4 tablets oral starting Headache, dizziness, Should be taken west of Panama Canal, dose, followed by 4 tablets orally vomiting with fatty Haiti, Dominican 8 h later, followed by 4 tablets foods Republic, and parts orally twice a day for 2 d of the Middle East) OR Quinineb 625 mg salt orally 3 times a day for Cinchonism,c hypo- 7 d for patients infected in Southeast glycemia Asia or for 3 d in other patients Doxycycline 100 mg orally twice a day Nausea, vomiting, or Tetracycline 250 mg orally 4 times a day abdominal pain, candidiasis, photosensitivity or Clindamycin 6-7 mg /kg orally 3 times a day Nausea, vomiting, for 7 d diarrhea, abdominal pain ………………………………………………………………………………………………………… Mefloquineb 750 mg salt oral loading dose Nausea, vomiting, vivid followed by 500 mg salt orally dreams, dysphoria, 6-12 h after initial dose mood changes, QT prolongation

Chloroquine-sensitive Chloroquineb 1000 mg salt oral loading dose Nausea, vomiting, area (Central America followed by 500 mg salt orally headache, dizziness, west of Panama Canal, at 6 h, 24 h, and 48 h pruritis (usually in Haiti, Dominican African patients), Republic, and parts photosensitivity of the Middle East) ………………………………………………………………………………………………………… Hydroxychloroquineb 800 mg salt oral loading dose followed Retinal toxicity unlikely by 400 mg salt orally at 6 h, with short-term use 24 h, and 48 h

Malaria—severe Artesunate per CDC protocol 2.4 mg/kg IV at 0 h, 12 h, 24 h, and Can be requested Usually 48 h, then once per day if IV from CDC still necessary Malaria Hotlined Atovaquone-proguanil, doxycycline, clindamycin, or mefloquine ………………………………………………………………………………………………………… Quinidineb Loading dose of 10 mg/kg salt IV Infusion-related hypo- Continuous ECG over 1-2 h followed by 0.02 mg/kg/min tension, QT and QRS and close BP and salt continuous infusion for 24 h prolongation, arrhyth- blood glucose mias, hypoglycemia monitoring mandatory Once improved, switch 625 mg salt orally 3 times a day to oral quinine Doxycycline 100 mg IV/orally twice daily for 7 d or Tetracycline 250 mg orally 4 times daily for 7 d or Clindamycin 10 mg/kg IV loading dose then 5 mg/kg IV every 8 h (or oral dose as above) for 7 d Total duration of quinidine/quinine therapy is 7 d for patients infected in Southeast Asia, 3 d for elsewhere

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Systemic protozoa Malaria—uncomplicated Chloroquine See P or Followed by primaquineb 52.6 mg salt orally every day for 14 d Nausea and vomiting,

hemolytic anemia with All regions except G6PD deficiency Papua New Guinea and ………………………………………………………………………………………………………… Indonesia (or other Hydroxychloroquine See P areas with documented Followed by primaquine chloroquine resistance)

Malaria—uncomplicated Quinine See P P vivax or Doxycycline, Chloroquine-resistant tetracycline, or areas (Papua New clindamycin Guinea and Indonesia) Followed by primaquine or Atovaquone-proguanil See P Followed by primaquine ………………………………………………………………………………………………………… Mefloquine See P Followed by primaquine Malaria—uncomplicated Chloroquine See P or or Hydroxychloroquine

African trypanosomiasis Pentamidine 4 mg/kg/d IM for 7-10 d Hypotension (with IV Early (hemolymphatic infusion), hypo- stage) glycemia, hepatitis,

pancreatitis, leukopenia, sterile abscesses, nephrotoxicity ………………………………………………………………………………………………………… Suramin 100-200 mg IV (test dose) followed Nephrotoxicity, rash Available from CDC by 1 g IV on days 1, 3, 7, 14, and 21 (including exfoliative Drug Servicee

dermatitis), fatal hypersensitivity reaction (1 in 20,000 doses), peripheral neuropathy, myelosuppression

Suramin Dosed as above Late (CNS stage) Eflornithine 100 mg/kg IV every 6 h for 14 d Fever, seizures, myelo- Given as prolonged suppression, peripheral infusion. Contact neuropathy, diarrhea, CDC Drug Service or Eflornithine 200 mg/kg IV every 12 h for 7 d hypertension, rash regarding avail- abilitye Nifurtimox 5 mg/kg orally 3 times a day for 10 d Nausea, vomiting, Available from CDC anorexia, abdominal Drug Servicee pain, insomnia, peripheral neuropathy, hepatitis. Avoid alcohol ………………………………………………………………………………………………………… Melarsoprol 2.2 mg/kg/d IV for 10 d Vomiting, nephrotoxicity, Available from CDC hepatitis, myocardial Drug Servicee

damage, peripheral neuropathy, fever, thrombocytopenia, reactive encephalopathy (often fatal). Encephalopathy risk reduced by coadministration of corticosteroids. Contraindicated with G6PD deficiency

TABLE 1. Continueda



565



Systemic protozoa Melarsoprol 2.0-3.6 mg/kg/d IV for 3 d. Repeat Available from CDC

course after 7 d and then again 7 d Drug Servicee

after the completion of the 2nd course

American trypanosomiasis Benznidazole 2.5-3.5 mg/kg orally twice a day Nausea, vomiting, Contact CDC Drug (Chagas disease) for 60 d anorexia, insomnia, Servicee regarding peripheral neuropathy, availability dermatitis, myelo- Should be taken suppression. with food Disulfiram-like reaction with alcohol ………………………………………………………………………………………………………… Nifurtimox 2-3 mg/kg orally every 6-8 h for 90 d Should be taken after meals Available from CDC Drug Servicee

Leishmaniasis Visceral Liposomal amphotericin Immunocompetent adults: Nephrotoxicity, Multiple regimens 3 mg/kg IV once a day on days electrolyte wasting, used, including 1-5, 14, and 21 hypertension, infusion shorter-course Immunocompromised adults: reaction, chills/rigors amphotericin-based 4 mg/kg IV once a day on days regimens and 1-5, 10, 17, 24, 31, and 38 combination regimens ………………………………………………………………………………………………………… Sodium stibogluconate 20 mg/kg IV or IM once a day for 28 d or Miltefosine 2.5 mg/kg/d (maximum 150 mg/d) Nausea, vomiting, Not commercially orally for 28 d severe vertigo, available in the headache, diarrhea US; contact Caligor Rx, Inc, for availabilityf

or Paromomycin 15 mg/kg/d IM for 21 d Nephrotoxicity, ototoxicity, hepatitis

Cutaneous Sodium stibogluconate 20 mg/kg/d IV or IM for 20 d Pentavalent antimonials: Available from CDC nausea, vomiting, Drug Servicee

abdominal pain, Decision whether to pancreatitis, hepatitis, use systemic ther- myalgias, myelo- apy for cutaneous suppression, ECG leishmaniasis is abnormalities complex. When used, most appropriate drug depends in part on infecting species and region acquired ………………………………………………………………………………………………………… Miltefosine 2.5 mg/kg/d (maximum 150 mg/d) orally for 28 d or Fluconazole 200 mg orally once a day for 6 wk Headache, anorexia, hepatitis, alopecia or Liposomal amphotericin 3 mg/kg IV once a day on days 1-5, Optimal dosing reg- 14, and 21 imen not defined or Pentamidine 2-3 mg/kg IV or IM once a day or every other day for 4-7 d

TABLE 1. Continueda



566



Systemic protozoa ( ) Mucocutaneous Sodium stibogluconate 20 mg/kg/d IV or IM for 28 d ………………………………………………………………………………………………………… Liposomal amphotericin 3 mg/kg IV once a day Multiple regimens or Amphotericin deoxycholate 0.5-1.0 mg/kg IV once a day for 1 mo used or Miltefosine 2.5 mg/kg (maximum 150 mg/d) orally once a day for 28 d

Babesiosis Atovaquone 750 mg orally twice a day Rash, abdominal Higher doses, pain, diarrhea, longer duration of nausea, vomiting, therapy for headache, insomnia, immunosuppressed methemoglobinemia, patients (see text) hepatotoxicity Azithromycin 500 mg orally for 1 d then 250 mg Nausea, vomiting, orally once a day for 7-10 d abdominal pain, diarrhea, headache, hepatotoxicity ………………………………………………………………………………………………………… Quinine 650 mg orally 3 times a day Clindamycin 300-600 mg IV every 6 h or 600 mg orally 3 times a day for 7-10 d

Toxoplasmosis Pyrimethamine 200 mg orally once followed by Myelosuppression, No treatment for 50 mg (if <60 kg) or 75 mg abdominal pain, rash, acute illness in (if >60 kg) orally once a day headaches, dysgeusia nonpregnant/ immunocompetent patients Sulfadiazine 1 g/kg (if <60 kg) or 1.5 g/kg Myelosuppression, Duration of therapy (if >60 kg) orally 4 times a day rash, crystal-induced based on nephropathy clinical situation Folinic acid 10-25 mg orally once a day ………………………………………………………………………………………………………… TMP-SMX 5/25 mg/kg orally or IV every 12 h Rash, urticaria, nausea, Consider Higher doses have been used in vomiting, myelo- concomitant some cases suppression. Rarely: systemic Stevens-Johnson corticosteroids for syndrome, renal chorioretinitis insufficiency, hyper- kalemia, hepatitis For patients with sulfa allergy: Pyrimethamine Folinic acid Doses as above Clindamycin 600 mg IV every 6 h or 450 mg orally 4 times a day or Atovaquone 750 mg orally every 6 h

Acquired Consider spiramycin Spiramycin: nausea, Commercially during pregnancy or Pyrimethamine/sulfadiazine abdominal pain, unavailable depending on clinical situation diarrhea in the US but can and gestational age (see text) be obtained from Suggest expert consultation PAMF-TSLg

(see box to right)

Congenital Consider prolonged University of pyrimethamine/sulfadiazine Chicago Congenital Suggest expert consultation Toxoplasmosis (see box to right) Study Group may be able to provide clinical guidanceh

TABLE 1. Continueda



567



Intestinal/genitourinary protozoa Giardiasis Tinidazole 2 g orally once Anorexia, metallic taste, or Metronidazole 250 mg orally 3 times a day for 5-7 d alcohol-induced disulfiram-like reaction, headache, peripheral neuropathy, seizures, neutropenia ………………………………………………………………………………………………………… Nitazoxanide 500 mg orally twice a day for 3 d Nausea, vomiting, abdominal pain, diarrhea

Amebiasis ( ) Asymptomatic carrier Luminal agent: Paromomycin 8-12 mg/kg orally 3 times a day Nausea, vomiting, for 7 d abdominal pain or Iodoquinol 650 mg orally 3 times a day for 20 d Nausea, vomiting, diarrhea, pruritis, headache ………………………………………………………………………………………………………… Diloxanide 500 mg orally 3 times a day for 10 d Commercially unavailable in the US but may be available through Abbott India Ltdi Amebic colitis Metronidazole 500-750 mg orally 3 times a day for 10 d or Tinidazole 2 g orally once a day for 3 d Followed by luminal agent (see above)

Amebic liver abscess or Metronidazole 750 mg orally or IV 3 times daily Length of metroni- other disseminated or Tinidazole 2 g orally once a day dazole or tinida- disease Followed by luminal agent zole component of (see above) therapy often based on clinical response

Cryptosporidiosis Non–AIDS-associated Nitazoxanide 500 mg orally twice a day for 3 d AIDS-associated HAART Consider nitazoxanide Cyclosporiasis Non–AIDS-associated TMP-SMX 1 DS tablet orally twice a day for 7-10 d AIDS-associated TMP-SMX 1 DS tablet orally 4 times a day for 10 d followed by twice a day for 3 wk ………………………………………………………………………………………………………… Ciprofloxacin 500 mg orally twice a day for 7 d Nausea, vomiting, followed by 1 tablet orally 3 times abdominal pain. Rarely: a week for 2 wk tendinopathy, neuropsychiatric effects

Isosporiasis Non–AIDS-associated TMP-SMX 1 DS tablet orally twice a day for 10 d AIDS-associated TMP-SMX 1 DS tablet orally 4 times a day for 10 d followed by twice a day for 3 wk ………………………………………………………………………………………………………… Ciprofloxacin 500 mg orally twice a day for 7 d

Dientamoebiasis Iodoquinol 650 mg orally 3 times a day for 20 d

Nitazoxanide 500 mg orally twice a day for 3 d Treatment controversial

TABLE 1. Continueda



568



TTABLE 1. Continueda



Intestinal/genitourinary protozoa Trichomoniasis Tinidazole 2 g orally once Sexual partners should be treated ………………………………………………………………………………………………………… Metronidazole 2 g orally once or 500 mg orally twice a day for 7 d

Free-living amebae Therapy should include amphotericin B Consider intrathecal amphotericin Combination systemic therapy is essential: consider addition of azoles, rifampin, or other antimicrobial agents (see text)

species GAE and disseminated Combination therapy disease is essential and should include pentamidine, azoles, sulfonamides, and possibly flucytosine (see text)

keratitis Topical chlorhexidine 0.02% May be available Polyhexamethylene 0.02% via compounding biguanide pharmaciesj

Combination therapy is essential and should likely include flucytosine, pentamidine, fluconazole, sulfadiazine, macrolides (see text)

a BP = blood pressure; CDC = Centers for Disease Control and Prevention; CNS = central nervous system; DS = double-strength; ECG = electrocardiography; GAE = granulomatous amebic encephalitis; G6PD = glucose-6-phosphate dehydrogenase; HAART = highly active antiretroviral therapy; IM = intramuscular; IV = intravenous; TMP-SMX = trimethoprim-sulfamethoxazole; PAMF-TSL = Palo Alto Medical Foundation Toxoplasma Serology Laboratory; US = United States.

b Dosing conversion for base formulation dose based on salt formulation dose: oral quinine 625 mg salt = 542 mg base; IV quinidine 10 mg/kg salt = 6.25 mg/kg base and 0.02 mg/kg/min salt = 0.0125 mg/kg/min base; oral mefloquine 750 mg salt = 684 mg base, and 500 mg salt = 456 mg base; oral chloroquine 1000 mg salt = 600 base, and 500 mg salt = 300 mg base; oral hydroxychloroquine 800 mg salt = 620 mg base and 400 mg salt = 310 mg base; oral primaquine 52.6 mg salt = 30 mg base.

c Symptoms of cinchonism include nausea, vomiting, dizziness, tinnitus, and high-frequency hearing loss.d CDC Malaria Hotline (770-488-7788 M-F 9:00 am to 5:00 pm EST or 770-488-7100 other hours).e CDC Drug Service (404-639-3670).f Caligor Rx, Inc, New York, NY (212-369-6000 or for emergencies 917-692-0195).g PAMF-TSL (650-853-4828).h University of Chicago Congenital Toxoplasmosis Study Group (773-834-4152).i Diloxanide may be available from Abbott India Ltd, Mumbai, India (+91 22 67978888).j A compounding pharmacy that specializes in ophthalmic drugs is Leiter’s Park Avenue Pharmacy in San Jose, CA (800-292-6773).

Pentamidine, an aromatic diamidine, is preferred for early-stage disease. Pentamidine reduces the mitochondrial membrane potential and binds to nucleic acids. It is given intramuscularly and can cause hypotension, hypoglycemia, leukopenia, nephrotoxicity, hepatitis, and pancreatitis. Suramin, a sulfonated naphthylamine, inhibits multiple trypanosome metabolic enzymes. It is a second-line treat-ment for early-stage disease because of toxicity, including

exfoliative dermatitis, peripheral neuropathy, nephrotoxic-ity, myelosuppression, and a potentially fatal hypersensi-tivity reaction. Suramin is active against

and reactions (from dying parasites) can occur in coinfected patients.14

Eflornithine, which inhibits ornithine decarboxylase, is the preferred drug for late-stage disease. It is less toxic than melarsoprol but not reliably effective

569



against . Adverse reactions include fever, myelosuppression, hypertension, rash, peripheral neuropa-thy, and diarrhea. Melarsoprol, an organic arsenical agent, remains the most widely used drug against late-stage HAT despite be-ing the most toxic. Its mechanism of action is unknown. The most feared adverse effect is reactive encephalopathy, which occurs in 5% to 10% of patients and is fatal in half of cases.14 Coadministration of corticosteroids lowers the risk of encephalopathy.15 Other adverse effects include vomit-ing, abdominal pain, thrombophlebitis, peripheral neurop-athy, fever, and thrombocytopenia. Nifurtimox-eflornithine combination therapy was more effective than eflornithine monotherapy for late-stage

and enabled shorter treatment courses in 2 clini-cal trials.16 Another trial found that melarsoprol-nifurtimox combination therapy was more effective than melarsoprol alone.17 However, a subsequent study found that patients with late-stage disease who were treated with melarsoprol-nifurtimox had higher death rates than those treated with other combination regimens.18

T b rhodesiense. There is little new clinical evidence re-garding the treatment of . Suramin is used for early-stage disease, and melarsoprol is used for late-stage disease (Table 1).14

Resistance. Up to 30% of patients infected with do not respond to melarsoprol,19 and 6% to 8%

may receive no benefit from eflornithine in some regions.20 Suramin and melarsoprol resistance have occurred in clini-cal isolates of from Tanzania.21

Drugs in Development. Clinical trials with fexinida-zole, an oral 5-nitroimidazole active against and are under way.22

American Trypanosomiasis. American trypanoso-miasis (Chagas disease) is caused by , which is endemic only to Latin America and is usually transmitted by blood-feeding triatomine insects. Acute infection is often asymptomatic, but patients may have unilateral palpebral edema or an erythematous, indurated skin lesion with regional lymphadenopathy. Fever, diffuse lymphadenopathy, hepatosplenomegaly, and (less com-monly) meningoencephalitis and myocarditis may occur. Acute disease is generally self-limited. Most patients are subsequently asymptomatic (a state termed

). Years to decades later, 20% to 40% of cases prog-ress to chronic Chagas disease, which affects the heart (eg, cardiomyopathy, chronic heart failure, and arrhythmias) and the gastrointestinal tract (eg, achalasia, megaesopha-gus, constipation, obstruction, and megacolon). The nitroheterocyclic compounds nifurtimox and ben-znidazole are used to treat Chagas disease (Table 1). Ben-

znidazole is better tolerated and generally considered the drug of choice.23 Contraindications to treatment include pregnancy and renal and hepatic insufficiency. Nifurtimox is a 5-nitrofuran derivative; its mechanism of action is not well understood. Adverse effects include anorexia, abdominal pain, vomiting, insomnia, paresthe-sias, peripheral neuropathy, and hepatitis. Discontinuation due to intolerance is common.24 During therapy, clinicians should screen for peripheral neuropathy, monitor liver and renal function, and obtain a complete blood cell count (CBC). Benznidazole is a nitroimidazole derivative that may in-crease phagocytosis. Adverse effects include vomiting, an-orexia, dermatitis, and myelosuppression. Dose-dependent peripheral neuropathy, severe rash, fever, or lymphade-nopathy should prompt discontinuation. Clinicians should check for rash and monitor CBCs as well as liver and renal function test results during treatment. Although clinical evidence supporting treatment for Chagas disease is limited, most authorities recommend treatment for acute and congenital infections, infections in children, and reactivated infections in immunocompro-mised patients.23 The role of therapy in indeterminate and chronic Chagas disease in adults is more controversial, but evidence is emerging that select patients in these groups may benefit.25 Recent studies suggest that benznidazole for indeterminate or early chronic Chagas disease may im-prove parasite clearance rates26,27 and prevent progression to cardiomyopathy.28 A multicenter, placebo-controlled trial involving benznidazole for the treatment of chronic Chagas disease is under way.29

Resistance and Drugs in Development. Although strains of resistant to both nifurtimox and benznida-zole can be generated in vitro documentation of clinical resistance is scarce. Several new triazoles, squalene syn-thase inhibitors, and cysteine protease inhibitors have shown efficacy in animal models.25 A phase 2 clinical trial of posaconazole vs benznidazole for chronic Chagas dis-ease is under way.30

Leishmaniasis. species are transmitted pri-marily by sandflies and cause 3 clinical syndromes: vis-ceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and mucocutaneous leishmaniasis (ML). Visceral Leishmaniasis. Visceral leishmaniasis is caused predominantly by on the In-dian subcontinent and East Africa and by

elsewhere. Infection with these species re-sults in subclinical infection in most patients and kala-azar (fever, weight loss, hepatosplenomegaly, hyperglobuline-mia, neutropenia, and death) in a minority. Ninety percent of VL cases occur in India, Bangladesh, Nepal, Sudan, and

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Brazil. The drug of choice for VL in the United States is liposomal amphotericin (Table 1). Multiple dosing sched-ules and other treatment regimens are used globally. Liposomal amphotericin, a polyene, forms pores in cell membranes. In India, single-dose liposomal amphotericin was as effective as 29 days of amphotericin B deoxycholate in a recent trial.31 Amphotericin causes nephrotoxicity, electrolyte loss, fever, and rigors; however, these occur less frequently with liposomal formulations. Miltefosine, a synthetic phospholipid analogue and the only orally available drug for VL, causes apoptosis-like cell death. Cure rates appear similar to those obtained with amphotericin in India.32 Adverse effects include nausea, vomiting, vertigo, diarrhea, hepatitis, renal insufficiency, and teratogenicity. There is concern that monotherapy may lead to drug resistance.33

Pentavalent antimonial agents, such as sodium stibog-luconate, were previously the therapeutic choice for VL. Currently, resistance limits their use, especially in South Asia.34 Antimonial agents inhibit several parasitic en-zymes, but they are poorly tolerated. Adverse effects in-clude anorexia, vomiting, pancreatitis, hepatitis, myalgias, cytopenias, QT prolongation, and arrhythmias. Renal and liver function tests, CBCs, amylase/lipase measurements, and electrocardiography should be monitored during treat-ment. Response rates are variable and relapses common. Paromomycin, an aminoglycoside that inhibits metab-olism and mitochondrial respiration, is an alternative for VL. Paromomycin was noninferior to amphotericin in In-dia in a recent study.35 Adverse effects include ototoxicity, nephrotoxicity, and hepatotoxicity. Combination therapy for VL may shorten treatment du-ration, decrease toxicity, and prevent resistance.36 In Su-dan, paromomycin plus antimony was more effective than antimony alone.37 Single-dose liposomal amphotericin plus short-course miltefosine was effective and well tolerated in India, as was single-dose liposomal amphotericin plus short-course paromomycin and short-course miltefosine plus paromomycin.38

Cutaneous Leishmaniasis. Cutaneous leishmaniasis usually presents as nodular skin lesions that slowly enlarge and ulcerate. Ninety percent of CL cases occur in Afghani-stan, Pakistan, Syria, Saudi Arabia, Algeria, Iran, Brazil, and Peru. Because the lesions of CL usually heal sponta-neously, the decision to treat depends on lesion location and size, the region of acquisition and infecting species, the risk of progression to ML (limited to some New World CL infecting species), and patient preference. New World CL is commonly caused by

, , and When the decision is made to treat, antimonial agents

are usually used (Table 1). Combination therapy with al-

lopurinol or pentoxifylline plus antimonial agents may be more effective than antimonial agents alone.39 A 4-week course of miltefosine was as effective as antimonial agents in Colombia but less effective than antimonial agents in Guatemala.40 Pentamidine has been used for CL caused by

in French Guyana, Surinam, and Brazil but is toxic and less effective.41

Old World CL is caused mainly by or When sys-

temic treatment is deemed necessary, antimonial agents are usually used (Table 1). Fluconazole cured 79% of CL pa-tients in Saudi Arabia with at 3 months; however, a subsequent observational study showed no benefit from fluconazole.42,43 Miltefosine has been used successfully to treat Old World CL.44 Topical therapy, such as 15% paro-momycin-12% methylbenzethonium ointment and intra-lesional antimonial agents, may be an alternative treatment option for Old World CL. Imiquimod, a topical immuno-modulator, improved cure rates in Peru when given with parenteral antimonial agents45; however, no benefit was seen in a similar trial in Iran.46

Amphotericin (particularly liposomal formulations) has been used successfully in a growing number of CL patients infected in both the Old and New World. Infections caused by at least 5 different species have been suc-cessfully treated with liposomal amphotericin; however, experience remains limited, and the optimal dosing regi-men has not yet been determined.47

Mucocutaneous Leishmaniasis. Patients with CL caused by certain New World species (eg,

) can develop ML (ulcerative lesions in the nose, mouth, and pharynx). Mucocutaneous leishmaniasis is usually treat-ed with a 28-day course of antimonial therapy, but response rates are variable and relapses common (Table 1).33 Cure rates with antimonial agents plus pentoxifylline were higher than with antimonial agents alone in Brazil.48 Amphotericin and pentamidine have also been used. Oral miltefosine cured 83% of patients with mild ML and 58% with more extensive ML in Bolivia.49

Resistance. Resistance to pentavalent antimonial agents occurs in 40% to 60% of patients with VL in Bihar, India.34 Resistance has also been reported from Sudan.50

Drugs in Development. Sitamaquine (an oral 8-amino-quinoline) cured 50% to 90% of patients with VL in phase 2 trials. Adverse effects included nephrotoxicity and meth-emoglobinemia (with G6PD deficiency).51 Trials with azithromycin, amphotericin, miltefosine, and low-dose an-timonial agents for CL are ongoing. Babesiosis. is the most common cause of babesiosis. This predominantly tick-borne zoonosis is endemic to southern New England, New York, the north

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central American Midwest, and Europe. species parasitize red blood cells. Infections are commonly asymptomatic but can be associated with a mild to moderate febrile illness or fulminant hemolytic anemia (usually in patients with immunosuppression or splenectomy). Treat-ing asymptomatic, immunocompetent patients is gener-ally unnecessary unless parasitemia persists for 3 months or more.52 For mild to moderate illness, atovaquone plus azithromycin is as effective (and better tolerated) than the previous standard, oral quinine plus clindamycin (Table 1).53 Severe disease can be treated with a 7- to 10-day course of oral quinine plus intravenous clindamycin.52 Relapse is common in immunocompromised patients, and some authors recommend 6 or more weeks of therapy (including 2 weeks after blood smears are negative).54 Exchange transfusion is indicated for severe babesiosis (parasitemia of 10% or more; significant hemolysis; or renal, hepatic, or pulmonary compromise). Coinfection with Lyme disease or anaplasmosis should be considered in patients with babesiosis because the same tick trans-mits all 3 pathogens. Atovaquone monotherapy can induce resistance in ani-mal models, and resistance emerged during atovaquone and azithromycin treatment in 3 immunocompromised patients.55

Toxoplasmosis. Toxoplasmosis is most commonly ac-quired by consuming undercooked meat or other food or water containing cysts. After acute infec-tion, remains latent and persists for life. Although acute infection is usually asymptomatic, 10% to 20% of pa-tients develop lymphadenopathy or a self-limited mononu-cleosis-like syndrome. can also cause chorioretini-tis. Immunocompromised patients can develop toxoplasmic encephalitis (usually reactivation of latent disease) and, less commonly, disseminated disease. Toxoplasmosis acquired during pregnancy can cause spontaneous abortion, hydro-cephalus, intracranial calcifications, mental retardation, and seizures in the baby. Nonpregnant, immunocompetent patients with acute toxoplasmosis generally do not require antimicrobial therapy. For eye disease, treatment usually includes anti- agents plus systemic corticosteroids. Immunocompromised patients with toxoplasmosis should be treated with 2 antimicrobial agents. Pyrimethamine (the most effective anti- agent available) plus sulfadiazine (with folinic acid) is preferred (Table 1). Pyrimethamine inhibits dihydrofo-late reductase, depleting folate and impairing nucleic acid synthesis. Adverse effects include dose-dependent my-elosuppression (which can be ameliorated with concur-rent folinic acid), abdominal pain, rash, and headaches. Pyrimethamine is combined with sulfadiazine, another

folate antagonist. In addition to rash and myelosuppres-sion, sulfadiazine can cause crystal-induced nephropa-thy. Trimethoprim-sulfamethoxazole (TMP-SMX) has similar efficacy to pyrimethamine-sulfadiazine for toxo-plasmic encephalitis and chorioretinitis; however, unlike pyrimethamine-sulfadiazine, it is also available intrave-nously. 56,57 Pyrimethamine plus clindamycin is also effec-tive. If none of these drugs can be used, clarithromycin, azithromycin, atovaquone, and dapsone are alternatives. Toxoplasmosis During Pregnancy. In the United States, spiramycin is generally recommended for toxoplas-mosis acquired during pregnancy to reduce the risk of con-genital toxoplasmosis (Table 1),58 although its efficacy is controversial.59 Spiramycin, a macrolide that inhibits pro-tein synthesis, is well tolerated. Its main adverse effects are abdominal pain and diarrhea. When maternal infection oc-curs at 18 weeks of gestation or later, or fetal transmission is confirmed, pyrimethamine-sulfadiazine plus folinic acid is usually recommended. Congenitally infected infants are generally treated for 12 months with pyrimethamine-sulfa-diazine plus folinic acid (Table 1). New Developments. A clinical trial comparing spiramy-cin with pyrimethamine-sulfadiazine for the prevention of congenital toxoplasmosis in the babies of women infected at 14 weeks of gestation or later is under way.

INTESTINAL AND GENITOURINARY PROTOZOA

Giardiasis. (also called and ) infects the small intestine. It

is found worldwide and is a common cause of travelers’ di-arrhea and childhood diarrhea in areas with poor sanitation. Water-borne transmission is most common, followed by person-to-person and food-borne spread. Some infections are asymptomatic, but most cause diarrhea (often lasting several weeks). Abdominal cramps, bloating, flatulence, weight loss, lactose intolerance, and malabsorption with oily, foul-smelling stools can occur. Giardiasis can be treated with a single dose of tinida-zole (Table 1), which cures more than 90% of cases.60 This 5-nitroimidazole is converted into toxic radicals that dam-age DNA. Adverse effects include dysgeusia, nausea, ab-dominal discomfort, and alcohol-induced disulfiram-like reactions. Rarely, peripheral neuropathy, seizures, and neutropenia occur. Metronidazole, widely used to treat gi-ardiasis in the United States, has a similar mechanism of action and similar adverse effects; a 5- to 7-day course has slightly lower efficacy.60 Nitazoxanide, an oral nitrothiaz-olyl-salicylamide, appears to inhibit pyruvate:ferredoxin oxidoreductase. A 3-day course cures 80% to 85% of pa-tients.60,61 It is generally well tolerated but can cause nausea and vomiting. A recent meta-analysis found that albenda-

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zole had comparable efficacy and was better tolerated than metronidazole.62

Amebiasis. a protozoan transmit-ted by the fecal-oral route, is most common in tropical re-gions. Most infected persons remain asymptomatic, but 10% annually develop invasive disease that presents as nonbloody diarrhea or amebic dysentery. Most adults have gradually worsening diarrhea and abdominal pain; rare complica - tions include liver abscess, toxic megacolon, and ameboma. Asymptomatic persons infected with are treat-ed to prevent transmission and invasive disease (Table 1). For asymptomatic infections, a “luminal agent” (that is ac-tive against cysts), such as paromomycin or iodoquinol, is sufficient. Iodoquinol is an 8-hydroxyquinoline; both it and paromomycin are poorly absorbed and can cause nausea and abdominal cramps. Optic and peripheral neuropathy can oc-cur with prolonged use. Diloxanide is an alternative luminal agent. Symptomatic infections should be treated with a tis-sue amebicide (eg, metronidazole or tinidazole) plus a lu-minal agent. Tinidazole may be better tolerated and more effective than metronidazole.63 Cure rates of greater than 90% have been seen with nitazoxanide,64 but comparative data with nitroimidazoles are limited. Cryptosporidiosis. and

the most common causes of cryp-tosporidiosis, are found worldwide. They cause diarrhea, which is usually self-limited in immunocompetent hosts. In immunocompromised hosts (particularly patients with AIDS), diarrhea may be severe and persistent. Nitazox-anide accelerates symptom resolution in human immuno-deficiency virus (HIV)–negative patients, but results have been mixed in HIV-infected patients, with efficacy greatest in those with CD

4 cell counts higher than 50/μL (Table 1).65

In patients with AIDS, initiation of antiretroviral agents, particularly protease inhibitors, improves symptoms.65 Paromomycin, nitazoxanide, macrolides, and rifamycins appear to be ineffective in HIV-infected patients.66 Several thiazolides have in vitro activity against .67

Cyclosporiasis. is found world-wide, with highest prevalence in Haiti, Guatemala, Peru, and Nepal. It causes watery diarrhea with abdominal cramps, fa-tigue, and anorexia. Diarrhea can persist for months, par-ticularly in HIV-infected patients. Cyclosporiasis is treated with TMP-SMX (Table 1). Ciprofloxacin is a less effective alternative; limited data suggest nitazoxanide may also be effective.68,69

Isosporiasis. Found most commonly in tropical and sub-tropical regions, isosporiasis is caused by .

Symptoms are similar to those of cyclosporiasis. Diarrhea is often self-limited in immunocompetent hosts but may be prolonged in those who are immunocompromised. Treat-ment is with TMP-SMX, and, as with cyclosporiasis, higher doses are used in patients with AIDS (Table 1). Ciprofloxa-cin, pyrimethamine (with folinic acid),70 and nitazoxanide71 are alternatives. Dientamoeba fragilis. is a trichomonad that may cause diarrhea and may be associated with irritable bowel syndrome. Iodoquinol is the preferred treatment; metronidazole, paromomycin, and tetracyclines have also been used successfully (Table 1).72

Blastocystis hominis. is a protozoan that has also been linked to irritable bowel syndrome. Whether it truly causes disease is controversial, but some evidence supports a trial of antiparasitic therapy in infected pa-tients with abdominal pain or diarrhea and no alternative explanation for their symptoms.73 Therapeutic options include nitazoxanide, metronidazole, and iodoquinol (Table 1). Trichomonas vaginalis. Trichomoniasis is a common sexually transmitted infection caused by . In women, can cause vaginal discharge and pru-ritis, but 50% of infections may be asymptomatic. In men, infections are usually asymptomatic but can cause urethri-tis. Treatment with a single dose of tinidazole cures 86% to 100% of patients; metronidazole is an alternative (Table 1).74 Sexual partners should also be treated. In one study, 10% of isolates were resis-tant to metronidazole and less than 1% were resistant to ti-nidazole.75 Patients who do not respond to single-dose met-ronidazole should be treated with 500 mg of metronidazole twice daily for 7 days. If no improvement is seen, 2 g of metronidazole or tinidazole daily for 5 days is recommend-ed.74 Other successful regimens have included high-dose tinidazole plus doxycycline or ampicillin with clotrimazole pessaries76 and intravaginal paromomycin.77

Free-Living Amebae Naegleria fowleri. is a thermophilic protist found worldwide in soil and fresh water. It causes primary amebic meningoencephalitis, which is almost universally fa-tal within days of infection via the nasopharynx from warm fresh water. Symptoms may begin with altered taste or smell, followed by fever, vomiting, and rapid progression to confu-sion, coma, and death. Most survivors have received am-photericin, and drugs used successfully in combination with amphotericin include miconazole, fluconazole, ornidazole, rifampin, sulfisoxazole, and chloramphenicol.78,79 Miltefos-

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ine, voriconazole, and chlorpromazine have been effective in experimental settings. Treatment should include intravenous amphotericin and consideration of intrathecal amphotericin in confirmed or highly suspect cases (Table 1). Combination antimicrobial therapy seems warranted; the addition of azoles, rifampin, or other antimicrobial agents should be considered. Acanthamoeba Species. species are found worldwide in soil, dust, and fresh water. They cause gran-ulomatous amebic encephalitis and disseminated disease, which usually occur in immunocompromised persons, and amebic keratitis, which occurs in immunocompetent hosts with contact lens use or ocular trauma. Granulomatous ame-bic encephalitis presents insidiously, with altered mental sta-tus, focal neurologic deficits, fever, headache, seizures, and CNS mass lesions, and is usually fatal. The drugs used most frequently in successfully treated cases are pentamidine, azoles, sulfonamides, and possibly flucytosine (Table 1). Al-most all patients who survived received combination chemo-therapy.78,80,81 Amebic keratitis is a vision-threatening infec-tion that causes corneal ulceration and blindness if not treated promptly. Topical chlorhexidine or polyhexamethylene bigu-anide appear to be the most effective medical treatments. Balamuthia mandrillaris. Found worldwide in soil,

causes a subacute or chronic meningoen-cephalitis in immunocompromised and immunocompe-tent hosts. Patients may present with skin lesions, fever, headache, vomiting, seizures, CNS mass lesions, and focal neurologic deficits. Clusters of disease have recently been reported in patients with previously unexplained encepha-litis and in transplant recipients.82,83 Only 8 cases of suc-cessfully treated infections with species have been reported; all received a prolonged course of combi-nation chemotherapy. Successful treatment regimens have included flucytosine, pentamidine, fluconazole, sulfadiaz-ine, and a macrolide; albendazole and itraconazole; and albendazole, fluconazole, and miltefosine (Table 1).84,85

HELMINTHS AND THE DISEASES THEY CAUSE

Helminths are multicellular worms that do not reproduce in humans (with the exceptions of and illaria). They often provoke an eosinophilic response in their human hosts, particularly when they invade tissue. Helminths are broadly categorized as cestodes, trema-todes, or nematodes.

CESTODES (TAPEWORMS)Cestodes cause disease as segmented, ribbon-like adult tapeworms in the gastrointestinal lumen or as juvenile tis-

sue cysts. The preferred treatment is praziquantel for most intestinal cestodes and benzimidazoles for tissue/larval cestodes.

Taenia saginata. Also known as beef tapeworm, is the most common species that infects hu-

mans. It is found worldwide, with highest prevalence in Latin America, Africa, the Middle East, and Central Asia. Humans become infected after consuming undercooked/raw infested beef. Most infections are asymptomatic, but some patients have abdominal cramps or malaise. Treat-ment is with praziquantel; niclosamide and nitazoxanide are alternatives (Table 2).86 Praziquantel is very effective for taeniasis. It is an oral pyrazinoisoquinolone derivative that damages the tegument and causes paralysis. Adverse effects include dizziness, headache, abdominal pain, vom-iting, diarrhea, and hepatitis. Niclosamide works by uncou-pling oxidative phosphorylation. Adverse effects include nausea and abdominal pain.

Taenia solium. Also known as pork tapeworm, is endemic to Latin America, sub-Saharan Africa, and

Asia, where free-range pigs are raised. Taeniasis, intesti-nal infection with the adult tapeworm, results from eat-ing undercooked pork containing cysticerci (larval cysts). Cysticercosis (tissue infection with larval cysts) results from ingestion of eggs, which are spread from a person with intestinal taeniasis or via fecal-oral au-toinfection. Cysticercosis involving subcutaneous tissue or skeletal muscle is usually asymptomatic. With neurocystic-ercosis (NCC), cysts in the CNS can cause seizures, hydro-cephalus, or chronic meningitis. Although intestinal infection is usually asymp-tomatic, patients are treated to prevent cysticercosis. Praziquantel is first-line treatment, and niclosamide is an alternative (Table 2). The decision to treat NCC with antiparasitic agents is complex; the location, number, and type of cysts and clinical manifestations should be consid-ered. Corticosteroids are given concurrently to decrease the inflammatory response and risk of seizures as the parasite degenerates. In general, patients with intraparenchymal cysts should be treated with albendazole plus corticosteroids. Pa-tients with only intraparenchymal calcifications generally do not require antiparasitic therapy. Patients with subarach-noid cysts should generally receive prolonged courses of albendazole plus corticosteroids. Surgical removal is in-dicated for intraventicular, intraocular, and spinal cysts. Intraocular cysts should be excluded before initiating an-tiparasitic therapy for cysticercosis. If present, intraocular cysts should be surgically removed before administration of antiparasitic treatment to avoid irreversible eye damage due to the resulting inflammatory response.

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TABLE 2. Treatment Regimens for Helminth Infections in Adultsa



Cestodes Intestinal tapeworm infection Praziquantel 5-10 mg/kg orally once Dizziness, headache,

abdominal pain, nausea, hepatitis ………………………………………………………………………………………………………… Niclosamide 2 g orally once Nausea, vomiting, Not commercially diarrhea, headache available in the US but may be obtained from Expert Compound- ing Pharmacyb

Tablets should be chewed before swallowing or Nitazoxanide 500 mg orally twice a day for 3 d Nausea, vomiting, abdominal pain, diarrhea

Praziquantel 25 mg/kg orally once ………………………………………………………………………………………………………… Niclosamide 2 g orally once, followed by 1.5 g orally once a day for 6 d or Nitazoxanide 500 mg orally once a day or twice a day for 3 d

Cysticercosis Albendazole 400 mg orally twice a day for 2-4 wk Abdominal pain, nausea, Should be taken (see above for intestinal with corticosteroids given before, vomiting, myelo- with food infection) during, and after treatment to suppression, alopecia, Decision regarding decrease seizure risk hepatitis. Can precipitate whether to treat seizures in patients with is complex (see neurocysticercosis text). Ocular cysticercosis should be excluded before initiating systemic

therapy ………………………………………………………………………………………………………… Praziquantel 33 mg/kg orally 3 times a day for 1 d Can precipitate seizures followed by 15 mg/kg orally 3 times in patients with neuro- a day for 2-4 wk with corticosteroids cysticercosis given before, during, and after treatment to decrease seizure risk

Echinococcosis Albendazole 400 mg orally twice a day for 1-6 mo; Treatment decision consider PAIR is complex; management strategies depend in part on cyst stage (see text) Consider albendazole; definitive therapy is surgical

Trematodes Schistosomiasis , Praziquantel 20 mg/kg orally twice a day for 1 d

or

Praziquantel 20 mg/kg orally 3 times a day for 1 d or

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Trematodes Fascioliasis Triclabendazole 10 mg/kg orally once or twice Abdominal pain Contact CDC Drug Service regarding availabilityc

………………………………………………………………………………………………………… Bithionol 30-50 mg/kg orally every other day Nausea, vomiting, Unavailable in US for 20-30 d abdominal pain, pruritis, urticaria or Nitazoxanide 500 mg orally twice a day for 7 d

Clonorchiasis/ Praziquantel 25 mg/kg orally 3 times a day for 2 d opisthorchiasis ………………………………………………………………………………………………………… Albendazole 10 mg/kg/d orally for 7 d

Paragonimiasis Praziquantel 25 mg/kg orally 3 times a day for 2 d ………………………………………………………………………………………………………… Triclabendazole 10 mg/kg orally twice Contact CDC Drug Service regarding availabilityc

or Bithionol 30-50 mg/kg orally every other day Unavailable in US for 20-30 d

Intestinal flukes Praziquantel 25 mg/kg orally 3 times a day for 1 d

Nematodes Intestinal nematodes Ascariasis Albendazole 400 mg orally once or Mebendazole 500 mg orally once or 100 mg orally twice a day for 3 d ………………………………………………………………………………………………………… Ivermectin 150-200 μg/kg orally once Nausea, diarrhea, hepatitis, or dizziness or Pyrantel pamoate 11 mg/kg (maximum 1 g) orally Abdominal pain, nausea, Can be obtained from for 3 d vomiting, diarrhea Expert Compound- ing Pharmacyb

Trichuriasis (whipworm) Albendazole 400 mg orally once a day for 3-7 d or Mebendazole 100 mg orally twice a day for 3-7 d ………………………………………………………………………………………………………… Ivermectin 200 μg/kg orally once a day for 3 d

Hookworm Albendazole 400 mg orally once ( or Mebendazole 100 mg orally twice a day for 3 d ) ………………………………………………………………………………………………………… Pyrantel pamoate 11 mg/kg (maximum 1 g) orally once a day for 3 d

Enterobiasis (pinworm) Albendazole 400 mg orally once Treatment course or Mebendazole 100 mg orally once should be repeated 2 wk later ………………………………………………………………………………………………………… Ivermectin 200 μg/kg orally once Strongyloidiasis Chronic intestinal Ivermectin 200 μg/kg orally once a day infection for 2 d ………………………………………………………………………………………………………… Albendazole 400 mg orally twice a day for 10-14 d or Thiabendazole 25 mg/kg orally twice a day for 3-7 d Similar to albendazole

Disseminated/ Ivermectin 200 μg/kg orally once a day until hyperinfection Possible role for 7-14 d after clearance of parasite subcutaneous (veterinary) formulations of ivermectin or combination ivermectin/ albendazole regimens

TTABLE 2. Continueda



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Extra-intestinal nematodes Trichinellosis Albendazole 400 mg orally twice a day for 8-14 d Consider or Mebendazole 200-400 mg orally 3 times a day concomitant for 3 d, followed by 400-500 mg corticosteroids orally 3 times a day for 10 d

Toxocariasis Visceral larva migrans Albendazole 400 mg orally twice a day for 5 d Consider or Mebendazole 100-200 mg orally twice a day for 5 d concomitant Ocular larva migrans Albendazole 400-800 mg orally twice a day corticosteroids for 28 d

Filarial infections Lymphatic filariasis DEC 2 mg/kg orally 3 times a day for 1 d Nausea, fever, asthma- or 12 d like symptoms, and arthralgias ………………………………………………………………………………………………………… Ivermectin 150-400 μg/kg orally once albendazole 400 mg orally once Possible role for doxycycline 200 mg/d for 4-8 wk Tropical pulmonary eosinophilia DEC 2 mg/kg orally 3 times a day for 2-3 wk

Onchocerciasis Ivermectin 150 μg/kg orally once, repeated DEC contraindicated every 6-12 mo until asymptomatic Possible role for doxycycline 200 mg/d for 4-8 wk

Loaiasis DEC 2-3 mg/kg orally 3 times a day for Available from CDC 2-3 wk Drug Servicec Antiparasitic therapy associated with encephalopathy in patients with high-grade parasitemia; consider pretreatment apheresis ………………………………………………………………………………………………………… Albendazole 200 mg orally twice a day for 3 wk

Other tissue nematodes Cutaneous larva migrans Albendazole 400 mg orally once a day for 3 d ………………………………………………………………………………………………………… Ivermectin 200 μg/kg orally once a day for 1-2 d

Albendazole 400 mg orally twice a day for 2-3 wk (plus corticosteroids) (eosinophilic meningitis)

Baylisascariasis Albendazole 400 mg orally twice a day for 1-2 wk (plus corticosteroids)

Gnathostomiasis Albendazole 400 mg orally twice a day for 21 d ………………………………………………………………………………………………………… Ivermectin 200 μg/kg orally once a day for 2 d

Capillariasis Mebendazole 200 mg orally twice a day for 20 d ………………………………………………………………………………………………………… Albendazole 400 mg orally twice a day for 10 d

a CDC = Centers for Disease Control and Prevention; DEC = diethylcarbamazine; PAIR = percutaneous puncture, aspiration, injection, reaspiration.b Expert Compounding Pharmacy, Lake Balboa, CA (800-247-9767).c Contact CDC Drug Service (404-639-3670).

TABLE 2. Continueda



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Albendazole is a broad-spectrum benzimidazole that in-hibits microtubule formation. It can cause nausea, abdomi-nal pain, rash, alopecia, leukopenia, and hepatitis. Emerg-ing evidence suggests that antiparasitic therapy decreases seizures in patients with live intraparenchymal cysts.87 Praziquantel is a second-line agent for NCC. Disadvantag-es of praziquantel include lower efficacy, lower drug levels when coadministered with corticosteroids, and more drug-drug interactions. Dwarf Tapeworm. The dwarf tapeworm

is found worldwide, with highest prevalence in Asia, southern/eastern Europe, Latin America, and Africa. Transmission is usually fecal-oral. Infections are usually asymptomatic, but some patients have abdominal discom-fort and diarrhea. Treatment is with praziquantel at high-er doses and longer courses than for taeniasis (Table 2). Niclosamide and nitazoxanide are alternatives.71,88

Diphyllobothrium latum. Infection with results from eating raw or undercooked fish. Outbreaks have oc-curred in South America, Japan, Siberia, Europe, and North America. Infection is usually asymptomatic, but some pa-tients have weakness, dizziness, salt craving, diarrhea, and passage of proglottids in their stool. The parasite interferes with vitamin B

12 absorption and can cause megaloblastic

anemia. Treatment is with praziquantel or, alternatively, niclosamide (Table 2). Drugs in Development. Tribendimidine is a diamidine derivative of amidantel, an older acetylcholine receptor agonist used to treat hookworm. Treatment with triben-dimidine has yielded cure rates similar to albendazole for intestinal taeniasis.89

Echinococcosis. and

cause cystic and alveolar echi-nococcosis, respectively. infection results from ingesting food or water contaminated with

eggs or from contact with infected dogs. The disease af-fects pastoral communities, particularly in South America, the Mediterranean littoral, Eastern Europe, the Middle East, East Africa, Central Asia, China, and Russia. After infection, the parasites encyst, usually in the liver, or less commonly in the lungs. Initially, cysts are asymptomatic, but over the course of months to years they enlarge and cause symptoms. Cyst rupture can cause anaphylaxis. With infection (which is less common than ), cysts usually form in the liver. They are aggressive, eventually invading contiguous structures with tumor-like progression and can metastasize, usually to the lungs and brain. Management strategies depend on the cyst stage and include percutaneous puncture, aspiration, injection, and

reaspiration (PAIR); surgery; antiparasitic chemotherapy; and expectant management.90 Select patients may be treat-ed with albendazole alone (Table 2). A prolonged course is recommended to prevent recurrence after surgery or percu-taneous treatment. There may be some benefit to combina-tion praziquantel plus albendazole before and after surgical interventions.91

TREMATODES (FLATWORMS)With the exception of fascioliasis, the preferred treatment for trematodes (flukes) is praziquantel. Schistosomiasis. More than 200 million people glob-ally are infected by species. The 3 species of primary medical importance are (found primarily in Africa, the Arabian Peninsula, and South America), (China, the Phil-ippines, Southeast Asia, and Indonesia), and

(Africa and the Arabian peninsula). Infection occurs after skin contact with infested fresh water; 1 to 2 days later, patients may develop a papular, pruritic rash. About 1 to 2 months later, a minority develop Katayama fever, with myalgias, cough, eosinophilia, abdom-inal pain, fever, and hepatosplenomegaly. and S

can cause chronic hepatic/intestinal disease (ab-dominal pain, hepatic fibrosis, and portal or pulmonary hy-pertension). can cause genitourinary disease (hematuria, genital lesions, urinary strictures/obstruction, and bladder cancer). In endemic areas, schistosomiasis contributes to anemia and growth retardation in children. The treatment of choice for schistosomiasis is prazi-quantel (Table 2).92 Higher doses are recommended for S

(and ) infections compared with the other species. Praziquantel has little activity against eggs or immature worms (schistosomulae) and cannot abort early infection. Patients treated early in their infection must be retreated with praziquantel after the adult worms have matured (usually in 6 to 12 weeks). Although artesunate has activity against schistosomulae, it is not usually used for schistosomiasis, in part because of concern about causing artemisinin-resistant malaria.93 For Katayama fever, corticosteroids are often coadministered with praziquantel.94 resistance to praziquantel has been observed.95 can also be treated with oxamniquine, and with metrifonate (Table 2); however, these drugs are not currently available in the United States.96

Fascioliasis. Fascioliasis, caused mainly by

, is endemic to more than 60 countries and is most highly prevalent in sheep-raising areas of Peru, Bolivia, France, Portugal, Egypt, and Iran. Infection results from

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eating freshwater plants infested with metacercariae. About 6 to 12 weeks after infection, larvae enter the liver. This acute (migratory) stage of infection can last 2 to 4 months and presents with marked eosinophilia, abdominal pain, fever, and weight loss. Computed tomography reveals mul-tiple migratory, branching hepatic abscesses. later moves to the bile ducts, where it produces eggs after 3 to 4 months. Some patients develop intermittent biliary obstruction, but many are asymptomatic during the chronic (biliary) stage of infection. Unlike other trematodes,

responds poorly to praziquantel, and triclabenda-zole (a benzimidazole that inhibits microtubule formation) is the treatment of choice (Table 2). Efficacy is 80% to 90%, but resistance has been reported.97 Triclabendazole is well tolerated aside from abdominal pain. Bithionol is an alternative but requires longer courses and causes more adverse effects. Cure rates are 60% with a 7-day course of nitazoxanide and 70% with a 10-day course of artesunate.98

Clonorchiasis and Opisthorchiasis. The Opisthor-chiidae family of liver flukes contains 3 major species:

and . Infection results from eating undercooked

freshwater fish infested with metacercariae. is en-demic primarily to East Asia, to Southeast Asia, and to Russia and other former Soviet re publics. Adult worms deposit eggs in the biliary system; symptoms are uncommon, but patients may have fever, abdominal pain, hepatomegaly, and eosinophilia. Complications include ascending cholangitis, pancreatitis, and biliary pigment stones. Infection may increase the risk of cholangiocar-cinoma. The treatment of choice is praziquantel (Table 2)99; albendazole is an alternative.100 Tribendimidine pre-liminarily appears to be as efficacious as praziquantel.101

Paragonimiasis. Paragonimiasis is caused by

species lung flukes, of which is the best described. It is most common in East

and Southeast Asia. Infection results from eating under-cooked crabs or crayfish infested with metacercariae. Adult worms lay eggs in the lung, and acute infection can cause diarrhea, abdominal pain, fever, chest pain, eosinophilia, and cough. Subsequently, patients may de-velop eosinophilic pleural effusions or bronchiectatic and cavitary lung disease with cough and hemoptysis, often mimicking tuberculosis. Less commonly, lesions develop in the CNS, skin, or other sites. Treatment with prazi - quan tel results in rapid clinical improvement and has high cure rates (Table 2).102 Triclabendazole is also effective.103 Bithionol is an alternative but requires longer courses and is more toxic.104

Intestinal Flukes. More than 60 flukes infect the hu-man intestinal tract. The best known are

, , and species. Most cases occur in Asia, but there are foci in Africa and the Middle East. All intestinal flukes are food-borne, and most result in asymptomatic in-fection. Praziquantel is the preferred treatment; however, triclabendazole is also effective (Table 2).105

NEMATODES (ROUNDWORMS)Nematodes are a diverse group of parasites that are among the most prevalent of human infections. They are catego-rized as intestinal or extraintestinal. Except for

and filarial infections, benzimidazoles are the treat-ments of choice.

Intestinal Nematodes Soil-Transmitted Helminths. The most common intes-tinal nematodes are

(whipworm), and the human hookworms and These organisms are

also termed (STHs) because their eggs or larvae must develop in soil before becoming infectious. More than 1 billion people are infected with

, and nearly as many with whipworm or hookworm, most commonly in tropical areas with poor sanitation. Humans acquire and primarily through the fecal-oral route and hookworm primarily by walking barefoot on infested soil. Although pulmonary symptoms can occur early after infection with or hookworm, adult worms in the bowel lumen generally cause no symp-toms or only mild abdominal pain, nausea, or diarrhea.

can rarely cause intestinal or biliary obstruction, appendicitis, and intestinal perforation. Whipworm can cause rectal prolapse, and hookworm causes chronic ane-mia. Chronic infection with the STHs can impair growth and cognitive development in children and adversely af-fect pregnancies. Short-course albendazole (or mebendazole) cures 88% to 95% of infections with (Table 2).106 For

, short-course cure rates are low, and patients should receive 3 to 7 days of therapy.107 Preliminary data suggest mebendazole may be superior to albendazole for whipworm and that combination therapy with ivermectin may be superior to benzimidazole monotherapy.107 For hookworm, albendazole is preferred over mebendazole.106 Soil-transmitted helminths may be developing resistance to benzimidazoles.108

None of the available alternative therapies is superior to albendazole or mebendazole for all 4 STH species. The acetylcholine receptor agonist pyrantel pamoate is an al-ternative for and hookworm, and ivermectin is an

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alternative for and whipworm. Newer treatments include nitazoxanide for and whipworm and triben-dimidine for and hookworm.109,110

Enterobius vermicularis. (pinworm) causes enterobiasis, which occurs worldwide and does not disproportionately affect residents of tropical countries. The worms live in the proximal colon and migrate to the perianal region to lay eggs that become infectious after 6 hours. Transmission is mainly person-to-person, often via fecal-oral contamination of hands or fomites. Institutional or familial spread is common. Although most infections are asymptomatic, perianal pruritis can be severe. Single-dose albendazole or mebendazole is highly effective (Table 2).111 Alternatives include ivermectin or pyrantel pamoate. Household and other close contacts should be treated, and treatment should be repeated after 2 weeks because of fre-quent reinfection and autoinfection.112

Strongyloides stercoralis. Strongyloidiasis is caused by , an intestinal nematode usually acquired by walking barefoot on infested soil. is found in the tropics, subtropics, and limited foci in the United States and Europe, where poor sanitation and a warm, moist climate coexist. Unlike nearly all other helminths,

can complete its life cycle within humans, allowing for amplification of the parasite, person-to-person transmission, and lifelong persistence. Chronic infection is usually asymptomatic, although abdominal pain, nau-sea, eosinophilia, and diarrhea can occur. Acute infection causes eosinophilia and sometimes rash or cough. In im-munosuppressed patients, hyperinfection (a dramatic in-crease in the worm burden) and dissemination can occur, causing abdominal pain, diarrhea, polymicrobial sepsis, bronchopneumonia, or meningitis. Hyperinfection risk is highest in patients receiving corticosteroids or cancer che-motherapeutics, and in those coinfected with human T-cell lymphotropic virus. Uncomplicated strongyloidiasis should be treated with oral ivermectin, which cures 70% to 85% of chronically infected patients (Table 2).113 This monocyclic lactone binds chloride channels in helminth nerve and muscle cells, resulting in paralysis and death. Ivermectin is well tolerated, only rarely causing nausea, diarrhea, hepatitis, or dizziness when used for intestinal nematodes. Resistance is rare. Less effective alternatives include thiabendazole and albendazole.114 Hyperinfection or disseminated strongy-loidiasis should be treated with oral ivermectin, usually in prolonged courses.115 Experimental use of veterinary parenteral ivermectin has been successful in treating dis-seminated strongyloidiasis.116,117 Patients have also been successfully treated with ivermectin plus albendazole.118 Screening should be considered in anyone (particularly pa-tients with current or impending immunosuppression) with

any history of exposure to endemic areas, even if many years before. Due to the risk of hyperinfection, all patients infected with should be treated. Extraintestinal (Tissue) Nematodes Trichinellosis. Trichinellosis is caused by multiple spe-cies in the genus, of which is the best described. Infection results from eating under-cooked meat containing cysts (traditionally pork, but most US cases are now due to bear or other wild game meat). Symptoms include diarrhea, myositis, perior-bital edema, conjunctivitis, fever, and eosinophilia. Rarely, patients can die of myocarditis or encephalitis. The benefit of antiparasitic therapy is uncertain, but most patients are treated with albendazole (or mebendazole) plus corticoster-oids (Table 2).119

Toxocariasis. Toxocariasis is usually caused by Toxo or . The eggs of or

which are the most common causes of toxocariasis, are passed in dog or cat (respectively) feces into the environ-ment, where they become infectious after 3 to 4 weeks. Human infections, which result from ingesting eggs in contaminated soil, can be asymptomatic (covert toxocari-asis) or present as a larva migrans syndrome. Visceral larva migrans (VLM) occurs most commonly in young children. It is usually asymptomatic but can cause cough, fever, and wheezing. Visceral larva migrans causes eosinophilia and often hepatomegaly; splenomegaly and lymphadenopathy are less common. It is usually self-limited, and treatment with antihelminthic agents is controversial. If antiparasit-ics are used, albendazole is the drug of choice (Table 2); alternatives include mebendazole, thiabendazole, ivermec-tin, or the piperazine diethylcarbamazine (DEC).120,121 Cor-ticosteroids are usually added in severe cases. Ocular larva migrans usually presents as a chorioretinal granuloma. Al-bendazole may be effective but in higher doses and longer courses than for VLM (Table 2).122 Surgery is sometimes required.

Filariasis. The filariae are vector-borne tissue nema-todes generally found in residents of endemic areas, al-though travelers occasionally become infected. Lymphatic filariasis (LF) is caused by the mosquito-borne helminths and species. More than 120 million people have LF, mainly in South-ern Asia, sub-Saharan Africa, Oceania, and parts of Latin America. Adult worms reside in lymphatics and release mi-crofilariae, which circulate nocturnally in the blood. These parasites harbor rickettsia-like endosymbionts, which female worms require to reproduce. Most patients have asymptomatic eosinophilia, but fever, adenolymphan-

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gitis, lymphedema, hydrocele, or elephantiasis can occur. Some patients develop tropical pulmonary eosinophilia, with nocturnal asthma, cough, fever, weight loss, and high-grade eosinophilia. Parasitemic patients should receive DEC. A 1-day course appears to be as effective as the traditional 12-day regimen (Table 2).123 Antiparasitic treatment in patients with lymphedema or elephantiasis who are not actively infected is controversial. Patients with tropical pulmonary eosinophilia should receive a 2- to 3-week course of DEC. Adverse effects include nausea, fever, asthma-like symp-toms, and arthralgias. Therapy for all filarial infections may be associated with allergic-like reactions resulting from degenerating filariae and for which anti-histamines and corticosteroids may be useful. Diethylcar-bamazine kills microfilariae but has only modest activity against adult worms. It should not be given to persons from areas coendemic for onchocerciasis or Loa loa unless these infections have been excluded. Alternatives for LF include ivermectin and albendazole. Prolonged courses of doxycy-cline (which kills and sterilizes adult worms as a result of anti- activity) may have a role.124

Onchocerciasis, also known as , is caused by Transmitted by

blackflies, onchocerciasis is found in equatorial Af-rica and limited foci in Latin America and the Arabian Peninsula. Infection can cause dermatitis, subcutaneous nodules, keratitis, chorioretinitis, and blindness. Ivermec-tin is the treatment of choice (Table 2), although it kills only microfilariae, not adult worms.125 Ivermectin must be used with caution if coinfection with L loa is possible. The adverse effects of ivermectin include fever, rash, diz-ziness, pruritis, myalgias, arthralgias, and lymphadenopa-thy, mostly due to dying filariae and . Suramin is active against adult worms, but toxicity precludes use in most cases. Moxidectin, a drug in development that is closely related to ivermectin (but with higher potency), is also active against onchocerciasis.126 Prolonged doxycy-cline therapy may have a role because of its anti-

activity. Diethylcarbamazine should not be admin-istered to persons infected with onchocerciasis because blindness can result from the subsequent ocular inflam-matory response. Loaiasis is caused by L loa, a helminth that is trans-mitted by flies and is endemic to Central and West Africa. Adult worms migrate in subcutaneous tis-sues, and microfilariae circulate diurnally in the blood. L loa does not harbor . Most infected persons have asymptomatic eosinophilia; some have urticaria, Calabar swellings (migratory, subcutaneous, angio-edematous lesions), and visible “eye worms” migrating across the conjunctivae. Hematuria, proteinuria, and en-

cephalitis (usually precipitated by treatment) also oc-cur. Diethylcarbamazine is effective against loaiasis, al-though multiple courses may be necessary (Table 2).127 Treatment can cause pruritis, arthralgias, Calabar swell-ings, fever, eye worms, diarrhea, and renal failure. Pa-tients with detectable microfilaremia (particularly >2500 microfilariae/mL) are at risk of treatment-associated encephalopathy, which may be ameliorated by pretreat-ment apheresis. Ivermectin is active against L loa, but al-bendazole (which acts more slowly) is associated with a lower risk of encephalopathy than DEC or ivermectin.128

Other Tissue Nematodes Cutaneous Larva Migrans. Migration of dog and cat hookworms (eg, ) in the dermis can cause a serpiginous rash termed . The rash occurs after skin contact with infested soil and is usually seen on the lower extremities. Cutaneous larva migrans can be associated with eosinophilia or pulmonary infiltrates but is self-limited. Albendazole or ivermectin may hasten resolution (Table 2).129

Angiostrongylus cantonensis. Human infection with occur after ingesting snails, slugs, or leafy

vegetables containing snails, slugs or slime trails with larvae. Endemic primarily to Asia and Oceania, infection can cause a prolonged (but usually self-limited) eosino-philic meningitis. Although antiparasitic therapy is con-troversial, albendazole plus corticosteroids is often used (Table 2).130

Baylisascaris procyonis. (ie, raccoon round-worm) can rarely cause a form of VLM. Human infections result from contact with soil contaminated with raccoon feces. Severe meningoencephalitis can occur, usually in children. Treatment is not well defined, but albendazole plus corticosteroids has been used successfully (Table 2).131 Gnathostoma spinigerum. , which is ac-quired by eating undercooked freshwater fish, chicken, or pork, is the most common cause of gnathostomiasis. Al-though it is endemic primarily to Southeast Asia, infections also occur in Latin America and elsewhere. Symptoms in-clude eosinophilia, migratory subcutaneous swellings, and (rarely) fulminant meningoencephalitis. Treatment is with albendazole or ivermectin (Table 2).132

Capillaria philippinensis. is the most common cause of capillariasis, which results from eating infected freshwater fish. Endemic primarily to Southeast Asia and the Middle East, the parasite inhabits the small bowel, causing diarrhea, malabsorption, and (uncommon-ly) fever and eosinophilia. As with , these helminths can multiply in humans, sometimes causing overwhelming infection. Mebendazole or albendazole can be life-saving (Table 2).133

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CONCLUSION

A wide array of parasites infect humans, causing some of the most prevalent infectious diseases globally. Recent advances in the treatment of malaria, leishmaniasis, and Chagas disease have brought needed improvements to the management of these diseases. Helminth infections are managed with a smaller pharmaceutical armamentarium than protozoal infections, but good treatment options are now available for many trematode, intestinal cestode, and intestinal nematode infections. Despite a relatively narrow therapeutic pipeline for new antiparasitic drugs, there have been significant improvements in the treatment of these widespread infections in the past 2 decades.

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67. Gargala G, Le Goff L, Ballet JJ, Favennec L, Stachulski AV, Rossignol JF. Evaluation of new thiazolide/thiadiazolide derivatives reveals nitro group-independent efficacy against in vitro development of

. 2010;54:1315-1318. 68. Verdier RI, Fitzgerald DW, Johnson WD Jr, Pape JW. Trimethoprim-sulfamethoxazole compared with ciprofloxacin for treatment and prophy-laxis of and infection in HIV-infected patients: a randomized, controlled trial. . 2000;132:885- 888. 69. Zimmer SM, Schuetz AN, Franco-Paredes C. Efficacy of nitazoxanide for cyclosporiasis in patients with sulfa allergy. . 2007;44: 466-467. 70. Weiss LM, Perlman DC, Sherman J, Tanowitz H, Wittner M. li infection: treatment with pyrimethamine. . 1988;109:474-475. 71. Romero Cabello R, Guerrero LR, Munoz Garcia MR, Geyne Cruz A. Nitazoxanide for the treatment of intestinal protozoan and helminthic infec-tions in Mexico. . 1997;91:701-703. 72. Stark D, Barratt J, Roberts T, Marriott D, Harkness J, Ellis J. A re-view of the clinical presentation of dientamoebiasis. . 2010;82:614-619. 73. Rossignol JF, Kabil SM, Said M, Samir H, Younis AM. Effect of nita-zoxanide in persistent diarrhea and enteritis associated with

. 2005;3:987-991. 74. Workowski KA, Berman S; Centers for Disease Control and Preven-tion (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR

. 2010;59:1-110. 75. Schwebke JR, Barrientes FJ. Prevalence of isolates with resistance to metronidazole and tinidazole.

. 2006;50:4209-4210. 76. Mammen-Tobin A, Wilson JD. Management of metronidazole-resistant

—a new approach. . 2005;16:488-490. 77. Tayal SC, Ochogwu SA, Bunce H. Paromomycin treatment of recalci-trant . 2010;21:217-218. 78. Schuster FL, Visvesvara GS. Opportunistic amoebae: challenges in pro-phylaxis and treatment. . 2004;7:41-51. 79. Vargas-Zepeda J, Gomez-Alcala AV, Vasquez-Morales JA, Licea-Ama-ya L, De Jonckheere JF, Lares-Villa F. Successful treatment of

meningoencephalitis by using intravenous amphotericin B, fluconazole and rifampicin. . 2005;36:83-86. 80. Saxena A, Mittal S, Burman P, Garg P. meningitis with successful outcome. . 2009;76:1063-1064. 81. Aichelburg AC, Walochnik J, Assadian O, et al. Successful treatment of disseminated sp. infection with miltefosine. . 2008;14:1743-1746. 82. Centers for Disease Control and Prevention (CDC). Notes from the field: transplant-transmitted —Arizona, 2010. MMWR

. 2010;59:1182. 83. Schuster FL, Yagi S, Gavali S, et al. Under the radar: ame-bic encephalitis. . 2009;48:879-887. 84. Deetz TR, Sawyer MH, Billman G, Schuster FL, Visvesvara GS. Suc-cessful treatment of amoebic encephalitis: presentation of 2 cases.

. 2003;37:1304-1312. 85. Martinez DY, Seas C, Bravo F, et al. Successful treatment of

amoebic infection with extensive neurological and cutaneous involvement. . 2010;51:e7-e11. 86. Lateef M, Zargar SA, Khan AR, Nazir M, Shoukat A. Successful treat-ment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide. . 2008;12:80-82. 87. Garcia HH, Pretell EJ, Gilman RH, et al. A trial of antiparasitic treat-ment to reduce the rate of seizures due to cerebral cysticercosis. . 2004;350:249-258. 88. Chero JC, Saito M, Bustos JA, Blanco EM, Gonzalvez G, Garcia HH.

infection: symptoms and response to nitazoxanide in field conditions. . 2007;101:203-205. 89. Xiao SH, Hui-Ming W, Tanner M, Utzinger J, Chong W. Tribendimi-dine: a promising, safe and broad-spectrum anthelmintic agent from China.

. 2005;94:1-14. 90. Brunetti E, Kern P, Vuitton DA. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. . 2010;114:1-16. 91. Bygott JM, Chiodini PL. Praziquantel: neglected drug? ineffec-tive treatment? or therapeutic choice in cystic hydatid disease? . 2009;111:95-101. 92. Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis.

. 2006;368:1106-1118.

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93. Boulanger D, Dieng Y, Cisse B, et al. Antischistosomal efficacy of arte-sunate combination therapies administered as curative treatments for malaria attacks. . 2007;101:113-116. 94. Ross AG, Vickers D, Olds GR, Shah SM, McManus DP. Katayama syn-drome. . 2007;7:218-224. 95. Ismail M, Botros S, Metwally A, et al. Resistance to praziquantel: direct evidence from isolated from Egyptian villagers.

. 1999;60:932-935. 96. Ferrari ML, Coelho PM, Antunes CM, Tavares CA, da Cunha AS. Ef-ficacy of oxamniquine and praziquantel in the treatment of

infection: a controlled trial. . 2003;81:190-196. 97. Moll L, Gaasenbeek CP, Vellema P, Borgsteede FH. Resistance of

against triclabendazole in cattle and sheep in The Netherlands. . 2000;91:153-158.

98. Favennec L, Jave Ortiz J, Gargala G, Lopez Chegne N, Ayoub A, Ros-signol JF. Double-blind, randomized, placebo-controlled study of nitazoxanide in the treatment of fascioliasis in adults and children from northern Peru. Ali

. 2003;17:265-270. 99. Bunnag D, Harinasuta T. Studies on the chemotherapy of human opist-horchiasis in Thailand: I. Clinical trial of praziquantel.

. 1980;11:528-531. 100. Liu YH, Wang XG, Gao P, Qian MX. Experimental and clinical trial of albendazole in the treatment of . 1991;104:27-31. 101. Soukhathammavong P, Odermatt P, Sayasone S, et al. Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate, tribendimidine, and praziquantel in patients with : a randomised, exploratory, open-label, phase 2 trial. . 2011;11:110-118. 102. Udonsi JK. Clinical field trials of praziquantel in pulmonary paragon-imiasis due to in endemic populations of the Ig-wun Basin, Nigeria. . 1989;40:65-68. 103. Calvopina M, Guderian RH, Paredes W, Chico M, Cooper PJ. Treat-ment of human pulmonary paragonimiasis with triclabendazole: clinical toler-ance and drug efficacy. . 1998;92:566-569. 104. Kim JS. Treatment of infections with bithi-onol. . 1970;19:940-942. 105. Bunnag D, Radomyos P, Harinasuta T. Field trial on the treatment of fasciolopsiasis with praziquantel. . 1983;14:216-219. 106. Keiser J, Utzinger J. Efficacy of current drugs against soil-transmitted helm-inth infections: systematic review and meta-analysis. . 2008;299:1937-1948. 107. Knopp S, Mohammed KA, Speich B, et al. Albendazole and mebenda-zole administered alone or in combination with ivermectin against

: a randomized controlled trial. . 2010;51:1420-1428. 108. Albonico M, Bickle Q, Ramsan M, Montresor A, Savioli L, Taylor M. Efficacy of mebendazole and levamisole alone or in combination against in-testinal nematode infections after repeated targeted mebendazole treatment in Zanzibar. . 2003;81:343-352. 109. Galvan-Ramirez ML, Rivera N, Loeza ME, et al. Nitazoxanide in the treatment of in a rural zone of Colima, Mexico.

. 2007;81:255-259. 110. Diaz E, Mondragon J, Ramirez E, Bernal R. Epidemiology and control of intestinal parasites with nitazoxanide in children in Mexico.

. 2003;68:384-385. 111. Wen LY, Yan XL, Sun FH, Fang YY, Yang MJ, Lou LJ. A randomized, double-blind, multicenter clinical trial on the efficacy of ivermectin against intestinal nematode infections in China. . 2008;106:190-194. 112. Matsen JM, Turner JA. Reinfection in enterobiasis (pinworm in-fection). Simultaneous treatment of family members. . 1969;118:576-581.

113. Igual-Adell R, Oltra-Alcaraz C, Soler-Company E, Sanchez-Sanchez P, Matogo-Oyana J, Rodriguez-Calabuig D. Efficacy and safety of ivermectin and thiabendazole in the treatment of strongyloidiasis.

. 2004;5:2615-2619. 114. Marti H, Haji HJ, Savioli L, et al. A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of

and other soil-transmitted helminth infections in children. . 1996;55:477-481.

115. Keiser PB, Nutman TB. in the immunocom-promised population. . 2004;17:208-217. 116. Turner SA, Maclean JD, Fleckenstein L, Greenaway C. Parenteral ad-ministration of ivermectin in a patient with disseminated strongyloidiasis.

. 2005;73:911-914. 117. Marty FM, Lowry CM, Rodriguez M, et al. Treatment of human dis-seminated strongyloidiasis with a parenteral veterinary formulation of iver-mectin. . 2005;41:e5-e8. 118. Pornsuriyasak P, Niticharoenpong K, Sakapibunnan A. Disseminated strongyloidiasis successfully treated with extended duration ivermectin com-bined with albendazole: a case report of intractable strongyloidiasis.

. 2004;35:531-534. 119. Watt G, Saisorn S, Jongsakul K, Sakolvaree Y, Chaicumpa W. Blinded, placebo-controlled trial of antiparasitic drugs for trichinosis myositis.

. 2000;182:371-374. 120. Sturchler D, Schubarth P, Gualzata M, Gottstein B, Oettli A. Thiabenda-zole vs. albendazole in treatment of toxocariasis: a clinical trial.

. 1989;83:473-478. 121. Magnaval JF. Comparative efficacy of diethylcarbamazine and mebenda-zole for the treatment of human toxocariasis. . 1995;110(pt 5):529-533. 122. Barisani-Asenbauer T, Maca SM, Hauff W, et al. Treatment of ocu - lar toxocariasis with albendazole. . 2001;17:287- 294. 123. Centers for Disease Control and Prevention (CDC). Parasites—lym-phatic filariasis: guidance for evaluation and treatment. http://www.cdc.gov /parasites/lymphaticfilariasis/health_professionals/dxtx.html. Accessed April 29, 2011. 124. Hoerauf A. Filariasis: new drugs and new opportunities for lymphatic filariasis and onchocerciasis. . 2008;21:673-681. 125. Udall DN. Recent updates on onchocerciasis: diagnosis and treatment.

. 2007;44:53-60. 126. Taylor MJ, Hoerauf A, Bockarie M. Lymphatic filariasis and onchocer-ciasis. . 2010;376:1175-1185. 127. Padgett JJ, Jacobsen KH. Loiasis: African eye worm.

. 2008;102:983-989. 128. Klion AD, Massougbodji A, Horton J, et al. Albendazole in hu-man loiasis: results of a double-blind, placebo-controlled trial. . 1993;168:202-206. 129. Albanese G, Venturi C, Galbiati G. Treatment of larva migrans cutanea (creeping eruption): a comparison between albendazole and traditional thera-py. . 2001;40:67-71. 130. Chotmongkol V, Wongjitrat C, Sawadpanit K, Sawanyawisuth K. Treat-ment of eosinophilic meningitis with a combination of albendazole and corti-costeroid. . 2004;35:172-174. 131. Pai PJ, Blackburn BG, Kazacos KR, Warrier RP, Begue RE. Full recov-ery from eosinophilic meningitis. . 2007;13:928-930. 132. Nontasut P, Bussaratid V, Chullawichit S, Charoensook N, Visetsuk K. Comparison of ivermectin and albendazole treatment for gnathostomiasis.

. 2000;31:374-377. 133. Cross JH. Intestinal capillariasis. . 1992;5:120-129.

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ANTIMICROBIAL PROPHYLAXIS IN ADULTS



From the Division of Infectious Diseases, Mayo Clinic, Rochester, MN.

Address correspondence to Mark J. Enzler, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]). Individual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com.


Antimicrobial Prophylaxis in Adults

Mark J. Enzler, MD; Elie Berbari, MD; and Douglas R. Osmon, MD, MPH

Antimicrobial prophylaxis is commonly used by clinicians for the prevention of numerous infectious diseases, including herpes simplex infection, rheumatic fever, recurrent cellulitis, meningo-coccal disease, recurrent uncomplicated urinary tract infections in women, spontaneous bacterial peritonitis in patients with cir-rhosis, influenza, infective endocarditis, pertussis, and acute nec-rotizing pancreatitis, as well as infections associated with open fractures, recent prosthetic joint placement, and bite wounds. Perioperative antimicrobial prophylaxis is recommended for vari-ous surgical procedures to prevent surgical site infections. Opti-mal antimicrobial agents for prophylaxis should be bactericidal, nontoxic, inexpensive, and active against the typical pathogens that can cause surgical site infection postoperatively. To maximize its effectiveness, intravenous perioperative prophylaxis should be administered within 30 to 60 minutes before the surgical incision. Antimicrobial prophylaxis should be of short duration to decrease toxicity and antimicrobial resistance and to reduce cost.

Mayo Clin Proc. 2011;86(7):686-701

AAOS = American Association of Orthopedic Surgeons; ADA = Ameri-can Dental Association; ANP = acute necrotizing pancreatitis; AP = antimicrobial prophylaxis; AUA = American Urological Association; CP = chemoprophylaxis; FDA = US Food and Drug Administration; HIV = human immunodeficiency virus; IDSA = Infectious Diseases Soci-ety of America; IE = infective endocarditis; IS = Information Statement; MRSA = methicillin-resistant Staphylococcus aureus; PJI = prosthetic joint infection; PJR = prosthetic joint replacement; RF = rheumatic fever; SBP = spontaneous bacterial peritonitis; SCIP = Surgical Care Improvement Project; Tdap = tetanus toxoid, reduced diphtheria tox-oid, and acellular pertussis vaccine, adsorbed; UGI = upper gastroin-testinal; UTI = urinary tract infection

Antimicrobial prophylaxis (AP) can be used effectively to prevent infection, but its use should be limited to

specific, well-accepted indications to avoid excess cost, toxicity, and antimicrobial resistance. Antimicrobial pro-phylaxis may be considered primary (prevention of an ini-tial infection) or secondary (prevention of the recurrence or reactivation of an infection), or it may also be administered to prevent infection by eliminating a colonizing organ-ism. This article reviews widely accepted indications for AP in nonsurgical and surgical patients and is an update of a previously published review of this topic.1 In selected situations, vaccination may be recommended as part of a prophylaxis regimen. This article is meant to be a point-of-care overview topic for the busy clinician. Many of these recommendations are based on expert opinion rather than on prospective clinical trials. Most of the recommended

antimicrobial agents are not approved by the US Food and Drug Administration (FDA) for prophylaxis. Current full prescribing information available in the package insert of each drug should be consulted before prescribing any prod-uct. Detailed information on individual topics can be found in the cited references. The potential risks and benefits of AP should be dis-cussed in detail with the patient. Potential risks include allergic reactions that may be severe or life-threatening as well as colitis with the use of anti-bacterial agents.2 Patients taking fluoroquinolones should be warned of the risk of developing tendinitis, including Achilles tendon rupture.3 For all antibiotic dosing recom-mended in this article, normal hepatic and renal function are assumed.

NONSURGICAL AP

RHEUMATIC FEVER

Rheumatic fever (RF), which is associated with tonsil-lopharyngitis caused by the group A β-hemolytic strepto-cocci, may result in carditis with or without valvulopathy. Primary prevention of RF involves prompt and appropriate antibiotic treatment of group A β-hemolytic streptococcal pharyngitis with a penicillin (drug of choice) or alternative antibiotic.4 Continuous secondary AP prevents recurrent episodes of RF, which could otherwise lead to worsening of the severity of rheumatic heart disease that developed after the initial attack or the development of rheumatic carditis in those who did not develop carditis with the ini-tial RF episode. Guidelines for secondary AP of RF have recently been updated (recommendations for AP regimens are summarized in Table 1).4 Penicillins are the antibiotics of choice for secondary prophylaxis for RF, and intramus-

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cular penicillin is superior to oral penicillins.25 Macrolides (eg, erythromycin, clarithromycin, azithromycin) should be reserved for patients who are allergic to both penicillin and sulfa antibiotics. The duration of secondary prophylaxis for RF is reviewed in detail elsewhere and is summarized in Table 2.4 Physicians should tailor the duration of secondary prophylaxis to the individual patient, taking into account the patient’s risk factors for RF recurrence, such as exposure to young children and the presence of carditis with or with-out underlying valvular disease. Antimicrobial prophylaxis should be considered for at least 10 years or until age 40 years (whichever is longer) for patients with carditis with persistent valvular disease. Prophylaxis should be continued in patients even after prosthetic valve replacement surgery. Antibiotic suppression for the prevention of RF is not ad-equate for infective endocarditis (IE) prophylaxis before dental procedures.

RECURRENT CELLULITIS

Patients with lymphedema or severe venous insufficien-cy of their extremities are at increased risk of recurring β-streptococcal cellulitis. Common scenarios for recur-rent cellulitis of the lower extremity include patients with venous insufficiency after saphenous vein graft harvesting or pelvic lymphadenectomy. Recurrent cellulitis has been observed in the upper extremity after lymphadenectomy performed at the time of mastectomy for breast cancer. An-timicrobial prophylaxis may be a useful addition to the con-trol of lymphedema with local measures and treatment of concurrent tinea pedis in the prevention of recurrent celluli-tis. However, this recommendation is based on small, uncon-trolled studies.26-28 Typically, more than 2 or 3 episodes per year should occur before AP is initiated. Recommended pro-phylactic antibiotics for recurrent cellulitis are summarized in Table 1. Oral penicillin V (phenoxymethylpenicillin) is a reasonable first choice, but optimal dosing of this agent is not well established.5-7 Although monthly administration of 1.2 MU of intramuscular benzathine penicillin is recommended as an alternative to oral penicillin V, this dosing regimen was shown to be effective only in those patients not at risk of cel-lulitis recurrence.28 Some experts recommend intramuscular administration of benzathine penicillin every 2 to 3 weeks for individuals who break through once-monthly intramus-cular benzathine penicillin regimens.5

Recurrent pyogenic skin infections caused by , including methicillin-resistant

(MRSA), may be managed by encouraging good personal hygiene, the avoidance of shared personal items, and the diligent cleaning of high-touch environmental surfaces. If a patient is found to be colonized by , nasal decolo-nization with mupirocin for 5 to 10 days with or without a topical body decolonization with a skin antiseptic solution

such as 4% chlorhexidine for 5 to 14 days may be reason-able in an attempt to decolonize the patient.8 Antimicrobial prophylaxis options are listed in Table 1 for recurrent methi-cillin-susceptible skin infections.9,29 Long-term oral AP of recurrent MRSA skin infections is not well studied, and formal recommendations for this situation were not in-cluded in recently published MRSA treatment guidelines.8

MENINGOCOCCAL DISEASE

Antimicrobial prophylaxis for meningococcal diseases should be offered to close contacts of sporadic cases of

infection (Table 1). Close contacts include household members, day care center staff, and any person directly exposed to an infected person’s oral secre-tions (for example, through kissing, mouth-to-mouth re-suscitation, endotracheal intubation, or endotracheal tube management).11 Public health authorities may recommend population-based prophylaxis in the event of an outbreak. Prophylaxis should be offered as soon as possible. Close contacts should be offered meningococcal vaccination if the outbreak strain is one that is contained in the currently available meningococcal tetravalent conjugate vaccine.30

ASPLENIC PATIENTS

Penicillin prophylaxis is recommended in children during the first few years after splenectomy to prevent overwhelm-ing sepsis.31 French and Ameri-can authorities have advocated this form of prophylaxis (eg, 250 mg of oral penicillin V or amoxicillin twice daily) in adults for 1 to 2 years after splenectomy, although data showing the efficacy of this approach are lacking.31-33

type B, meningococcal, and pneumo-coccal vaccinations should be current in asplenic adults.

URINARY TRACT INFECTION Several prophylactic antibiotic options are available to non-pregnant women with recurrent (≥3 per year), uncomplicat-ed urinary tract infections (UTIs)13 (Table 1). Continuous low-dose AP and patient-initiated treatment after onset of symptoms are both effective.13,14 During AP, monthly urine cultures should be performed to monitor for bacteriuria and the development of antibiotic resistance.34 Structural abnormality of the urinary tract, renal involvement with infection, or chronic prostatitis (in men) should be con-sidered in the setting of recurrent UTIs. Methenamine hippurate (dosage, 1 g twice daily) has been approved by the FDA for UTI prophylaxis. A recent Cochrane review concluded that methenamine hippurate may be effective for short-term prophylaxis (≤1 week) in patients without known renal tract abnormalities.35 The typical duration of an initial trial of continuous AP is 6 months. Patients with prolonged exposure to nitrofurantoin should be counseled

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TABLE 1. Selected Nonsurgical Antimicrobial Prophylaxis Regimens for Adultsa,b

Condition Antimicrobial agent Dose

Rheumatic fever4 Primary prophylaxis Appropriate treatment of group A streptococcal pharyngitis Secondary prophylaxisc

Preferred Penicillin G benzathine 1.2 million U IM every 4 wk (every 3 wk for patients at high riskd) Preferred oral agents Penicillin V (preferred) 250 mg orally twice daily or Sulfadiazine 1 g orally daily or Sulfasoxazole 1 g orally daily Alternative oral agents Erythromycin 250 mg orally twice daily or Clarithromycine

or Azithromycine

Recurrent cellulitis in conjunction Penicillin V 250-1000 mg orally twice dailyf with upper or lower extremity or Penicillin G benzathine 1.2 million U IM every 2 to 4 wk lymphedema or erysipelas5-7 Penicillin allergy Erythromycin 250-500 mg orally twice daily

Recurrent pyogenic or Etiology unknown or methicillin-susceptible staphylococcal soft tissue suspected infection8-10 Dicloxacillin 500 mg orally twice daily or Clindamycin 150 mg orally once daily MRSA Oral antimicrobial prophylaxis has not been studied8

Meningococcal disease (close Rifampin 600 mg orally every 12 h for 2 d contacts of sporadic cases)11 or Ciprofloxacin 500 mg orally for 1 dose (adults) or Ceftriaxone 250 mg IM once Travelers' diarrhea12 Daily oral doseg

Bismuth subsalicylate 2 tablets (262 mg/tablet) chewed 4 times daily Norfloxacinh 400 mg Ciprofloxacinh 500 mg Rifaximini 200 mg once or twice daily

Recurrent uncomplicated Continuous prophylaxis Daily oral dose (at bedtime) urinary tract infections in Trimethoprim-sulfamethoxazole ½ SS tablet (or 3 times/wk) nonpregnant women13-15 Trimethoprim 100 mg Norfloxacin 200 mg Ciprofloxacin 125 mg Nitrofurantoin 50-100 mg Cephalexin 125-250 mg Postcoital regimens Single oral dose Trimethoprim-sulfamethoxazole ½-1 SS tablet Cephalexin 125-250 mg Nitrofurantoin 50-100 mg Ciprofloxacin 125 mg Norfloxacin 200 mg Intermittent self-treatment Oral dose Trimethoprim-sulfamethoxazole 1 DS tablet twice daily for 3 d Ciprofloxacin 250 mg twice daily for 3 d Ofloxacin 200 mg twice daily for 3 d

Spontaneous bacterial peritonitis16 Ascites and upper GI bleeding Preferred (if taking a quinolone for long-term SBP prophylaxis) Ceftriaxone 2 g IV initially, then 1 g daily for 7 d Alternative Norfloxacin 400 mg orally twice daily for 7 d Primary or secondary prophylaxis, non–upper GI bleedingj

Trimethoprim-sulfamethoxazole 1 DS tablet orally every day or Norfloxacin 400 mg orally every day or Ciprofloxacin 500 mg orally every day

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about the rare but serious complications associated with this agent, including hepatitis, pulmonary reactions, and neuropathy. Cranberries contain 2 substances that prevent fimbriated from adhering to uroepithelial cells.36 Clinical studies have shown that cranberry juice and cranberry products may reduce the recurrence of UTIs

High-risk dog, cat, or human Initial IV antibioticsk

bite17-19 Ampicillin-sulbactam 3 g IV every 6 h or Piperacillin-tazobactam 3.375 g IV every 6 h or Ertapenem 1 g IV once daily or Metronidazole 500 mg orally or IV every 8 h ceftriaxone, 1 g IV every 24 h levofloxacin, 500 or 750 mg IV once daily or ciprofloxacin 400 mg IV every 12 h Oral antibiotic for 3-5 dl

Preferred Amoxicillin-clavulanatem 875 mg orally twice daily for 3-5 d Penicillin allergy Moxifloxacin monotherapy 400 mg orally once daily or Clindamycin 300-450 mg orally 4 times daily ciprofloxacin or 500 mg orally daily levofloxacin 750 mg orally dailyPertussis20 Primary agentsn Azithromycin 500 mg orally day 1, then 250 mg per day on days 2-5 or Clarithromycin 500 mg orally twice daily for 7 d or Erythromycin 2000 mg orally in 4 divided doses for 14 d Alternative agent Trimethoprim-sulfamethoxazole, DS 1 tablet orally twice daily for 14 d

Influenza21,22 Influenza A or B Oseltamiviro,p 75 mg orally daily or Zanamiviro,q 5 mg/blister for inhalation: 2 inhalations (10 mg) daily Influenza A only Rimanadines (amantadine and rimantadine) are no longer recommendedr

a DS = double-strength; GI = gastrointestinal; IM = intramuscularly; IV = intravenously; MRSA = methicillin-resistant ; SBP = spontaneous bacterial peritonitis; SS = single-strength; Tdap = tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine, adsorbed.

b Antibiotic doses assume normal renal and hepatic function; the choice of therapy should be guided by the patient’s history of allergy or intolerance to a specific agent.

c See Table 2 and text for duration of prophylaxis.d Administration of benzathine penicillin every 3 wk is recommended in the United States only for those who have recurrent acute rheumatic fever despite adherence

to a once-monthly regimen.e Dosing of these agents was not specified in the recently published guidelines.4 However, a clarithromycin dose of 250 mg twice daily was proposed to us by one of

the authors of those guidelines, Stanford T. Schulman, MD (written communication, January 5, 2011).f There is a wide range of recommended penicillin V dosing for this purpose; 250-500 mg twice daily would be a reasonable starting point.g Duration of prophylaxis for travelers’ diarrhea should be limited to 2-3 wk and should be stopped 2 d after returning from travel.h Other fluoroquinolones are likely to be effective but have not been studied for use in prophylaxis for travelers’ diarrhea.i Rifaximin prophylaxis has only been studied in travelers to Mexico.23

j Primary prophylaxis for SBP is indicated in patients with ascitic fluid protein <1.5 g/dL and at least 1 of the following criteria: serum creatinine level, ≥1.2 mg/dL (to convert to μmol/L, multiply by 88.4); blood urea nitrogen level, ≥25 mg/dL (to convert to mmol/L, multiply by 0.357); serum sodium level, ≤130 mEq/L (to convert to mmol/L, multiply by 1); or Child-Pugh score, ≥9 points with bilirubin level ≥3 mg/dL (to convert to μmol/L, multiply by 17.104).16

k Consider IV antibiotics for animal bites as initial dose in the emergency department and with hospitalized patients. Consider hospitalization and IV antibiotics as an initial therapy for human bites and in patients with fever, sepsis, spread of cellulitis, significant edema or crush injury, or loss of function and in those who are immunocompromised or nonadherent to treatment.

l Use oral antibiotics if treatment occurs soon after a dog or cat bite and only mild to moderate signs of infection are present.m Avoid penicillins in patients with a history of severe penicillin allergy.n Vaccinate with Tdap if indicated.o Choice of therapy should be dictated by resistance patterns of the circulating influenza virus; see text for discussion of treatment duration.p Common adverse effects include nausea, vomiting, and headaches. Taking oseltamivir with food may reduce the likelihood of nausea and vomiting.q Adverse effects include cough, nasal and throat discomfort, and (rarely) bronchospasm and decreased lung function. Zanamivir should be avoided in patients with

asthma or chronic obstructive lung disease.r The high prevalence of adamantane (rimantadine and amantadine) resistance in circulating influenza A viruses indicates that these agents have no current role

outside of clinical trials.24

TABLE 1. Continueda,b

Condition Antimicrobial agent Dose

in women. A recent Cochrane review noted limitations in these studies, including variable cranberry products and dosing used in the various studies, as well as high study participant dropout rates.37 Other patients who may be con-sidered for prophylaxis of frequent UTIs include pregnant women, persons with spinal cord injuries, persons with

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neurogenic bladders, renal transplant recipients, and men with chronic bacterial prostatitis.13,34 Postcoital regimens may be appropriate for female patients with UTIs tem-porally related to sexual intercourse.15,38 Patients who use postcoital regimens should be informed that only 1 dose per day is recommended, regardless of the frequency of in-tercourse. Postcoital AP in pregnancy can be managed with a single dose of either cephalexin (250 mg) or nitrofuran-toin (50 mg).34 Tetracyclines and fluoroquinolones should be avoided during pregnancy, and sulfonamides should be avoided during the last weeks of gestation to minimize the risk of hyperbilirubinemia and kernicterus in the newborn. Topical vaginal estrogen therapy has been shown to reduce the risk of recurrent UTIs in postmenopausal women; it may be a consideration for postmenopausal women who are not receiving estrogen replacement therapy and who have no contraindications to estrogen therapy.39

SPONTANEOUS BACTERIAL PERITONITIS

Spontaneous bacterial peritonitis (SBP) in patients with cir - rhosis is associated with increased morbidity and mor - tal ity. Aerobic gram-negative organisms and streptococci are the most frequent causes of this infection. In a recent Cochrane review of 12 treatment trials, empirical oral or parenteral antimicrobial treatment of patients with cirrho-sis and upper gastrointestinal (UGI) bleeding reduced the incidence of bacterial infections and was associated with shortened hospital stays and reduced rates of overall mor-tality, mortality from bacterial infections, and rebleeding.40 No one antibiotic regimen or route of administration was found to be superior. On the basis of these data, 7 days of empirical antibiotics are recommended for patients with ascites and UGI bleeding16 (Table 1). In prospective ran-domized clinical trials, primary prophylaxis in high-risk patients and secondary prophylaxis after an initial epi-sode of SBP have been shown to be effective in preventing SBP.41-44 A recent Cochrane review of 7 trials of empirical AP to prevent SBP in cirrhotic patients with ascites without UGI bleeding revealed a pooled reduction in SBP and mor-

TABLE 2. Duration of Secondary Rheumatic Fever Prophylaxisa

Category Duration after last attack

Rheumatic fever with carditis 10 years or until 40 years of age and residual heart disease (whichever is longer), sometimes (persistent valvular diseaseb) lifelong prophylaxisa

Rheumatic fever with carditis 10 years or until 21 years of age but no residual heart disease (whichever is longer) (no valvular diseaseb) Rheumatic fever without 5 years or until 21 years of age carditis (whichever is longer)

a See text and Gerber et al4 for discussion.b Clinical or echocardiographic evidence.Adapted from ,4 with permission from the American Heart Association.

tality but noted issues with trial methodology and findings suggestive of systematic bias in publication and design.45 A 1998 analysis concluded that prophylaxis in high-risk patients (serum bilirubin level >2.5 mg/dL [to convert to μmol/L, multiply by 17.104]; ascitic fluid protein level, <1 g/dL) is cost-effective.46 The American Association for the Study of Liver Diseases has published guidelines that recommend long-term daily AP for patients with previous SBP and for primary prophylaxis in those with an ascitic fluid protein level of less than 1.5 g/dL and at least 1 of the following criteria: a serum creatinine level of 1.2 mg/dL or higher (to convert to μmol/L, multiply by 88.4), a blood urea nitrogen level of 25 mg/dL or higher (to convert to mmol/L, multiply by 0.357), a serum sodium level of 130 mEq/L or less (to convert to mmol/L, multiply by 1), or a Child-Pugh score of 9 points or higher with a bilirubin level of 3 mg/dL or higher16 (Table 1). Before initiation of AP, SBP should be ruled out in all patients with ascites at hospital admission and in cirrhotic patients with ascites with signs, symptoms, or laboratory abnormalities sugges-tive of infection.16

ACUTE NECROTIZING PANCREATITIS

Severe pancreatitis with necrosis is associated with an over-all mortality rate of 17% and a mortality rate of 25% to 30% with infected necrosis. Debate is ongoing as to whether AP in the setting of acute necrotizing pancreatitis (ANP) leads to improved outcomes (some consider the use of antibiot-ics in this setting preemptive).47 A recent Cochrane data-base review of 7 randomized studies concluded that patients randomized to receive AP for ANP had no statistically sig-nificant reduction in infections.48 Recent practice guidelines published by the American College of Gastroenterology do not recommend AP for ANP.49 If AP is initiated, a broad-spectrum β-lactam such as imipenem-cilastatin is often rec-ommended and should be limited to computed tomography–documented pancreatic necrosis involving 30% or more of the pancreas for 14 days or less.50

BITE WOUND INFECTION

Five percent of dog bites and 30% of cat bites become secondarily infected because these wounds are highly con-taminated by microorganisms present in the oral cavity of these animals. These infections can lead to septic arthritis, tenosynovitis, severe soft tissue infection, or sepsis.51 The microbiology of dog and cat bite infections is typically polymicrobial and includes species as the most common isolate, followed by staphylococci, streptococci, and anaerobes.52 Although AP for animal bites remains controversial, a meta-analysis of 8 clinical trials by Cum-mings53 found that AP significantly protects against sub-sequent wound infection. Antimicrobial prophylaxis of a

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contaminated wound may be more accurately considered to prevent the development of a wound

infection in a contaminated but not yet infected wound. No clinical trials have shown superiority of one antibiotic regimen over another; choices should be based on the likely microbiology of dog and cat bite infections.54 Antimicrobial prophylaxis for bite wounds has recently been reviewed and should be offered to all patients who are thought to have an increased risk of infection17 (Table 1). High-risk situations include, but are not limited to, bites to body areas where deeper structures (tendons and bones) can become easily in-jured, bites to the hand(s) or close to a bone or joint, crush injuries, puncture wounds (difficult to clean), bites in which treatment is delayed more than 8 to 10 hours, wounds requir-ing closure, bites in compromised persons (diabetic patients, persons with no spleen, immunocompromised patients), bites in persons with indwelling prosthetic devices, and all cat bites.17,18 Consideration for hospitalization and intrave-nous antibiotics may be reasonable for patients in the set-ting of fever, sepsis, spread of cellulitis, significant edema or crush injury, loss of function, compromised immunity, or patient nonadherence to treatment.19 All dog and cat bites should be appropriately irrigated and débrided, and rabies prophylaxis should be administered, if indicated. Delayed primary closure of heavily contaminated wounds should be considered to decrease the risk of wound infection. Human bite wounds, including clenched fist injuries, are considered to be at high-risk of infection with organisms such as , , , and anaerobes. Recommended AP is similar to that for ani-mal bite wounds17,55 (Table 1). Patients who have sustained human bites should be assessed for human immunodeficien-cy virus (HIV) and hepatitis B infection risk, and prophylaxis should be offered as indicated according to published guide-lines. Tetanus immune globulin and tetanus toxoid should be administered to patients who have not been immunized or tetanus toxoid alone to any patient who has not received a tetanus booster within the past 5 years.

PERTUSSIS

Pertussis (whooping cough), an upper respiratory tract infection caused by , is associated with prolonged bouts of coughing that may last 1 to 6 weeks. Numerous pertussis outbreaks have occurred in the United States during the past 6 years among adolescents and adults as immunity from childhood vaccination has waned. Because pertussis is spread by aerosolized respira-tory droplets, it is recommended that all household and other close contacts of infected patients who did not use respiratory precautions while in contact with an infected patient receive AP, regardless of age or immunization sta-tus20 (Table 1).

The first tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine, adsorbed (Tdap) licensed for adults was approved by the FDA in 2005 (ADACEL; Sanofi Pasteur; Swiftwater, PA [US Headquarters]; Lyon, France [Global Headquarters]) as a single-dose booster vac-cine for persons aged 11 to 64 years to provide protection against tetanus, diphtheria, and pertussis. Tdap was initially recommended to replace the next adult booster dose of teta-nus- and diphtheria-toxoid vaccines in patients whose last tetanus booster was 10 years or more earlier. The interval between the most recent tetanus vaccination and Tdap for persons with contact with infants, child care providers, or health care professionals with direct patient contact could be as short as 2 years or less.56 Given the poor adult pertus-sis vaccine coverage (5.9% in 200857), and in the setting of increasing numbers of pertussis cases in the United States (16,858 cases in 2009, including 14 infant deaths58), the Per-tussis Vaccine Working Group of the Advisory Committee on Immunization Practices59 recommends the administration of a single Tdap (either ADACEL or BOOSTRIX [GlaxoS-mithKline Biologicals; Morrisville, NC]), when indicated, for any adult, at any interval since the previous tetanus-diph-theria vaccination. A single Tdap should be considered for adults 65 years or older who have or anticipate having close contact with an infant younger than 12 months as well as for children aged 7 through 10 years who are not fully vaccinat-ed against pertussis. Tdap is not licensed for revaccination. A provisional recommendation from the Advisory Committee on Immunization Practices (February 23, 2011) states that the data on the need for postexposure AP for Tdap-vacci-nated health care professionals are inconclusive.60 In view of this, Tdap-vaccinated health care professionals may still be at risk of acquiring pertussis and should be considered for chemoprophylaxis (CP) after a significant pertussis expo-sure, particularly if they are likely to be exposed to a patient at risk of severe pertussis, such as hospitalized neonates and pregnant women.

INFECTIVE ENDOCARDITIS

Infective endocarditis is a relatively rare endocardial infec-tion that can lead to catastrophic complications and death. Guidelines for the prevention of IE have been published by the American Heart Association for more than 50 years. The first 9 guidelines (1955-1997) were based on low-level evidence; more recently, guidelines have been stratified ac-cording to the lifetime risk of IE. The recommendations of the most recent (2007) guidelines reflected a new reticence about using AP for IE based on the following premises: (1) cumulative bacteremia risk is much greater with daily ac-tivities than dental procedures; (2) antibiotics do not elimi-nate bacteremia or clearly reduce IE risk; (3) there are no prospective, placebo-controlled AP trials; and (4) even if

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100% effective, antibiotics would prevent only rare cases of IE.61 The 2007 AP guidelines for IE from the Ameri-can Heart Association and the Infectious Diseases Soci-ety of America (IDSA) recommend AP only for patients at highest risk of complications of IE (Table 3) and only for selected dental procedures (Table 4). Administration of prophylactic antibiotics is no longer stratified according to lifetime IE risk. The antibiotics that are recommended for IE prophylaxis before dental procedures are listed in Table 5. Patients receiving a penicillin for RF prophylaxis should not receive a penicillin for IE dental prophylaxis. Prophylaxis is no longer recommended for uncompli-cated gastrointestinal bronchoscopy without incision of the respiratory mucosa and for urinary procedures. If the urine is colonized or infected before an elective cystoscopy, anti-biotic therapy to eradicate the infection before the urologic manipulation is recommended. If an urgent cystoscopy is to be performed in the setting of colonized or infected urine, then an antibiotic with activity against enterococci should be administered. Ampicillin or amoxicillin are the preferred agents in this setting; vancomycin should be used in the set-ting of severe penicillin intolerance. Urinary tract coloniza-tion or infection with enterococci known or suspected to be resistant (including those resistant to vancomycin) may re-quire a consultation with an infectious diseases expert.61

TABLE 3. Cardiac Conditions Associated With the Highest Risk of Adverse Outcome From Endocarditis for Which Prophylaxis With

Dental Procedures Is Reasonable

Prosthetic cardiac valve or prosthetic material used for cardiac valve repairPrevious infective endocarditisCongenital heart disease (CHD)a

Unrepaired cyanotic CHD, including palliative shunts and conduits Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 mo after the procedureb

Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization)Cardiac transplantation recipients who develop cardiac valvulopathy

a Except for the conditions listed above, antimicrobial prophylaxis is no longer recommended for any other form of CHD.

b Prophylaxis is reasonable because endothelialization of prosthetic mate-rial occurs within 6 mo after the procedure.

From ,61 with permission from the American Heart Association.

TABLE 4. Dental Procedures for Which Endocarditis Prophylaxis Is Reasonable for Patients in Table 3

that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosaa

a The following procedures and events do not need prophylaxis: routine anesthetic injections through noninfected tissue, taking dental radio-graphs, placement of removable prosthodontic or orthodontic appli-ances, adjustment of orthodontic appliances, placement of orthodontic brackets, shedding of deciduous teeth, and bleeding from trauma to the lips or oral mucosa.

From ,61 with permission from the American Heart Association.

Although many respiratory tract procedures reportedly cause bacteremia involving a wide variety of microorgan-isms, no published data conclusively demonstrate a link between these procedures and IE. Antimicrobial prophy-laxis (for regimens, see Table 5) is thought to be reasonable for patients at highest risk of complications from IE (Table 3) who undergo invasive procedures of the respiratory tract that involve incision or biopsy of the respiratory mucosa (eg, tonsillectomy, adenoidectomy). Patients at highest risk of complications from IE who undergo an invasive respira-tory tract procedure to treat an established infection, such as drainage of an abscess or empyema, should receive an antibiotic that is active against the viridans group strepto-cocci. If an infection is known or suspected to be caused by , the antibiotic regimen should contain an an-tistaphylococcal penicillin or a cephalosporin for patients who are unable to tolerate a penicillin. Vancomycin should be used in those in whom an infection is known or sus-pected to be caused by a methicillin-resistant strain of S

or in those who have a history of a severe reaction to β-lactam antibiotics.61

PROSTHETIC JOINT INFECTIONS

By 2030, an estimated 4 million total knee or hip arthro-plasties will be performed annually in the United States.62 Prosthetic joint infections (PJIs), which are rare but serious complications of prosthetic joint replacements (PJRs), oc-cur in 0.3% to 1.0% of patients after primary total hip re-placement and 1.0% to 2.0% of patients after primary total knee replacements, with the greatest risk occurring during the first 2 postoperative years (6.5, 3.2, and 1.4 infections per 1000 patient-years during the first year, second year, and after the second year, respectively).63,64 These infec-tions may be associated with devastating financial and per-sonal consequences. Most PJIs are acquired in the operating room as a result of colonization of the prosthesis at the time of implantation or airborne contamination of the wound.63 Infection of a prosthesis via hematogenous seeding is a less common cause of PJI. Among PJIs occurring via the he-matogenous route, most are the result of bactere-mia, skin infections, or urosepsis.65-67 The development of a PJI due to hematogenous seeding after dental procedures is thought to be a rare event. According to a recent literature review, this occurred in 0.04% to 0.20% of reported PJR case series; many of these infections were seen in patients with dental disease.68 Pins, plates, and screws not within the synovial joint are not thought to be at increased risk of hematogenous seeding by microorganisms. No stud-ies have shown that AP before dental procedures prevents PJI.69 A recently published prospective case-control study concluded that dental procedures were not risk factors for subsequent total hip or knee infection. Additionally, the use

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TABLE 5. Regimens for a Dental Procedurea

Regimen: single dose 30 to 60 min before procedure

Situation Agent Adults Children

Oral Amoxicillin 2 g 50 mg/kgUnable to take oral medication Ampicillin 2 g IM or IV 50 mg/kg IM or IV OR Cefazolin or ceftriaxone 1 g IM or IV 50 mg/kg IM or IV

Allergic to penicillins or Cephalexinb,c 2 g 50 mg/kg ampicillin—oral OR Clindamycin 600 mg 20 mg/kg OR Azithromycin or clarithromycin 500 mg 15 mg/kg

Allergic to penicillins or ampicillin Cefazolin or ceftriaxonec 1 g IM or IV 50 mg/kg IM or IV and unable to take oral medication OR Clindamycin 600 mg IM or IV 20 mg/kg IM or IV

a IM = intramuscularly; IV = intravenously.b Or other first- or second-generation oral cephalosporin in equivalent adult or pediatric dosage.c Cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema, or urticaria with penicil-

lins or ampicillin.Adapted from ,61 with permission from the American Heart Association.

of AP before dental procedures did not decrease the risk of subsequent total hip or knee infection.70

Despite the lack of data supporting AP before dental procedures, many surveys of health care professionals have shown that a substantial number of them recommend AP before dental procedures in patients with a PJR.71,72 Anti-microbial prophylaxis for patients with a prosthetic joint undergoing a dental procedure or other invasive medical procedure has been controversial for decades.67,71,73-75 Con-sensus guidelines for this practice were initially published in 1997 and affirmed in 2003 by the American Dental Association (ADA) and the American Association of Or-thopedic Surgeons (AAOS) on the basis of low-level evi-dence.69,76 It was proposed that AP be administered before dental procedures thought most likely to be associated with bacteremia for patients who were considered to be at high-est risk of bacteremia-associated PJI. High-risk patients are thought to include all patients during the first 2 years after joint replacement, immunocompromised or immunosup-pressed patients, patients with comorbid conditions (eg, diabetes, obesity, HIV infection, smoking), and patients with inflammatory arthropathies (eg, rheumatoid arthritis), systemic lupus erythematosus, medication- or radiation-in-duced immunosuppression, previous PJI, malnourishment, hemophilia, HIV infection, insulin-dependent (type 1) dia-betes, megaprosthesis, or malignancy. More recently (Feb-ruary 2009), the Patient Safety Committee of the AAOS posted an Information Statement (IS) advising that “clini-cians consider antibiotic prophylaxis for…all total joint replacement patients prior to any invasive procedure that may cause bacteremia.”77 The ADA no longer supports the 2003 AAOS/ADA Guidelines and refers patients and health

care professionals to the AAOS IS (Karen London, Ameri-can Dental Association, written communication, March 28, 2011).77 Although specific dental procedures that may cause bacteremia are not listed in the AAOS IS, the ADA lists the dental procedures that may cause bacteremia in the AAOS/ADA 2003 guidelines.76,77 The antibiotics recommended in the AAOS IS to be administered to patients with PJR before dental procedures include 2 g of oral cephalexin, cephradine, or amoxicillin 1 hour before dental procedures. The AAOS IS makes no mention of parenteral antibiotic options or an-tibiotic alternatives for penicillin-allergic patients. The 2003 AAOS/ADA advisory statement recommended 1 g of intra-venous cefazolin or ampicillin as parenteral antibiotic alter-natives or 600 mg of clindamycin (intravenous or oral) for penicillin-allergic patients, to be administered 1 hour before the dental procedure; in our opinion, these remain valid anti-biotic alternatives.76

A panel that included representatives from the ADA, AAOS, and IDSA was recently convened with the goal of producing an evidence-based antimicrobial guideline for patients with PJR before dental procedures (D.R.O. is a member of the working group). It is hoped that this will lead to a simpler consensus guideline for patients and health care professionals. Good dental health before and after total joint replacement and prompt treatment of active oral infection should be encouraged for all patients with PJR. Antimicrobial prophylaxis in patients undergoing in-vasive gastrointestinal procedures is not recommended by the American Society of Colon and Rectal Surgeons78 or the American Society for Gastrointestinal Endoscopy.79 If clinicians elect to recommend AP for the prevention of he-

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matogenous PJI in these patients, they should discuss with them the possibility of life-threatening adverse reactions (rare) and the more common drug toxicities. If used, anti-microbial agents should be chosen on the basis of the ex-pected flora at the site of the procedure. The American Urological Association (AUA) and the AAOS first published consensus- and expert opinion–based AP guidelines in 2003 for patients with total joint replace-ment who were undergoing urologic procedures.80 Antimi-crobial prophylaxis is recommended for patients at increased risk of hematogenous PJI who undergo urologic procedures associated with an increased risk of bacteremia. The details of these recommendations can be found in the 2007 AUA Best Practice Policy Statement on Urologic Surgery Anti-microbial Prophylaxis, which is available on the AUA Web site.80,81 The guidelines assume that the urine is sterile preop-eratively. If bacteriuria is present, it should be treated with appropriate antibacterial agents before manipulation of the urinary tract.

TRAVELERS’ DIARRHEA

Antibacterial agents have been shown to decrease the risk of travelers’ diarrhea by up to 84%.82-84 Antimicrobial agents are not routinely recommended for the prevention of travelers’ diarrhea because antibiotic self-treatment is so rapidly effec-tive. The traveler may be instructed to carry a supply of an antibiotic (often a 1- to 3-day course of a fluoroquinolone for travel to Central or South America or Africa or of azithromy-cin when traveling to Asia or the Indian subcontinent) to be taken on an as-needed basis.12 In certain circumstances (risk-averse travelers, athletes, persons taking antacids, or persons with diabetes, an elevated gastric pH, or inflammatory bowel disease), a daily oral antibiotic regimen may be considered on a short-term basis (ideally <2-3 weeks) to prevent travel-ers’ diarrhea. Fluoroquinolones may be less effective in areas with quinolone-resistant species infections (eg, India, Southeast Asia), so an agent such as azithromy-cin (250 mg once daily) may be considered, although this has not been studied. In a 14-day study among travelers to Mexico, rifaximin (200 mg 1-3 times daily) was 72% effec-tive in preventing travelers’ diarrhea.23 Bismuth subsalicylate prophylaxis (Pepto-Bismol [Proctor & Gamble; Cincinnati, OH]: two 262-mg chewable tablets 4 times daily, with meals and once in the evening) is less effective (62%-65% effective) than antibiotics, is inconvenient to take, contains a salicylate (to be avoided if receiving anticoagulant therapy or high-dose salicylates), causes a black tongue, and may interfere with the absorption of medications such as doxycycline.12 Probiotics containing GG or are of limited efficacy (0%-60% effective) in the prevention of travelers’ diarrhea and generally are not recommended for this purpose.85,86

OPEN FRACTURES

Open fractures, particularly Gustilo grade 3 fractures, are at an increased risk of infection.87 The key to infection avoid-ance of open class III fractures is wound irrigation, surgi-cal débridement of devitalized tissue, and delayed wound closure. A recent Surgical Infection Society Guideline rec-ommended AP with a first-generation cephalosporin after open fracture until 24 to 48 hours after wound closure.88 Some groups recommend adding gram-negative coverage for class III open fractures.89

HERPES SIMPLEX VIRAL INFECTION

Frequent recurrent genital herpes simplex viral infections (>5-6 episodes per year) are amenable to prophylaxis with continuous acyclovir (400 mg twice daily), famciclovir (250 mg twice daily), or valacyclovir (500-1000 mg once daily).90,91 Famciclovir may be less effective for suppres-sion of viral shedding, and 500 mg of valacyclovir once daily might be less effective than other valacyclovir or acy-clovir dosing regimens in patients who have very frequent recurrences (ie, ≥10 episodes per year).91 Patients should be counseled regarding consistent condom use and avoidance of sexual activity during recurrences in addition to suppres-sive antiviral therapy.

INFLUENZA

Chemoprophylaxis of influenza A and B infection with a neuraminidase inhibitor (zanamivir [inhaled] or oseltam-ivir [oral]) is 70% to 90% effective92,93 (Table 1). These agents are particularly useful for prophylaxis after expo-sure in unvaccinated high-risk patients and unvaccinated health care professionals in an outbreak setting in a medi-cal institution or community. Chemoprophylaxis is rec-ommended for persons who are at high risk of influenza complications (Table 6) and those who are hospitalized or have severe, complicated, or progressive illness.94 Low-risk, healthy persons who are not in contact with high-risk patients do not typically require CP. Adults for whom anti-viral CP should be considered during periods of increased influenza activity in the community are listed in Table 7. Zanamivir and oseltamivir are classified as category C (risk cannot be ruled out) for use during pregnancy. Influ-enza CP should be considered as an adjunct to influenza vaccination. Chemoprophylaxis should not be adminis-tered 48 hours before or 2 weeks after administration of the intranasal live-attenuated FluMist influenza vaccine (MedImmune, Gaithersburg, MD); CP has no effect on the inactivated influenza vaccine.21 Chemoprophylaxis may be stopped 10 days after exposure for household contacts and 7 days after other exposures.94 For control of outbreaks in long-term care facilities and hospitals, the Centers for Dis-ease Control and Prevention recommends CP for a mini-

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TABLE 6. Persons at High Risk of Influenza Complicationsa,b,c

Children aged <5 y (especially <2 y)

Adults aged >65 yc

Persons with chronic disorders, including the following: Pulmonary (including asthma) Cardiovascular (except hypertension alone) Renal Hepatic Hematologic (including sickle cell disease) Metabolic (including diabetes mellitus)

Persons with neurologic and neurodevelopment conditions,d including the following: Cerebral palsy Epilepsy Stroke Intellectual disability (mental retardation) Moderate to severe developmental delay Muscular dystrophy Spinal cord injury

Persons who are immunosuppressed as a result of medication or HIV infection

Women who are pregnant or postpartum (within 2 wk after delivery)

Persons aged ≤18 y who are receiving long-term aspirin therapy

American Indians and Alaska Natives

Persons who are morbidly obese (ie, BMI ≥40)

Residents of nursing homes and other long-term care facilities

a BMI = body mass index; HIV = human immunodeficiency virus.b Influenza vaccination is the primary tool to prevent influenza; antiviral

chemoprophylaxis is not a substitute for vaccination. Chemoprophylaxis should be administered in conjunction with inactivated vaccination.

c Highest risks for morbidity and mortality include the very elderly (aged >85 y) residents of nursing homes and those severely immunosuppressed (eg, allogenic stem cell transplant recipients).

d Affecting brain, spinal cord, peripheral nerve, or muscle.Adapted from ,22 with permission from Oxford University Press, and from .94

TABLE 7. Adults for Whom Antiviral Chemoprophylaxis Should Be Considered During Periods of Increased Influenza

Activity in the Communitya,b,c

Persons at high risk during the 2 wk after influenza vaccinationa

Persons at highest risk of influenza complications for whom influenza vaccine is contraindicated, unavailable, or a poor match (at particularly high risk are recipients of hematopoietic stem cell transplants, pregnant women, and those infected with the human immunodeficiency virus)

Family members or health care professionals who are unvaccinated and are likely to have ongoing, close exposure to persons at high risk, unvaccinated persons, or infants aged <6 mo

Persons at high risk, their family members and close contacts, and health care professionals, when circulating strains of influenza virus in the community are not matched with the vaccine strains

Persons with immune deficiencies or those who might not respond to vaccination (eg, persons who are infected with the human immunodeficiency virus, who have other immunosuppressed conditions, or who are receiving immunosuppressive medications)

Vaccinated and unvaccinated staff and other persons during response to an outbreak in a closed institutional setting with residents at high risk (eg, extended-care facilities)

a Chemoprophylaxis should be administered in conjunction with inacti-vated vaccination.

b Chemoprophylaxis does not need to be limited to these people.c Updates or supplements to these recommendations might be required.

Health care professionals should be alert to the announcement of recommendation updates and should check the Centers for Disease Control and Prevention influenza Web site periodically for additional information.

Adapted from ,22 with permission from Oxford University Press, and from .95

mum of 2 weeks, even for vaccinated persons, up to 1 week after the last known case was identified.22,94 In patients who are unable to receive influenza vaccination and who are at high risk of complications, treatment should be continued for the duration of the influenza season in the community. Oseltamivir- and zanamivir-resistant influenza A strains have been reported; one should monitor the Centers for Disease Control and Prevention influenza Web site (http://www.cdc.gov/flu) for seasonal updates. The adamantanes (amantadine and rimantadine) are active only against in-fluenza A; with the emergence of adamantane resistance in most seasonal A H3N2 and pandemic 2009-2010 A H1N1 strains, these agents are no longer recommended for CP.

SURGICAL AP

Surgical site infections account for 14% to 18% of all health care infections and are the third most frequently re-ported nosocomial infection.96,97 Factors that may increase the risk of surgical site infection include those related to

the patient (age, nutritional status, diabetes, smoking sta-tus, obesity, coexisting infections at a remote site, coloni-zation with a pathogenic microorganism, altered immune response, and length of preoperative stay) and the operative procedure (duration of surgical scrub, skin antisepsis, pre-operative shaving, preoperative skin preparation, duration of operation, AP, operating room ventilation, inadequate sterilization of instruments, foreign material at the surgical site, surgical drains, and surgical technique).98 The risk of surgical site infection also depends on whether the surgi-cal procedure is clean, clean-contaminated, contaminated, or dirty-infected based on standard definitions of these terms.98 Improvements in operating room ventilation, ster-ilization methods, barriers, and surgical technique as well as the use of perioperative topical, oral, and intravenous AP have been important in decreasing the incidence of surgical site infection.98,99

Perioperative antimicrobial surgical prophylaxis is recommended for operative procedures that have a high rate of postoperative wound infection, when foreign ma-terial is implanted, or when the wound infection rate is low but the development of a wound infection results in a disastrous event.98-100 Prophylactic antimicrobial agents should be bactericidal, nontoxic, and inexpensive and

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TABLE 8. Antimicrobial Prophylaxis for Surgerya,b

Nature of operation Common pathogens Recommended antimicrobial agents Adult dosage before surgeryc

Cardiacd (prosthetic valve, s, Cefazolin 1-2 g IV every 8 he

coronary artery bypass, coagulase-negative or Cefuroxime102 1.5 g IV every 12 h open heart surgery)103,104 staphylococci or Vancomycind,f 15 mg/kg IV every 12 h

Thoracic (noncardiac) , coagulase-negative Cefazolin 1-2 g IV every 8 h staphylococci, enteric gram- or Cefuroxime 1.5 g IV every 12 h negative bacilli or Vancomycin 15 mg/kg IV every 12 h

Pacemaker or defibrillator , coagulase-negative Cefazolin 1-2 g IV every 8 h implant10,105,106 staphylococci or Vancomycin 15 mg/kg IV every 12 h

Gastrointestinal Esophageal, gastroduodenal Enteric gram-negative bacilli, High-risk patients onlyg gram-positive cocci Cefazolinh 1-2 g IV every 8 h Biliary tract107-109 Enteric gram-negative bacilli, High-risk patientsi only enterococci, clostridia Cefazolinh 1-2 g IV every 8 h Colorectal110b Enteric gram-negative bacilli, Oral enterococci, anaerobes Neomycin sulfate NA Erythromycin basej

or Metronidazolej Parenteral Cefoxitinh or cefotetanh 1-2 g IV or Cefazolin 1-2 g IV Metronidazole 0.5 g IV or Ampicillin-sulbactamh 3 g IV Appendectomy, Enteric gram-negative bacilli, Cefoxitinh or cefotetanh 1-2 g IV nonperforatedk enterococci, anaerobes or Cefazolin 1-2 g IV Metronidazole 0.5 g IV or Ampicillin-sulbactamh 3 g IV

Genitourinary81 Enteric gram-negative bacilli, Cystoscopy alone enterococci High-risk patients onlyl

Ciprofloxacin 500 mg orally or 400 mg IV or Trimethoprim-sulfamethoxazole 1 DS tablet Cystoscopy with manipulation Ciprofloxacin 500 mg orally or 400 mg IV or upper tract instrumentationm Open or laparoscopic surgeryn Cefazolinh 1-2 g IV

Gynecologic and obstetric111 Vaginal, abdominal, or Gram-negative bacilli, enterococci, Cefoxitin,h or cefotetan,h or cefazolinh 1-2 g IV laparoscopic hysterectomy group B streptococci, anaerobes or Ampicillin-sulbactamh 3 g IV Cesarean section112 Same as for hysterectomy Cefazolinh 1-2 g IV Abortion111 Same as for hysterectomy Doxycycline 300 mg orallyo

Head and neck113,114 , oropharyngeal anaerobes, Clindamycin 600-900 mg IV Incision through oral or enteric gram-negative bacilli or Cefazolin 1-2 g IV pharyngeal mucosa Metronidazole 0.5 g IV

Neurosurgical , coagulase-negative Craniotomy/spine115-117 staphylococci Cefazolin 1-2 g IV Cerebrospinal fluid shunting118-121 or Vancomycinf 15 mg/kg IV

Ophthalmic122,123p , coagulase-negative Gentamicin, tobramycin, ciprofloxacin, Multiple drops topically staphylococci, streptococci, ofloxacin, gatifloxacin, levofloxacin, over 2 to 24 h enteric gram-negative bacilli, moxifloxacin species or Neomycin-gramicidin-polymyxin B Cefazolin 100 mg subconjunctivally

have in vitro activity against the common organisms that cause postoperative wound infection after a specific sur-gical procedure. Consensus panels most often recommend cefazolin and other cephalosporins because they meet the aforementioned criteria.98,100 Broad-spectrum antibiotics

(eg, ertapenem) should be avoided for surgical prophy-laxis.100,101 Perioperative antimicrobial surgical prophylaxis regimens for various surgical procedures adapted from the published recommendations of 2 consensus panels are summarized in Table 8.99,100,102 The use of vancomycin

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Orthopedic124,125 , coagulase-negative Cefazolinq or 1-2 g IV every 8 h for 24 h Total joint replacementr staphylococci cefuroximeq 1.5 g IV every 12 h Implantation of internal or Vancomycinf,q 15 mg/kg IV every 12 h fixation device for 2 doses

Vascular126,127 , coagulase-negative Arterial surgery involving a staphylococci, enteric Cefazolin 1-2 g IV every 8 h for 24 h prosthesis, the abdominal gram-negative bacilli or Vancomycinf 15 mg/kg IV every 12 h aorta, or a groin incision for 2 doses Lower extremity amputation , coagulase-negative Cefazolin 1-2 g IV due to ischemia staphylococci, enteric or Vancomycinf 1 g IV (or 15 mg/kg) gram-negative bacilli, clostridia

a DS = double-strength; IV = intravenously; NA = not available.b We agree with the consultants who do not recommend the use of broad-spectrum drugs (eg, ertapenem), third-generation cephalosporins

(eg, cefotaxime, ceftriaxone, cefoperazone, ceftizoxime), or fourth-generation cephalosporins (eg, cefepime) for routine surgical prophylaxis because they are expensive, the activity of some against staphylococci is less than first- or second-generation cephalosporins, and their spectrum of activity in-cludes organisms rarely encountered in elective surgery. These drugs should be reserved for treatment of serious infections, particularly those likely to be caused by organisms resistant to other antimicrobial agents.100

c Parenteral prophylactic antimicrobial agents can be given as a single IV dose begun ≤60 min before the operation. For prolonged operations (>4 h) or those with major blood loss, additional intraoperative doses should be given at intervals 1 to 2 times the half-life of the drug: ampicillin-sulbactam, every 2-4 h; cefazolin, every 2-5 h; cefuroxime, every 3-4 h; cefoxitin, every 2-3 h; clindamycin, every 3-6 h; vancomycin, every 6-12 h; and metronidazole, every 6-8 h102 for the duration of the procedure in patients with normal renal function. If vancomycin or a fluoroquinolone is used, the infusion should be started 60-120 min before the initial incision to minimize the possibility of an infusion reaction close to the time of induction of anesthesia and to have adequate tissue levels at the time of incision.

d The Society of Thoracic Surgeons recommends vancomycin plus cefazolin in patients not allergic to penicillins who are at increased risk of methicillin-resistant staphylococcal surgical site infections and nasal mupirocin in all patients who are nasally colonized with or in whom nasal colonization status is unavailable.104 Adjunctive decolonization of carriers may also decrease the incidence of surgical site infection.128,129 Dura-tion of prophylaxis up to 48 h may be appropriate.

e Some consultants recommend an additional dose when patients are removed from bypass during open heart surgery.f Vancomycin can be used in hospitals in which methicillin-resistant (MRSA) and are a frequent cause of postopera-

tive wound infections, in patients previously colonized with MRSA, or in those who are allergic to penicillins or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is administered for a period of 60 min, hypotension may occur; treatment with diphenhydramine and further slowing of the infusion rate may be helpful. Some experts would give 15 mg/kg of vancomycin to patients weighing more than 75 kg, up to a maximum of 1.5 g, with a slower infusion rate (1.5 g for 90 min). For operations in which enteric gram-negative bacilli are common pathogens, adding another drug, such as an aminoglycoside (gentamicin, tobramycin, or amikacin), may be reasonable.

g Patients with morbid obesity, esophageal obstruction, decreased gastric acidity, decreased gastrointestinal motility, hemorrhage, gastric cancer, gastric bypass, or percutaneous endoscopic gastrostomy are at high risk, as are those being treated with an H

2 blocker or a proton pump inhibitor.130 Some experts

recommend prophylaxis for all gastroduodenal operations in which there is entry into the lumen of the gastrointestinal tract.99

h For patients allergic to penicillins and cephalosporins, clindamycin with either gentamicin, ciprofloxacin, levofloxacin, or aztreonam is a reasonable alternative.

i Risk factors for infection resulting from biliary procedures, including laparoscopic cholecystectomy: emergency procedures, diabetes, longer procedure duration, intraoperative gallbladder rupture, age >70 y, open cholecystectomy, conversion of laparoscopic to open cholecystectomy, higher American Society of Anesthesiologists (ASA) score, episode of colic within 30 d before surgery, reintervention in <1 mo for noninfectious complications, acute cholecystitis, bile spillage, jaundice, pregnancy, nonfunctioning gallbladder, immunosuppression, obstructive jaundice, common duct stones, or insertion of a prosthetic device. Some experts recommend prophylaxis for all biliary operations.99

j 1 g of neomycin plus 1 g of erythromycin at 1 pm, 2 pm, and 11 pm or 2 g of neomycin plus 2 g of metronidazole at 7 pm and 11 pm the day before an 8 am operation.

k For a ruptured viscus, therapy is often continued for about 5 d (therapeutic course).l Preoperative urine culture positive or unavailable, preoperative catheter, transrectal prostatic biopsy, or placement of prosthetic material.m Shockwave lithotripsy, ureteroscopy.n Including percutaneous renal surgery, procedures with entry into the urinary tract, and those involving implantation of a prosthesis. If manipulation of the

bowel is involved, prophylaxis is given according to colorectal guidelines.o Divided into 100 mg an hour before the abortion and 200 mg a half hour after.p There is no consensus supporting a particular choice, route, or duration of antimicrobial prophylaxis for ophthalmic surgeries.122

q If a tourniquet is to be used in the procedure, the entire dose of antibiotic must be infused before its inflation.r Antibiotic containing polymethyl methacrylate cement in addition to cefazolin or vancomycin may be appropriate for high-risk procedures, including

revision arthroplasty.73 Adjunctive decolonization of carriers may also decrease the incidence of surgical site infection.131

Adapted from ,100 with special permission, and from ©1999. American Society of Health-System Pharmacists, Inc. All rights reserved. Distributed with permission (R1109).

TABLE 8. Continueda,b

Nature of operation Common pathogens Recommended antimicrobial agents Adult dosage before surgeryc

698



for prophylaxis is appropriate in the event of true type I hypersensitivity or other serious reaction to penicillin or when the incidence of surgical site infection is high due to methicillin-resistant staphylococci.132 Adherence to this practice will help to avoid the emergence of vancomycin-resistant organisms and vancomycin-related toxicity.133-136

Prophylactic antimicrobial agents should be administered not more than 30 to 60 minutes before surgery, including cesarian sections.100,112,137,138 Exceptions to this include oral administration of antimicrobial agents before colonic and urologic procedures (Table 8). Infusions should be com-pleted before the tourniquet is placed with orthopedic sur-geries. Vancomycin and fluoroquinolone infusions should be started 90 to 120 minutes before surgical incision be-cause these require at least 1 hour to infuse. Therapeutic concentrations of antimicrobial agents should be present in the tissue throughout the period that the wound is open. Additional antibiotic doses may need to be administered intraoperatively for prolonged procedures or with antimi-crobial agents with short half-lives.102,139 Initiating intrave-nous antimicrobial therapy before the perioperative period provides no benefit. Prolonged postoperative AP should be discouraged because of the possibility of added antimicro-bial toxicity, selection of resistant organisms, and unnec-essary expense. The duration of AP for most procedures should not exceed 24 hours, with the exception of cardiac surgeries, in which antibiotics may be continued for up to 48 hours.99,100,102,103,140 The duration of antibiotic therapy for ophthalmic procedures has not been established. An advi-sory statement for AP in dermatologic surgery has been published recently.141 The IDSA, American Society of Health-System Pharmacists (ASHP), Society for Health-care Epidemiology of America, and Surgical Infection So-ciety are currently in the process of revising the 1999 ASHP Antimicrobial Prophylaxis in Surgery Guideline.99

In 2002, the Center for Medicaid and Medicare Ser-vices implemented a quality initiative project, currently entitled the Surgical Care Improvement Project (SCIP), in an attempt to decrease postoperative surgical site infec-tions.140 As part of the SCIP, medical institutions are be-ing graded on 3 surgical AP performance measures with cardiothoracic, vascular, colon, hip/knee, and vaginal or abdominal hysterectomy surgeries: (1) the proportion of patients who have parenteral AP initiated within 1 hour before surgical incision, (2) the proportion of patients who are provided an antibiotic agent that is consistent with currently published guidelines, and (3) the propor-tion of patients whose prophylactic antibiotic is discon-tinued within 24 hours after the end of the operation (48 hours for cardiothoracic surgery). The most up-to-date list of approved antibiotics for various surgeries is posted on the SCIP Web site.140

CONCLUSION

The use of AP has led to the prevention of a large num-ber and variety of infections and to substantial declines in surgical site infections. Antimicrobial prophylaxis should be limited to specific, well-accepted indications to avoid excess cost, toxicity, and antimicrobial resistance. Patients should understand the potential risks and benefits of any AP regimen. Although some AP practices are evidence-based, many are based on low-level evidence or expert opinion. More studies in the area of AP are needed.

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108. Higgins A, London J, Charland S, et al. Prophylactic antibiotics for elec-tive laparoscopic cholecystectomy: are they necessary? . 1999;134(6): 611-613. 109. Meijer WS, Schmitz PI, Jeekel J. Meta-analysis of randomized, con-trolled clinical trials of antibiotic prophylaxis in biliary tract surgery. . 1990;77(3):282-290. 110. Baum ML, Anish DS, Chalmers TC, Sacks HS Smith H Jr, Fager-strom RM. A survey of clinical trials of antibiotic prophylaxis in colon sur-gery: evidence against further use of no-treatment controls. . 1981;305(14):795-799. 111. American College of Obstetricians and Gynecologists (ACOG) Com-mittee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No. 104: antibiotic prophylaxis for gynecologic procedures. . 2009; 113(5):1180-1189. 112. American College of Obstetricians and Gynecologists (ACOG) Com-mittee. Antimicrobial prophylaxis for cesarean delivery: timing of administra-tion: . 2010;116(3):791-792. 113. Simo R, French G. The use of prophylactic antibiotics in head and neck oncological surgery. . 2006;14:55- 61. 114. Weber RS. Wound infection in head and neck surgery: implications for perioperative antibiotic treatment. . 1997;76(11):790-791, 795-798. 115. Barker FG II. Efficacy of prophylactic antibiotics for craniotomy: a meta-analysis. . 1994;35(3):484-490. 116. Barker FG II. Efficacy of prophylactic antibiotics in spinal surgery: a meta-analysis. . 2002;51(2):391-400. 117. Barker FG II. Efficacy of prophylactic antibiotics against meningitis after craniotomy: a meta-analysis. . 2007;60(5):887-894. 118. Infection in Neurosurgery Working Party of the British Society for Anti-microbial Chemotherapy. Antimicrobial prophylaxis in neurosurgery and after head injury. . 1994;344(8936):1547-1551. 119. Haines SJ, Walters BC. Antibiotic prophylaxis for cerebrospinal fluid shunts: a metanalysis. . 1994;34(1):87-92. 120. Langley JM, LeBlanc JC, Drake J, Millner R. Efficacy of antimicrobial prophylaxis in placement of cerebrospinal fluid shunts: meta-analysis. Clin In

. 1993;17(1):98-103. 121. Ratilal B, Costa J, Sampaio C. Antibiotic prophylaxis for surgical in-troduction of intracranial ventricular shunts: a systematic review.

2008;1:48-56. 122. DeCroos FC, Afshari NA. Perioperative antibiotics and anti-inflamma-tory agents in cataract surgery. . 2008;19:22-26. 123. Liesegang TJ. Perioperative antibiotic prophylaxis in cataract sur-gery [published correction appears in 2000;19(1):123]. . 1999;18(4):383-402. 124. Gillespie WJ, Walenkamp G. Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures.

. 2001;(1): CD000244. 125. Prokuski L. Prophylactic antibiotics in orthopaedic surgery.

. 2008;16:283-293.

126. Homer-Vanniasinkam S. Surgical site and vascular infections: treatment and prophylaxis. . 2007;11(suppl 1):S17-S22. 127. Stewart AH, Eyers PS, Earnshaw JJ. Prevention of infection in peripher-al arterial reconstruction: a systematic review and meta-analysis. . 2007;46:148-155. 128. Kluytmans JA, Mouton JW, VandenBergh MF, et al. Reduction of surgical-site infections in cardiothoracic surgery by elimination of nasal carriage of . . 1996; 17(12):780-785. 129. Perl TM, Cullen JJ, Wenzel RP, et al. Intranasal mupirocin to prevent postop-erative infections. . 2002;346:1871-1877. 130. Rey JR, Axon A, Budzynsak A, Kruse A, Nowak A. Guidelines of the European Society of Gastrointestinal Endoscopy (ESGE) antibiotic prophy-laxis for gastrointestinal endoscopy. . 1998;30(3):318-324. 131. Gernaat-van der Sluis AJ, Hoogenboom-Verdegaal AMM, Edixhoven PJ, Spies-van Rooijen NH. Prophylactic mupirocin could reduce orthopedic wound infections: 1,044 patients treated with mupirocin compared with 1,260 historical controls. . 1998;69:412-414. 132. Centers for Disease Control and Prevention (CDC). Recommendations for preventing the spread of vancomycin resistance: recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR

. 1995;44(RR-12):1-13. 133. Centers for Disease Control and Prevention (CDC). Interim guide-lines for prevention and control of staphylococcal infection associated with reduced susceptibility to vancomycin. 1997;46(27):626-628; 635. 134. Centers for Disease Control and Prevention (CDC). Reduced suscepti-bility of to vancomycin—Japan, 1996.

. 1997;46(27):624-626. 135. Centers for Disease Control and Prevention (CDC).

with reduced susceptibility to vancomycin—United States, 1997 [pub-lished correction appears in 1997;46:851].

. 1997;46(33):765-766. 136. Southorn PA, Plevak DJ, Wright AJ, Wilson WR. Adverse effects of vancomycin administered in the perioperative period. Mayo Clin Proc. 1986;61:721-724. 137. Burke JF. The effective period of preventive antibiotic action in experi-mental incisions and dermal lesions. . 1961;50:161-168. 138. Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of antibiotics and the risk of surgical wound infection. . 1992;326(5):281-286. 139. Zanetti G, Giardina R, Platt R. Intraoperative redosing of cefazo-lin and risk for surgical site infection in cardiac surgery. . 2001;7:828-831. 140. Surgical Care Improvement Project (SCIP). QualityNet Web site. http://www.aha.org/aha/issues/Quality-and-Patient-Safety/scip.html. Accessed May 20, 2011. 141. Wright TI, Baddour LM, Berbari EF, et al. Antibiotic prophylaxis in dermatologic surgery: advisory statement 2008. . 2008;59:464-473.




805

ANTIFUNGAL PHARMACOLOGY


Current Concepts in Antifungal Pharmacology


From the University of Houston College of Pharmacy and The University of Texas M. D. Anderson Cancer Center, Houston.

Dr Lewis receives research support from Merck, Astellas, and Gilead and has served on advisory boards for Merck and Astellas.

Address correspondence to Russell E. Lewis, PharmD, University of Houston College of Pharmacy, Texas Medical Center Campus, 1441 Moursund St, Unit 424, Houston, TX 77030 ([email protected]). Individual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com.


The era of systemic antifungal chemotherapy effectively began with the introduction of amphotericin B-deoxy-

cholate in 1958 by Squibb Laboratories, after exhaustive at-tempts to develop orally bioavailable formulations of more than 200 polyene macrolide antibiotics produced by the soil actinomycete .1 Although amphotericin B was to become the criterion standard treatment for serious fungal infections for more than 40 years, infusion-related adverse effects and dose-limiting nephrotoxicity prompted the con-tinued search for equally effective but less toxic alternatives that could be administered both intravenously and orally. This goal was not realized until more than 3 decades later with the introduction of fluconazole in 1990 (Figure 1). Unlike amphotericin B and the earlier imidazole an-tifungal agents (miconazole, ketoconazole), fluconazole possessed excellent oral bioavailability; predictable linear pharmacokinetics with wide distribution into many tissues, including the cerebral spinal fluid and vitreous chamber of the eye; and a much lower risk of drug interactions and tox-icity in critically ill patients compared with earlier azoles.2 Fluconazole was also effective for the treatment of oropha-ryngeal candidiasis in patients with AIDS; however, resis-tance could be problematic in patients receiving prolonged treatment who had declining CD4+ cell counts.3 Fluconazole

Russell E. Lewis, PharmD

The introduction of new antifungal agents (eg, echinocandins, second-generation triazoles) in the past decade has transformed the management of invasive mycoses to the point that drug toxic-ity is no longer the major limiting factor in treatment. Yet, many of these newer antifungal agents have important limitations in their spectrum of activity, pharmacokinetics, and unique predisposition for pharmacokinetic drug-drug interactions and unusual toxicities associated with long-term use. This article reviews key pharmaco-logical aspects of systemic antifungal agents as well as evolving strategies, such as pharmacokinetic-pharmacodynamic optimiza-tion and therapeutic drug monitoring, to improve the safety and efficacy of systemic antifungal therapy.

Mayo Clin Proc. 2011;86(8):805-817

AUC = area under the curve; CYP = cytochrome P450; 5-FC = flucyto-sine; GI = gastrointestinal; MIC = minimum inhibitory concentration; TDM = therapeutic drug monitoring

quickly became one of the most widely prescribed anti-fungal agents for mucosal and systemic yeast infections. However, the lack of activity against opportunistic molds (ie, , Mucorales, and species) and in-trinsic resistance among some species (eg, Can

, ) created a need for broad-er-spectrum alternatives. Itraconazole (1992) was a partial solution to the limitations of fluconazole because the drug had improved activity against endemic fungi and

species, but the oral dosing formulations were plagued by erratic absorption (capsules)4 or adverse gastrointesti-nal (GI) effects (solution formulation)5 that limited its ef-fectiveness in cancer patients with mucositis or nausea and vomiting.6

The introduction of the broader-spectrum triazoles vori-conazole (2002) and posaconazole (2006) transformed the management of invasive mold infections in severely im-munocompromised patients. Voriconazole was shown to be more effective than conventional amphotericin B for the treatment of invasive aspergillosis7 and is a useful agent for fusariosis,8 whereas posaconazole had a spectrum of activ-ity that included not only and species but also many Mucorales.9,10 Both agents could be admin-istered orally, paving the way for their use not only for the treatment of suspected or documented mold infections but also as prophylaxis in severely immunocompromised pa-tients.11-13 Unfortunately, the broader spectrum of activity with triazole antifungal agents often comes at the expense of increased pharmacokinetic variability and risk of drug interactions. Newer triazoles currently under investigation (ie, isavuconazole) appear to have a spectrum of activity

806



similar to voriconazole and posaconazole, with less phar-macokinetic variability and drug interactions.14 Efforts un-der way to reformulate the posaconazole suspension into better oral and intravenous dosage forms could address many of the drug’s pharmacokinetic shortcomings. The final milestone of antifungal drug discovery in the 20th century was the identification and development of echi-nocandin antifungal agents. Echinocandins are semisyn-thetic lipopeptides that inhibit synthesis of β-1,3-d-glucan in susceptible fungi, leading to damage of the fungal cell wall. Because a glucan-rich cell wall is a target not found in mammalian cells, these agents were predicted to be effec-tive antifungal agents with very little collateral toxicity in mammalian cells—a prediction that has been proven true in clinical trials of patients with invasive candidiasis15-17 and aspergillosis.18 However, echinocandins still lack activity against some common opportunistic yeasts ( species) and less common molds (ie,

, and Mucorales) that often develop as breakthrough infections in severely immunocompromised patients. Therefore, although considerable progress has been achieved since the dawn of systemic antifungal therapy in the 1950s, the current antifungal armamentarium is far from perfect. No single antifungal agent is appropriate for all patients for a given mycosis because of patient-specific comorbid conditions, hypersensitivities, risk of drug in-teractions, immunosuppression, site of infection, and risk of infection with more intrinsically antifungal-resistant pathogens. This article reviews key aspects of the clinical pharmacology of older vs newer antifungal agents, with a particular emphasis on pharmacokinetic issues that arise

with newer agents and emerging data on toxicity with lon-ger-term therapy.

OVERVIEW OF ANTIFUNGAL PHARMACOLOGY

Despite differences in the composition of the cell mem-brane and the presence of the cell wall, fungi are meta-bolically similar to mammalian cells and offer few patho-gen-specific targets. Systemic antifungal agents can be generally grouped on the basis of their site of action in pathogenic fungi (Figure 2). Azole and polyene antifungal agents exert their antifungal effects by targeting ergoster-ol—the principal cell membrane sterol of many pathogenic fungi. By inhibiting 14α-demethylase (lanosterol dem-ethylase), a fungal cytochrome P450 (CYP)–dependent enzyme, azole antifungal agents deplete cell membrane ergosterol, impair membrane fluidity, and lead to accumu-lation of toxic 14α-methylated sterols, resulting in growth arrest and eventual fungal cell death.19 However, this in-hibition is not entirely selective to fungi; indeed, collat-eral inhibition of human CYP enzymes by azoles is often responsible for pharmacokinetic drug-drug interactions. The fungal target for azole binding is a heme-containing pocket on the 14α-demethylase enzyme.20 Differences in the conformation of the 14α-demethylase binding pocket and azole structure largely define the binding affinity of each drug, and in some fungal species, the potential for cross-resistance among triazoles.20 For molecules derived from ketoconazole (ie, itraconazole, posaconazole), exten-sion of the nonpolar side chains enhances azole binding to the 14α-demethylase apoprotein, resulting in an enhanced

FIGURE 1. Timeline of systemic antifungal drugs.

807



spectrum of activity against molds (Figure 3).21 Voricon-azole, a derivative of fluconazole, possesses an α-o-methyl group that confers activity against species and other filamentous fungi.21,22 Resistance to triazole antifun-gal agents is most commonly the result of mutations in the azole binding pocket of 14α-demethylase21,22 and/or the overexpression of efflux pumps that expel flucon-azole or the multidrug adenosine triphosphate–dependent efflux pumps and , which expel all triazoles, thereby leading to cross-resistance.3 Because intrinsic resis-tance in is a result of impaired binding of flucon-azole to 14α-demethylase, newer triazoles with enhanced binding to the enzyme retain activity against fluconazole-resistant strains such as .23 However, fluconazole resistance in is frequently a result of the expres-sion of multidrug efflux pumps; hence, cross-resistance may be observed with all azole antifungal agents.24

Similar to azole antifungal agents, the allylamine ter-binafine inhibits ergosterol biosynthesis by inhibiting

squalene monoxygenase—an enzyme in fungi responsible for conversion of squalene to squalene epoxide, which is a precursor to lanosterol in the ergosterol synthesis path-way.20 Although allylamines do not seem to have the same collateral effects on human CYP enzymes as azole anti-fungal agents, drugs such as rifampin that strongly induce CYP metabolism in mammals will increase the metabolism of terbinafine.25 Once taken orally, terbinafine concentrates in the skin and nail beds and has relatively low bloodstream concentrations.26 Consequently, its use as a systemic anti-fungal agent is primarily restricted to the treatment of ony-chomycosis and cutaneous fungal infections.26

The broad-spectrum polyene amphotericin B is the only other antifungal agent that targets the fungal cell mem-brane (Figure 2). Amphotericin B directly binds to ergos-terol, forming complexes that intercalate the cell mem-brane, thereby resulting in pore formation and leakage of intracellular contents.27 Amphotericin B has greater avidity for ergosterol-rich fungal cell membranes vs cholesterol-rich

FIGURE 2. Sites of action and mechanisms of systemic antifungal agents. FKS1, FKS2 catalytic subunits of the glucan synthase complex are the putative target binding site of echinocandins. Rho is a cell wall–regulating protein. *Isavuconazole is still in phase 3 trials.

Cell membrane

Cell wall

Intracellular

Ergosterol inhibitors/binders

Imidazoles

Triazoles

Mechanism Drug class Drugs

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mammalian cell membranes; however, this specificity may be lost when the drug accumulates to high concentrations in or-gans such as the kidney, where the drug causes direct damage to distal tubular membranes.28 Consequently, nephrotoxicity is a common dose-limiting adverse effect of amphotericin B therapy. Amphotericin B also directly stimulates release of proinflammatory cytokines by mononuclear phagocytic cells, often resulting in fever, rigors, and chills during drug infu-sion.29,30 This infusion reaction can be attenuated to varying degrees by reformulation of amphotericin B into lipid carri-ers. However, the principal advantage of lipid amphotericin B formulations are their reduced distribution of amphotericin B to the kidneys, which reduces but does not eliminate the neph-rotoxicity of amphotericin B.31 Two formulations of amphot-ericin B—a liposomal formulation and a lipid complex—are now commonly used to treat a wide range of invasive fungal infections. Although development of amphotericin B resis-tance during therapy is a rare clinical phenomenon, substitu-tion of alternative cell wall sterols3,32 and increased resistance to oxidative damage in the cell membrane through increased production of neutralizing enzymes33 are 2 mechanisms that have been identified in clinical isolates exhibiting innate or acquired resistance to amphotericin B.

Of the antifungal agents currently in clinical use, echi-nocandins are the only ones that target the fungal cell wall by competitively inhibiting the synthesis of β-1,3-d-glucan polymers—key cross-linking structural components of the cell wall in some pathogenic fungi (Figure 2).34 Echinocan-dins bind to the β-1,3-d-glucan synthase enzyme complex in susceptible fungi, resulting in a glucan-depleted cell wall that is susceptible to osmotic lysis, especially in rapidly growing cells.35 The degree of β-1,3-d-glucan polymeriza-tion in the fungal cell wall and the expression of the glu-can synthase enzyme target largely define the spectrum of this antifungal class, which is generally considered to have fungicidal activity against species and fungistatic activity against species (Figure 3).36 Although bona fide echinocandin resistance remains a relatively rare clinical phenomenon, mutations in defined “hot spot” re-gions of the and catalytic subunits of the glu-can synthase are associated with reduced echinocandin inhibitory activity against the enzyme, higher minimum inhibitory concentrations (MICs), and an increased risk of treatment failure.37

Two groups of antifungal agents selectively target in-tracellular processes in fungi via mechanisms analogous to

FIGURE 3. Spectrum of action of systemic antifungal agents. Solid blocks represent species in which the antifungal agent has demon-strated microbiological and clinical efficacy. Blocks with dotted lines indicate fungal genera/species in which resistance is common. AMB = amphotericin; ANID = anidulafungin; CAS = caspofungin; 5-FC = flucytosine; FLU = fluconazole; ITRA = itraconazole; MICA = micafungin; POSA = posaconazole; VORI = voriconazole.

Candida albicansCandida tropicalis

Candida parapsilosisCandida krusei

Candida glabrataCryptococcus neoformans

Aspergillus fumigatusAspergillus terreus

MucoralesFusarium species

Histoplasma capsulatumBlastomyces dermatitidis

Coccidioides immitis

AMB FLU ITRA VORI POSA ANID CAS MICA 5-FC

Yeas

tsM

olds

Dim

orph

ic

Polyene Triazoles Echinocandins Other

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those of cancer chemotherapeutic agents and are generally not effective as monotherapy for systemic mycoses (Figure 2). Flucytosine (5-FC) is selectively taken up by 2 fungus-specific enzymes, cytosine permease and cytosine deami-nase, and is converted to cytostatic 5-fluorouracil in fungal cells, where the active drug inhibits thymidylate synthase and causes RNA miscoding.28,38 However, resident intes-tinal bacterial flora in the human gut can convert 5-FC to 5-fluorouracil, resulting in nausea, vomiting, diarrhea, and bone marrow suppression.28,39 Flucytosine is primarily ac-tive against yeasts but must be given in combination with other drugs to avoid resistance that arises with mutations in cytosine permease and cytosine deaminase, resulting in decreased importation and conversion of the drug to its ac-tive form (Figure 3).39 Griseofulvin is a systemic antifungal agent that binds to tubulin, interfering with microtubule for-mation. Because the drug concentrates in keratinocytes, it is

only used for noninvasive dermatophyte infections. Interest-ingly, griseofulvin inhibits the proliferation of many types of cancer cells in vitro, which has led to renewed interest in this agent as a potential adjunctive treatment for breast cancer.

PHARMACOKINETIC CONSIDERATIONS

Besides spectrum of activity, antifungal pharmacokinetic properties are often the most important consideration in drug selection because impaired GI tract function or re-duced renal/hepatic drug clearance can profoundly influ-ence the safety and efficacy of antifungal therapy. Key pharmacokinetic characteristics of systemic antifungal agents are summarized in Table 1. Several classes of antifungal agents must be admin-istered intravenously, including amphotericin B and the echinocandins, because these agents are not sufficiently

TABLE 1. Comparative Pharmacokinetic and Pharmacodynamic Properties of Systemic Antifungal Agentsa

Oral PK:PD Typical bioavail- C

max AUC Protein CSF Vitreous Urine Metabo- Elimina- T

1/2 (total drug

Drug adult dosing ability (μg/mL) (mg × h/L) (%) (%) (%) (%) lism tion (h) unless indicated)

AMB 0.6-1.0 mg/kg/d <5 0.5-2.0 17.0 >95.0 0-4 0-38b,c 3-20 Minimal Feces 50 Cmax

:MIC 4-10 or AUC:MIC >100 ABCD 4 mg/kg/d <5 4.0 43.0 >95.0 <5 0-38b,c <5 Minimal ND 30 ND ABLC 5 mg/kg/d <5 1.7 14.0 >95.0 <5 0-38b,c <5 Minimal ND 173 C

max:MIC >40 or

AUC:MIC >100

LAMB 3-5 mg/kg/d <5 83 555 >95.0 <5 0-38b,c 5 Minimal Minor 100- Cmax

:MIC >40 or urine; 153 AUC:MIC >100 fecesFLU 6-12 mg/kg/d >90 6-20 400-800 10.0 >60 28-75b,c 90 Minor Renal 31 AUC:MIC >25 hepaticITRAd 200 mg twice daily 50 0.5-2.3 29.2 99.8 <10 10b 1-10 Hepatic Hepatic 24 AUC:MIC >25 VOR 6 mg/kg every 12 h >90 3.0-4.6 20.3 58.0 60 38b,c <2 Hepatic Renal 6 AUC:MIC >25 for 2 doses, then 4 mg/kg every 12 h POS 600-800 mg/d in ND 1.5-2.2 8.9 99.0 ND 26b,c <2 Modest Feces 25 AUC:MIC >400 divided doses hepatic (8-25 free drug)ANIe 200 mg × 1 loading dose, <5 6-7 99 84.0 <5 0c <2 None Feces 26 C

max:MIC >10 or

then 100 mg/d serum (unbound) AUC:MIC >20 CAS 70-mg loading <5 8-10 119 97.0 <5 0b <2 Hepatic Urine 30 C

max:MIC >10 or

dose, then serum (unbound) 50 mg/d AUC:MIC >20 MICAb 100-150 mg/d; <5 10-16 158 99.0 <5 <1c <2 Hepatic Feces 15 C

max:MIC >10 or

50 mg/d serum (unbound) (prophylaxis) AUC:MIC >20 5-FC 100 mg/kg/d in 80 30-40 30-62 4.0 60-100 49c 90 Minor Renal 3-6 Time > MIC divided doses intestinal 20%-40%

a ABCD = amphotericin B colloidal dispersion; ABLC = amphotericin lipid complex; AMB = amphotericin B; ANI = anidulafungin; AUC = area under the curve; CAS = caspofungin; C

max = maximum concentration; CSF = cerebrospinal fluid; 5-FC = flucytosine; FLU = fluconazole; ITRA = itraconazole; LAMB = liposomal AMB; MIC =

minimum inhibitory concentration; MICA = micafungin; ND = not determined; PK-PD = pharmacokinetics-pharmacodynamics; POS = posaconazole; VOR = voriconazole; T

1/2 = half-life.

b Data derived from human studies.c Data derived from animal studies.d Oral solution formulation.e Data are for the 100-mg dose.

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absorbed from the GI tract. This problem has been solved with the introduction of triazole antifungal agents; how-ever, the degree of absorption varies considerably from one drug to the next (Table 1). Fluconazole and voriconazole both have oral bioavailability exceeding 90% and can be administered without regard to food (fluconazole) or pref-erably on an empty stomach (voriconazole).40 Itraconazole capsules and posaconazole suspension require food to pro-long gastric residence time to enhance drug dissolution, which is not an issue with the oral cyclodextrin formulation of itraconazole that is administered on an empty stomach. However, patients may prefer to take itraconazole solution with food because of GI intolerance and the unpalatable aftertaste of the solution.41

The oral absorption of a posaconazole suspension can be unpredictable in patients with poor appetite, nausea, diarrhea, and GI dysfunction associated with cancer che-motherapy (mucositis) or transplant (graft-vs-host disease involving the gut, colitis) or in patients taking acid suppres-sion therapy, especially with potent agents such as proton pump inhibitors.42,43 Absorption of posaconazole is dose limited at 800 mg/d but can be maximized when the drug is administered with a high-fat (>50% of the calories from fat) food or nutritional supplement.44 Administration of the drug in divided doses improved the exposure by 180% compared with a single daily dose.42,45 Therefore, posaconazole is usu-ally initiated at doses of 200 mg 3 to 4 times daily with food in patients with suspected or documented infections until infection stabilizes or adequate serum levels can be veri-fied (see Therapeutic Drug Monitoring section). Dosing can then be transitioned to 400 mg twice daily. Inadequate posa-conazole concentrations are better addressed with clinical approaches that improve drug dissolution and absorption (eg, administration with acidic cola or fruit juice or a high-fat meal, discontinuation of acid suppression therapy) than increasing drug doses above 800 mg/d. Unlike posaconazole, genetic variability in metabolism plays a more important role in the patient-to-patient phar-

macokinetic variability of voriconazole.46 Polymorphisms in the CYP2C19-encoding gene result in 3 populations of patients with markedly different rates of nonlinear vori-conazole clearance despite the administration of the same fixed daily dose: (1) homozygous patients who extensively metabolize voriconazole, (2) heterozygous patients with moderate clearance rates of voriconazole, and (3) homozy-gous patients who metabolize drug poorly through this pathway and have slow rates of voriconazole clearance.47 The poor metabolism genotype is more common in some ethnic groups, such as patients of Asian or Pan-Pacific ori-gin (14%-19%), than in patients of African origin or whites (2%).47 In contrast, pediatric patients often exhibit more rapid linear clearance of voriconazole, which may result in low or undetectable serum drug concentrations at standard adult doses.48,49 Therefore, higher weight-based doses are recommended in children (7 mg/kg every 12 hours, some-times increased up to 12 mg/kg every 12 hours without a loading dose) (Table 1). Drug interactions are another important cause of phar-macokinetic variability because coadministration of any triazole or caspofungin with potent inducers of phase 1 (CYP) and phase 2 metabolism (ie, rifampin, phenytoin) can potentially result in low (fluconazole, caspofungin, posaconazole) or undetectable (itraconazole, voriconazole) bloodstream concentrations of the antifungal agent and an increased risk of treatment failure.50 In the case of itracon-azole, voriconazole, and posaconazole, interactions with potent inducers of CYP3A4 cannot always be overcome with higher antifungal drug doses.51-54

Pharmacokinetic drug-drug interactions are further compounded by the fact that some antifungal agents inhibit the clearance or metabolism of other drugs. Nephrotoxicity associated with amphotericin B therapy (often accelerated by calcineurin inhibitors, aminoglycosides, intravenous ra-diocontrast agents, foscarnet, or aggressive diuresis) will reduce the clearance of other renally eliminated drugs.55 Pharmacokinetic drug-drug interactions are most problem-atic, however, with triazole antifungal agents because all of these agents inhibit human CYP enzymes to varying de-grees (Table 2).56,57 These interactions can be dangerous if not anticipated in patients receiving drugs with a narrow therapeutic index, such as chemotherapeutic agents, immu-nosuppressants, and some cardiovascular medications. Al-though a detailed discussion of drug interactions is beyond the scope of this review, several recent reviews have been published on this topic.50,57-59

Finally, the site of infection is an important consider-ation in the selection of antifungal therapy because some antifungal agents have limited distribution to anatomi-cally privileged sites, such as the central nervous system and vitreous fluid, or, in the case of oral itraconazole and

TABLE 2. Cytochrome P450 (CYP) Inhibition Profile of Triazole Antifungal Agents

Flu- Itra- Posa- Vori- Mechanism conazole conazole conazole conazoleInhibitor CYP2C19 + – – +++ CYP2C9 ++ + – ++ CYP3A4 ++ +++ +++ ++ Substrate CYP2C19 – – – +++ CYP2C9 – – – + CYP3A4 + +++ – +

– = no activity; + = minimal activity; ++ = moderate activity; +++ = strong activity. Data are derived from reference 57.

811



posaconazole, may not achieve sufficient concentrations in the bloodstream to treat hematogenous infection (Table 1). Fungal infections involving the central nervous system are notoriously difficult to treat, and many antifungal agents have high molecular weights and a large degree of protein binding that limit their ability to penetrate the blood-brain barrier.60,61 Of the currently available antifungal agents, 5-FC, fluconazole, and voriconazole have the best penetra-tion in the cerebrospinal fluid and vitreous chamber of the eye.62 However, liposomal amphotericin B and perhaps other triazoles and echinocandins may still achieve con-centrations in the brain parenchyma sufficient to be clini-cally effective.28,63 Lipid formulations of amphotericin B, newer triazole antifungal agents, and echinocandins have no role in the treatment of candiduria because only small amounts of microbiologically active drug are excreted in the urine.58

PHARMACODYNAMIC CONSIDERATIONS

Similar to antibacterial agents, antifungal agents display different patterns of activity in vivo (ie, concentration-independent or concentration-dependent as determined by the shape of the dose-response curve at clinically achieved concentrations).64 These patterns of activity in vivo can often be correlated with the drug dose and the pathogen MIC to identify dosing strategies that maximize antifungal efficacy while reducing the risk of toxicity. Pharmacody-namic data may also be useful for predicting sites of in-fection where antifungal drugs have a higher risk of treat-ment failure (ie, cerebrospinal fluid, vitreous fluid, urine) because inadequate distribution leads to ineffective drug concentrations. Flucytosine displays concentration-independent phar-macodynamic characteristics in vitro and in vivo against

and species; ie, increases in serum drug concentrations above the pathogen MIC do not appre-ciably increase the rate or extent of fungal killing.65 In dose fractionation studies in animals, the ability of a dosage regi-men to maintain serum drug concentrations above the MIC (percent of time greater than MIC of 20%-40%) was the best predictor of 5-FC activity against .65 This realization led in part to studies that used lower doses of 5-FC (100 mg/kg daily) in combination with higher am-photericin B treatment doses for cryptococcal meningitis, even though pharmacodynamic data for 5-FC in the treat-ment of are limited.66

Both in vitro and in vivo amphotericin B and lipid am-photericin B formulations generally display concentration-dependent fungicidal activity that begins to plateau once concentrations surpass the MIC of the infecting pathogen by 4- to 10-fold.67,68 Animal models69 and limited clinical

data70 suggest that a ratio of maximum concentration in se-rum to MIC of greater than 40 is associated with a higher probability of treatment response with liposomal amphot-ericin B. For most adults, standard liposomal amphoteri-cin B doses of 3 to 5 mg/kg should surpass the maximum concentration to MIC ratio of 40 unless the pathogen has an MIC of 2 μg/mL or greater. Moreover, a recent study that examined the benefits of dosage escalation to 10 mg/kg daily of liposomal amphotericin B in patients with proven or probable aspergillosis found that the escalated dosage provided no benefit over the 3 mg/kg daily dosage and nearly doubled the rate of nephrotoxicity and severe hypokalemia.71

The concentration-dependent activity of echinocandins against 72,73 and 74 species is optimized when the free-drug (non–protein-bound) serum area under the curve (AUC):MIC ratio approaches 20 for or 7 for less virulent isolates of and

.72 These pharmacokinetic-pharmacodynamic targets are generally achieved with currently recommended echinocandin dosages for greater than 90% of isolates with MICs less than 0.575 (Table 1). However, initial echinocan-din breakpoints for defining nonsusceptible MICs were set at greater than 2 μg/mL, suggesting that a portion of iso-lates with MICs of 1 to 2 μg/mL that are classified as “sus-ceptible” may not be treatable with currently recommended echinocandin dosages.75 A reassessment of echinocandin breakpoints on the basis of analysis of resistant isolates and molecular-biochemical resistance mechanisms suggested that nonsusceptibility breakpoints should be lowered to 0.25 μg/mL for susceptible, 0.5 μg/mL for intermediate, and 1 μg/mL for resistant with breakpoints of less than 2 μg/mL, 4 μg/mL, and greater than 8 μg/mL for susceptible, intermediate, and resistant , respectively.75

Triazole antifungal agents have perhaps the largest body of experimental and clinical literature establishing a cor-relation between drug dose, organism MIC, and outcome.76 Experimental studies in animals and clinical studies with fluconazole in the treatment of mucosal and invasive can-didiasis suggest that achieving a serum free-drug AUC:MIC ratio of greater than 25 is the parameter most closely linked to successful treatment.76-78 Although less data are available for other triazoles and mold infections, studies in animal models of aspergillosis also suggest that the AUC:MIC ra-tio is the best predictor of treatment response to posacon-azole, with 50% survival at total-drug AUC:MIC ratios of 100 to 150 and maximal responses at a ratio greater than 440 (free-drug AUC:MIC ratio of approximately 8-25).79,80

Clinical trial data for candidal infections have suggest-ed that this pharmacokinetic-pharmacodynamic relation-ship may be helpful for predicting treatment efficacy in

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humans77,81-83 and have formed the basis for susceptibility testing breakpoints in species. For example, iso-lates with fluconazole MICs of 16 or greater would be dif-ficult to treat with a standard dosage of 6 mg/kg daily (ie, 400 mg dose with an AUC of 400 μg/h per liter) because the AUC:MIC falls below 25 at this MIC with the standard dosage. Therefore, isolates with fluconazole MICs of 16 to 32 μg/mL are categorized as “susceptible-dose dependent” instead of “intermediate” because they may still be treat-able provided higher daily dosages of fluconazole are used (ie, 12 mg/kg daily or approximately 800 mg/d). isolates with MICs greater than 64 μg/mL would require fluconazole dosages of 1600 mg/d or greater and there-fore are classified as “resistant.”83 Recent studies using epidemiological cut-off analysis of wild-type susceptible and fluconazole-resistant species, however, have prompted reconsideration of these pharmacodynamics-driven breakpoints because they may not be sufficiently sensitive to detect emerging resistance, especially among non– isolates.84 Therefore, new species-specific MIC breakpoints for fluconazole have been proposed for C

, , and (suscep-tible, ≤2 μg/mL; susceptible-dose dependent, 4 μg/mL; re-sistant, ≥8 μg/mL) while maintaining current breakpoints for (susceptible-dose dependent, ≤32 μg/mL; resistant ≤64 μg/mL).84

THERAPEUTIC DRUG MONITORING OF ANTIFUNGAL AGENTS

Because some antifungal agents exhibit marked vari-ability in bloodstream concentrations that are difficult to predict on the basis of dosing alone, recent treatment guidelines and expert reviews85-88 have recommended therapeutic drug monitoring (TDM) for some antifungal agents in select patient populations. Therapeutic drug monitoring has long played an important role in improv-ing the safety of 5-FC because the drug is frequently ad-ministered with nephrotoxic agents such as amphotericin B that cause wide fluctuations in drug clearance. Bone marrow suppression and hepatotoxicity are the most common dose-limiting toxicities of 5-FC and have been strongly linked to serum peak concentrations greater than 100 μg/mL. In an analysis of 1000 5-FC concentrations from 233 patients with invasive fungal infections, only 20% of patients were found to have “therapeutic” serum concentrations, 5% had undetectable levels, and 39% had serum concentrations that are generally considered to be toxic (>100 μg/mL).89 Therefore, standard weight-based dosages of 5-FC (100 mg/kg daily) should be individual-ized on the basis of the patient’s renal function and serum 5-FC levels, which are determined 2 hours after the ad-

ministration of an oral dose.86,89 Target blood concentra-tions should fall between 20 to 50 μg/mL and be checked during the first week of therapy and 1 to 2 times weekly thereafter if the patient is receiving other nephrotoxic agents or has fluctuations in renal function.86

Mold-active triazole antifungal agents (itraconazole, voriconazole, and posaconazole) are the other antifungal class most frequently recommended for TDM because of erratic absorption (itraconazole and posaconazole), vari-able hepatic clearance (voriconazole), and propensity for multiple drug interactions.86 Several studies have exam-ined the association between itraconazole efficacy and serum drug levels when the drug is administered as pro-phylaxis90,91 or for the treatment5,92-94 of documented in-fections due to , , and

. All of these studies found a higher probability of treatment response when serum trough concentrations determined by bioassay surpassed 6 μg/mL (>1-2 μg/mL by high-performance liquid chromatog-raphy). According to studies by Glasmacher et al90,91 in patients with hematologic malignancy receiving itracon-azole prophylaxis, patients who did not achieve trough concentrations of greater than 0.5 μg/mL (determined by high-performance liquid chromatography) by the first week were at significantly higher risk of subsequent breakthrough aspergillosis. A recent analysis of the as-sociation between itraconazole serum concentrations and toxicity reported that serum concentrations greater than 5 μg/mL (determined by high-performance liquid chroma-tography) or 17 μg/mL (determined by bioassay) were as-sociated with an increased risk of GI adverse effects and peripheral edema.95

Voriconazole serum concentrations may vary up to 100- fold from one patient to the next depending on age, drug dose, concurrent illness, underlying liver function, drug-drug interactions, and genetic polymorphisms affecting CYP2C19 metabolism.46 Pharmacokinetic variability can be especially problematic in patients undergoing he-matopoietic or solid organ transplant because these pa-tients have multiple concomitant conditions affecting voriconazole clearance and are at higher risk of severe drug interactions.96,97

Common adverse effects reported with voriconazole (ie, photopsia, liver function test abnormalities) can be retrospectively correlated with serum drug concentrations, but data are conflicting as to whether specific threshold serum voriconazole concentrations are of tox-icity. For example, an analysis of the association between hepatotoxicity and serum voriconazole concentrations from phase 3 clinical trials revealed the odds of a greater than 3 times the upper limit of normal increase in levels of aspartate aminotransferase, alkaline phosphatase, and

813



bilirubin to be 13.1%, 16.5%, and 17.2%, respectively, for every 1-μg/mL increase in voriconazole plasma con-centrations, especially in recipients of hematopoietic stem cell transplants.98 However, no single concentration was of subsequent hepatotoxicity by receiver operator curve analysis, suggesting that elevated voricon-azole concentrations were a consequence (not necessarily a cause) of hepatic dysfunction. Although less common toxicities have been reported in the setting of high vori-conazole exposures (eg, encephalopathy, hallucinations, hypoglycemia, electrolyte disturbances, pneumonitis), their association with plasma voriconazole concentra-tions are less well established. A stronger case for TDM of voriconazole can be made on the basis of clinical efficacy because inadequate drug exposures that cannot be predicted on the basis of dose alone could increase the probability of treatment failure. Exploratory pharmacokinetic-pharmacodynamic analysis of 3736 plasma samples from 1053 patients enrolled in voriconazole therapeutic studies found that the rate of treatment success appeared proportionately lower in pa-tients with mean plasma concentrations less than 0.5 μg/mL than in patients with concentrations between 0.5 and 5 μg/mL.99 The difference in clinical outcome was not sta-tistically significant, however, because of the heteroge-neous response rates in each quartile of drug exposure—a reflection of the varied response rate among different pa-tient groups included in the analysis (ie, those receiving transplants, those with lymphoma, those with leukemia). Similarly, patients with possible or proven invasive asper-gillosis who have random voriconazole serum concentra-tions less than 2.05 μg/mL were shown to have poorer treatment responses.100 Subsequent studies in adults101 and pediatric patients48 have also demonstrated that the proba-bility of successful outcome while receiving voriconazole therapy declines when trough serum concentrations in pa-tients are less than 1 μg/mL. Therefore, many experts cur-rently recommend dosing voriconazole to achieve trough concentrations of 1 to 5 μg/mL.86

Collectively, most data from single-institution stud-ies and randomized trials suggest that nearly one-third of patients who receive voriconazole at currently ap-proved dosing may be at increased risk of therapeutic failure due to suboptimal drug exposures.86 The absolute threshold voriconazole concentration (ie, 0.5, 1.0, or 2.0 μg/mL) required for clinical efficacy is not well estab-lished and probably varies by infecting pathogen. How-ever, trough concentrations of less than 0.5 μg/mL in patients receiving voriconazole prophylaxis, or trough con-centrations of less than 1 to 2 μg/mL in patients receiving treatment for suspected or documented infection, should prompt an increase in the voriconazole dose by 50- to

100-mg increments or a switch to an alternative agent(s), especially if there is evidence of progressing infection.86

Risk factors for impaired posaconazole absorption and suboptimal serum concentrations include graft-vs-host disease of the gut or chemotherapy-associated mu-cositis, severe nausea and/or diarrhea, poor appetite, and treatment with potent acid suppression therapy or induc-ers of hepatic phase 1/2 metabolism.42,102-105 In 2 pivotal phase 3 trials that evaluated the effectiveness of posacon-azole (200 mg 3 times daily) as antifungal prophylaxis in patients with graft-vs-host disease after hematopoietic stem cell transplant13 or with neutropenia after remission induction chemotherapy for acute myeloid leukemia/myeloid dysplastic syndrome,12 the probability of break-through infections while receiving posaconazole therapy increased significantly when random plasma concentra-tions fell below 0.719 μg/mL.106 Similarly, in an open-label study evaluating posaconazole as salvage ther - apy for invasive aspergillosis,105 the highest clinical re-sponse rates were observed in a cohort of patients who had plasma posaconazole exposures of at least 0.719 to 1.250 μg/mL. Taken together, these studies indicate that plasma con-centrations of posaconazole may serve as a useful surro-gate end point for identifying patients at higher risk of drug failure due to inadequate drug absorption. In the absence of more definitive data, trough concentrations greater than 0.5 μg/mL could be considered a practical provisional target trough concentration for patients receiving posaconazole prophylaxis, with targets of 0.5 to 1.5 μg/mL for patients with documented mold infections.86

The frequency and timing of serum sampling for tri-azole TDM is not well established. Sampling of the trough concentration (immediately before the next dose) once the patient reaches steady state (5-7 days into ther-apy) is the most practical approach and is less prone to sampling error.86,87 Trough concentrations do not provide sufficient information about drug absorption or AUC but can help identify patients with overall low exposures and excessively rapid drug clearance.87 For drugs such as pos-aconazole that have a long half-life but are administered in divided daily doses, the serum concentration curve is relatively flat, so even random samples can identify pa-tients with suboptimal plasma concentrations because of poor drug absorption.

TOXICITIES OF ANTIFUNGAL AGENTS

Although the safety and tolerability of systemic antifungal therapy has improved considerably, a growing proportion of heavily immunocompromised patients are receiving sys-temic antifungal agents for progressively longer treatment

814



courses. As a result, clinicians need to be aware of not only the more familiar dose-limiting toxicities associated with systemic antifungal agents (ie, infusion-related toxicities and nephrotoxicity with amphotericin B, hepatotoxicity with triazole antifungal agents) but also longer-terms risks, including recurrent drug interactions, organ dysfunction, and cutaneous reactions and malignancies31,50 (Figure 4). Oral itraconazole can cause nausea and GI disturbances as-sociated with the cyclodextrin excipient, making it difficult to tolerate for prolonged treatment courses. Itraconazole has also been described as causing (mostly in older adults) a unique triad of hypertension, hypokalemia, and edema that may be related to a negative inotropic effect of the drug or adrenal suppression.107 Therefore, prolonged administra-tion of itraconazole is not recommended in patients with a history of heart failure. Although rash is reported with all antifungal classes in 5% to 15% of patients, voriconazole treatment in am-bulatory patients has been associated with unique reti-noid-like phototoxic reactions that present with cheilitis, erythema, and occasional blistering.108 This phototoxic reaction is not prevented through the use of sunscreens but is generally reversible after discontinuation of ther - apy. However, recent reports have linked this photo - toxic reaction to the subsequent development of squamous

cell car cinoma109 and melanoma,108 suggesting that all patients who re ceive long-term voriconazole treatment should under go careful screening for skin cancer, espe-cially if they manifest evidence of photosensitivity or cu-taneous photodamage.

CONCLUSION

The introduction of new systemic antifungal agents during the past decade has revolutionized the treatment of invasive mycoses. However, with these new therapies comes a need for increased awareness of the limitations in their spectrum of activity, pharmacokinetics, and risk for pharmacokinetic drug interactions. Newer broad-spectrum triazoles, in par-ticular voriconazole and posaconazole, display significant variability in bloodstream concentrations from one patient to the next that may necessitate TDM in select situations to guide drug therapy and dosing. Long-term toxicities have become more of a concern because ambulatory patients with long-term immunosuppression are taking antifungal therapies for prolonged periods. For most patients, how-ever, the benefits of safer and more effective antifungal therapy vastly outweigh the manageable risks of develop-ing toxicity and undertreating a life-threatening systemic fungal infection.

FIGURE 4. Common toxicities of antifungal agents. CNS = central nervous system; 5-FC = flucytosine; GI = gastroin-testinal; IV = intravenous; QTc = corrected QT interval.

Rash (all antifungal agents)Photosensitivity/malignancy? (voriconazole)

5-FC

Amphotericin B (anemia associated with decreased epoetin production)

Cardiomyopathy (itraconazole)

QTc prolongation (all azoles, especially with drug interactions)

Amphotericin BEchinocandins

ItraconazolePosaconazole5-FC

All azolesAmphotericin B5-FCEchinocandins

Amphotericin BCyclodextrins possibly toxic (IV voriconazole)

Voriconazole Voriconazole

Hepatic

GI Cardiac Infusion reactions Bone marrow suppression

Renal toxicity CNS Photopsia Cutaneous

815



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. 2008;46(3):327-360. 86. Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug moni-toring: established and emerging indications. . 2009;53(1):24-34. 87. Hope WW, Billaud EM, Lestner J, et al. Therapeutic drug monitoring for triazoles. . 2008;21(6):580-586. 88. Kauffman CA. Histoplasmosis. . 2009;30(2):217-225, v. 89. Pasqualotto AC, Howard SJ, Moore CB, et al. Flucytosine therapeu-tic monitoring: 15 years experience from the UK. . 2007;59(4):791-793. 90. Glasmacher A, Hahn C, Molitor E, et al. Itraconazole for antifungal prophylaxis in neutropenic patients: a meat-analysis of 2181 patients. In: Pro-ceedings of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago IL: 2001. 91. Glasmacher A, Hahn C, Molitor E, et al. Itraconazole trough concen-trations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-beta- cyclodextrin oral solution or coated-pellet capsules. My

. 1999;42(11-12):591-600. 92. Denning DW, Tucker RM, Hanson LH, Hamilton JR, Stevens DA. Itra-conazole therapy for cryptococcal meningitis and cryptococcosis.

1989;149(10):2301-2308. 93. Denning DW, Tucker RM, Hanson LH, et al. Treatment of invasive aspergillosis with itraconazole. . 1989;86(6):791-800. 94. Cartledge JD, Midgely J, Gazzard BG. Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis.

1997;50(6):477-480.

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95. Lestner JM, Roberts SA, Moore CB, et al. Toxicodynamics of itra-conazole: implications for therapeutic drug monitoring. . 2009;49(6):928-930. 96. Trifilio S, Pennick G, Pi J, et al. Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients. . 2007;109(8):1532-1535. 97. Trifilio S, Ortiz R, Pennick G, et al. Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients.

. 2005;35(5):509-513. 98. Tan K, Brayshaw N, Tomaszewski K, et al. Investigation of the po-tential relationships between plasma voriconazole concentrations and vi-sual adverse events or liver function test abnormalities. . 2006;46(2):235-243. 99. VFEND (voriconazole) Tablets, VFEND I.V., (voriconazole) VFEND (voriconazole) Oral Suspension [package insert]. New York, NY: Pfizer; 2004. http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021266s18 ,021267s19,021630s10lbl.pdf. Accessed June 28, 2011. 100. Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. . 2006;50(4):1570-1572. 101. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves safety and efficacy out-comes. 2007;46(2):201-211. 102. Kohl V, Muller C, Cornely OA, et al. Factors influencing pharmaco-kinetics of prophylactic posaconazole in patients undergoing allogeneic




stem cell transplantation. . 2010;54(1):207- 212. 103. Krishna G, Parsons A, Kantesaria B, et al. Evaluation of the phar-macokinetics of posaconazole and rifabutin following co-administration to healthy men. . 2007;23(3):545-552. 104. AbuTarif MA, Krishna G, Statkevich P. Population pharmacokinetics of posaconazole in neutropenic patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. . 2010;26(2):397-405. 105. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergil-losis with posaconazole in patients who are refractory to or intolerant of con-ventional therapy: an externally controlled trial. . 2007;44(1): 2-12. 106. Jang SH, Colangelo PM, Gobburu JV. Exposure-response of posacon-azole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma.

. 2010;88(1):115-119. 107. Ahmad SR, Singer SJ, Leissa BG. Congestive heart failure associated with itraconazole. . 2001;357(9270):1766-1767. 108. Riahi RR, Cohen PR. Voriconazole-associated phototoxicity [letter].

. 2011;17(2):15. 109. Morice C, Acher A, Soufir N, et al. Multifocal aggressive squamous cell carcinomas induced by prolonged voriconazole therapy: a case report.

2010;2010:351084.

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From the Division of Infectious Diseases, Mayo Clinic, Rochester, MN.

The author has no conflicts of interest to declare.

Address correspondence to Raymund R. Razonable, MD, Division of Infec-tious Diseases, 200 First St SW, Rochester, MN 55905 (razonable.raymund @mayo.edu). Individual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com.


Most diseases caused by viral pathogens are self-limited and do not require specific antiviral therapy.

Other than therapies targeting the human immunodefi-ciency virus (HIV), currently available antiviral drugs in the clinical setting target 3 principal groups of viruses—the herpes, hepatitis, and influenza viruses. This review article is structured to discuss antiviral therapeutics on the basis of these 3 major antiviral categories, with the caveat that some drugs discussed in these sections possess other potential applications, such as ribavirin for the treatment of respiratory syncytial virus (RSV) and cidofovir for the treatment of cytomegalovirus (CMV) and other DNA vi-ral infections. Nucleos(t)ide analogues for the treatment of chronic hepatitis B (CHB) may also possess anti-HIV properties, but their clinical utility for the treatment of HIV will be discussed in a separate article in this symposium. Experimental and novel therapies that have not reached clinical application will not be reviewed.

ANTIHERPES DRUGS

ACYCLOVIR

Acyclovir is a synthetic guanosine analogue used for treat-ing herpes simplex virus (HSV) and varicella zoster virus (VZV) infections.1-3 Intravenous (IV) acyclovir provides excellent tissue and fluid penetration, including the ce-rebrospinal fluid (CSF), whereas oral acyclovir provides modest bioavailability of 15% to 30%. Bioavailability is improved with the use of valacyclovir, the valyl ester for-mulation of acyclovir. Acyclovir is excreted by glomerular filtration and tubular secretion. Herpesviruses have varying degrees of susceptibility to acyclovir, with HSV type 1 (HSV-1) being most susceptible, followed by HSV type 2 (HSV-2) and VZV, and to a lesser extent Epstein-Barr virus (EBV).1-3 High acyclovir concen-trations may also inhibit CMV in vitro, but acyclovir is not recommended clinically for CMV treatment. Acyclovir is not active against human herpesvirus (HHV) 6, 7, and 8. To exert antiviral activity, acyclovir be converted to acyclovir-triphosphate; this process is initially catalyzed by

Antiviral Drugs for Viruses Other Than Human Immunodeficiency Virus

Raymund R. Razonable, MD

Most viral diseases, with the exception of those caused by hu-man immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antivi-ral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M2 protein or the en-zyme neuraminidase. Combination therapy with Interferon-α and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combina-tion of nucleos(t)ide analogues. Notably, almost all the nucleos(t)ide analogues for the treatment of chronic hepatitis B possess an-ti–human immunodeficiency virus properties, and they inhibit rep-lication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has lim-ited the clinical utility of M2 inhibitors for the prevention and treat-ment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects.

Mayo Clin Proc. 2011;86(10):1009-1026

ALT = alanine aminotransferase; CHB = chronic hepatitis B; CHC = chronic hepatitis C; CMV = cytomegalovirus; CSF = cerebrospinal fluid; EBV = Ep-stein-Barr virus; FDA = US Food and Drug Administration; HBeAg = hepa-titis B e antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HHV = human herpesvirus; HIV = human immunodeficiency virus; HSV = herpes simplex virus; HSV-1 = HSV type 1; HSV-2 = HSV type 2; IFN = interferon; IV = intravenous; mRNA= messenger RNA; RSV = respiratory syncytial virus; SC = subcutaneous; SVR = sustained virologic response; TK = thymidine kinase; VZV = varicella zoster virus

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viral thymidine kinase (TK) and subsequently by human en-zymes. Acyclovir-triphosphate serves as a competitive sub-strate for viral DNA polymerase, and its incorporation into the DNA chain results in termination of viral replication. Acyclovir is approved for the treatment of primary and recurrent genital HSV infection (Table 1).2,4,5 Topical acy-clovir may be used to treat genital herpes, but the oral for-mulation is generally recommended6; IV acyclovir is used for severe cases.1,4 Suppressive therapy with oral acyclovir is also indicated to reduce the incidence of recurrent geni-tal herpes.4,7

Oral acyclovir is modestly efficacious against orolabial herpes. In immunocompetent individuals, orolabial herpes is often self-limited, and antiviral treatment is generally not recommended.7 However, oral acyclovir may be indicated for severe cases, for those with recurrent orolabial herpes, and in those who are immunocompromised.7,8

Intravenous acyclovir is the first-line treatment for HSV encephalitis9 and should be started as soon as the disease is suspected clinically. Magnetic resonance im-aging of the brain typically demonstrates temporal lobe involvement, and diagnosis is confirmed by detection of HSV DNA in the CSF. Major studies have evaluated the efficacy of 10 days of acyclovir treatment for HSV en-cephalitis; however, the recommended duration of treat-ment in the clinical setting is 2 to 3 weeks because shorter durations have been associated with relapse.10 The treat-ment duration may be further prolonged in immunocom-promised patients.8

Acyclovir is also approved by the US Food and Drug Administration (FDA) for the treatment of VZV11,12; how-ever, young immunocompetent patients with zoster may not require treatment if the lesions are localized and have been present for more than 72 hours. Intravenous acyclovir is recommended for patients with disseminated zoster dis-ease or visceral involvement. Acyclovir treatment of zoster reduces duration of viral shedding, formation of new le-sions, and short- and long-term neuralgia.13 Therapy should be started early, but even delayed initiation of acyclovir may still be beneficial in immunocompromised patients. Short-course prednisone may be added as an adjunct to acyclovir treatment of zoster to improve quality of life, especially in elderly patients. Acyclovir has been used in the treatment of acute retinal necrosis (which is associated with HSV or VZV), eczema herpeticum, and oral hairy leukoplakia due to EBV. Oral acyclovir is used to prevent HSV during the early period after transplant in patients not receiving ganciclovir or val-ganciclovir prophylaxis.14

Acyclovir is generally well tolerated. However, IV acy-clovir may cause reversible nephrotoxicity in 5% to 10% of patients because of intratubular precipitation of acyclovir

crystals. Acyclovir crystalline nephropathy is more com-mon when acyclovir is given as a rapid infusion (reaching serum concentrations >25 μg/mL)15 and in patients with dehydration and preexisting renal impairment.16 Adequate hydration, a slower rate of infusion, and dosing based on renal function may reduce this risk. Reversible neuro-logic symptoms such as delirium and seizures may occur rarely in elderly people and those with renal impairment; this toxicity has been associated with high serum acy - clovir concentrations15 and high CSF levels of its metabo-lite 9-carboxymethoxymethylguanine.17-19 Other adverse effects are gastrointestinal symptoms, myelosuppression, and rash.3,20,21

Acyclovir-resistant HSV has been reported, especially in immunocompromised patients.22-24 Resistance occurs by selection of viral mutants that are deficient in TK (which results in an inability to activate acyclovir) or that have al-tered DNA polymerase with reduced affinity to acyclovir-triphosphate.23

BRIVUDIN

Brivudin is a 5ʹ-halogenated thymidine nucleoside analogue that is highly active against HSV-1 and VZV.25,26 Brivu-din is phosphorylated by viral TK and cellular kinases to brivudin-triphosphate, which serves as a competitive in-hibitor of viral DNA polymerase, thereby terminating viral DNA synthesis. It is available in some countries for the treatment of herpes zoster and herpes simplex. How-ever, concerns about its toxicity halted its clinical develop-ment in the United States. Its metabolite, bromovinyluracil, irreversibly inhibits dihydropyridine dehydrogenase, which regulates nucleoside metabolism. Coadministration with 5- fluorouracil has resulted in lethal bone marrow toxicity and severe gastrointestinal toxicity.25,26

CIDOFOVIR

Cidofovir is a nucleoside analogue used for the treatment of CMV, other herpesviruses, and other DNA viral infec-tions.27 It is available as an IV formulation, and an oral prodrug of cidofovir (known as ) is under clinical development.28 This investigational lipid ester formulation of cidofovir has enhanced bioavailability, resulting in im-proved 50% inhibitory concentrations.28 Direct intraocular injection of cidofovir is contraindicated due to ocular hy-potony.27 Serum cidofovir concentrations decline rapidly after IV infusion, with a half-life of 2 hours; however, the intracellular half-life of active cidofovir-diphosphate is as long as 65 hours. Cidofovir is eliminated by glomerular filtration and tubular secretion; probenecid reduces its ex-cretion by blocking tubular secretion.29,30

Cidofovir is phosphorylated by cellular kinases into cidofovir-diphosphate, a competitive substrate for viral

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TABLE 1. Suggested Antiviral Drugs for the Treatment of Herpesvirus infectionsa,b,c

Virus Clinical disease Drug name (route) Recommended dosage Comments

Herpes simplex Mucocutaneous Acyclovir (IV) 5 mg/kg IV every 8 h IV therapy is preferred for severe and viruses 1 and 2 disease disseminated disease Risk of crystalline nephropathy Acyclovir (oral) 400 mg orally 3 times daily Localized disease and genital herpes 800 mg orally twice daily 200 mg orally 5 times daily Valacyclovir (oral) 1 g orally twice daily First episode of genital herpes 500 mg orally twice daily Recurrent episodes of genital herpes HSV encephalitis Acyclovir (IV) 10 mg/kg IV every 8 h Risk of crystalline nephropathy Long-term Acyclovir (oral) 400 mg orally twice daily suppression (400-800 mg 2 to 3 times daily for HIV-infected patients) Valacyclovir (oral) 500 mg orally once daily Recurrence of <9 episodes per year 1 g orally once daily Recurrence of >9 episodes per yearVaricella zoster Varicella zoster Acyclovir (IV) 10-12 mg/kg IV every 12 h Recommended for immunocompromised virus hosts Acyclovir (oral) 600-800 mg orally 5 times daily Less preferred than valacyclovir because of 1 g orally every 6 h poor bioavailability Valacyclovir (oral) 1 g orally 3 times daily Preferred oral therapy for mild or localized diseaseCMV CMV disease in Ganciclovir (IV) 5 mg/kg IV every 12 h IV therapy is preferred for severe CMV transplant disease, gastrointestinal disease, recipients pneumonia, and encephalitis Transition to oral valganciclovir on clinical and virologic improvement Duration of therapy is guided by CMV surveillance using PCR or pp65 antigenemia Risk of myelosuppression Valganciclovir (oral) 900 mg orally twice daily Indicated for CMV syndrome and mild to moderate CMV disease Duration of therapy is guided by CMV surveillance using PCR or pp65 antigenemia Risk of myelosuppression Foscarnet (IV) Induction: 90 mg/kg every 12 h Second-line therapy OR Indicated for ganciclovir-resistant CMV 60 mg/kg every 8 h disease Maintenance: 90-120 mg/kg High risk of nephrotoxicity and electrolyte every 24 h abnormalities Duration of therapy is guided by CMV surveillance using PCR or pp65 antigenemia Cidofovir (IV) Induction: 5 mg/kg per dose once Alternative treatment of CMV disease; weekly for 2 doses second-line agent Maintenance: 5 mg/kg every 2 wk Indicated for ganciclovir-resistant CMV disease High risk of nephrotoxicity; requires concomitant hydration and probenecid use Duration of therapy is guided by CMV surveillance using PCR or pp65 antigenemia Antiviral Valganciclovir (oral) 900 mg orally once daily Preferred drug for CMV prophylaxis prophylaxis for Duration is generally for 3-6 mo; may be CMV prevention longer for lung transplant recipients in transplant Myelosuppression is major adverse effect recipients Ganciclovir (IV) 5 mg/kg IV once daily Preferred for intestinal transplant recipients or in clinical situations in which absorption is a concern Ganciclovir (oral) 1 g orally 3 times daily Effective for CMV prevention but no longer a preferred drug because of its poor bioavailability; valganciclovir is preferred Valacyclovir (oral) 2 g orally 4 times daily Shown to be effective mainly in kidney transplant recipients; not effective for other organ transplant recipients High doses increase risk of hallucinations and neurologic toxicities

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CMV Preemptive therapy Valganciclovir (oral) 900 mg orally twice daily CMV replication is detected by weekly (continued) for asymptomatic CMV surveillance using PCR or pp65 CMV infection antigenemia in transplant Preferred drug for the treatment of recipients asymptomatic CMV infection in solid organ and hematopoietic stem cell transplant recipients Ganciclovir (IV) 5 mg/kg IV every 12 h Less preferred than valganciclovir because of the logistics of IV administration Oral ganciclovir should not be used for treating active CMV infection CMV retinitis in Valganciclovir (oral) Induction: 900 mg orally twice For sight-threatening retinitis, use in HIV-infected daily for 14-21 d combination with ganciclovir intraocular patients Maintenance: 900 mg orally once implant (see below) daily until immune reconstitution Ganciclovir (IV) Induction: 5 mg/kg IV every 12 h For sight-threatening retinitis, use in for 14-21 d combination with ganciclovir intraocular Maintenance: 5 mg/kg IV every implant (see below) 24 h until immune reconstitution Ganciclovir One sustained-release intravitreal Replace every 6-8 mo until immune (intraocular implant (4.5 mg/implant) reconstitution implant) every 6-8 mo Use in combination with systemic ganciclovir (or valganciclovir) because of the systemic nature of CMV disease Foscarnet (IV) Induction: 90 mg/kg every 12 h Second-line therapy OR Indicated for ganciclovir-resistant CMV 60 mg/kg every 8 h disease Maintenance: 90-120 mg/kg every High risk of nephrotoxicity and electrolyte 24 h abnormalities Cidofovir (IV) Induction: 5 mg/kg per dose once Alternative treatment of CMV disease weekly for 2 doses Indicated for ganciclovir-resistant CMV Maintenance: 5 mg/kg every 2 wk disease High risk of nephrotoxicity; requires concomitant hydration and probenecid use CMV disease other Valganciclovir (oral) Induction: 900 mg orally twice than retinitis daily for 14-21 d in HIV-infected Maintenance: 900 mg orally once patients daily until immune reconstitution Ganciclovir (IV) Induction: 5 mg/kg IV every 12 h Preferred for severe disease (eg, for 14-21 d pneumonitis, encephalitis) and for those Maintenance: 5 mg/kg IV every with poor intestinal absorption 24 h until immune reconstitution Foscarnet (IV) Induction: 90 mg/kg every 12 h Second-line therapy OR Indicated for ganciclovir-resistant CMV 60 mg/kg every 8 h disease Maintenance: 90-120 mg/kg every High risk of nephrotoxicity and electrolyte 24 h abnormalities Cidofovir (IV) Induction: 5 mg/kg per dose once Alternative treatment for CMV disease weekly for 2 doses Indicated for ganciclovir-resistant CMV Maintenance: 5 mg/kg every 2 wk disease High risk of nephrotoxicity; requires concomitant hydration and probenecid use

a CMV = cytomegalovirus; HIV = human immunodeficiency virus; IV = intravenous; PCR = polymerase chain reaction.b Doses are given for persons with normal renal function. Please consult individual drug’s package insert for dose adjustments in persons with impaired

renal function.c No antiviral drugs have been approved for the treatment of Epstein-Barr virus or human herpesviruses 6, 7, and 8.

TABLE 1. Continueda,b,c

Virus Clinical disease Drug name (route) Recommended dosage Comments

DNA polymerase, thereby halting viral DNA synthesis.27 The major clinical indication for cidofovir is the treatment of CMV retinitis in HIV-infected patients (Table 1).31 Ci-dofovir is also used as rescue therapy for immunocompro-mised patients with CMV disease resistant or unresponsive

to ganciclovir.32 Because activation of cidofovir does not rely on viral kinases, it retains activity against CMV with the UL97 mutation and HSV with the TK mutation.33 Re-sistance to cidofovir occurs when the virus develops muta-tions in the DNA polymerase gene (ie, gene

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mutations).33 Cidofovir has also been used off-label for various illnesses, such as acyclovir-resistant HSV disease, condyloma acuminatum, BK virus–associated hemor-rhagic cystitis, JC virus–associated progressive multifocal leukoencephalopathy, and other infections due to double-stranded DNA viruses.34-47

Nephrotoxicity is the most common serious adverse ef-fect of cidofovir.27 The incidence and severity of nephrotox-icity may be reduced by hydration and probenecid.48 Blood cell counts should be monitored to assess myelosuppression, and ophthalmological surveillance is recommended because of the risk of ocular hypotony, uveitis, and iritis.49,50

FAMCICLOVIR

Famciclovir is a diacetyl 6-deoxy analogue of penciclovir. Oral famciclovir is rapidly absorbed and achieves a bio-availability of 77%.51 Famciclovir is metabolized into pen-ciclovir, reaching peak plasma penciclovir concentrations within 1 hour. Because of extensive hepatic metabolism, virtually no famciclovir is detectable in plasma.51 Famci-clovir is excreted renally as penciclovir and its 6-deoxy precursor.9

Famciclovir is active against HSV-1, HSV-2, and VZV, and, to a lesser extent, against EBV. Its mechanism of ac-tion is through penciclovir; penciclovir triphosphate in-hibits herpes DNA synthesis by acting as a substrate for viral DNA polymerase. The major clinical indications for famciclovir use are treatment of herpes zoster, recurrent genital herpes,52 and recurrent herpes labialis.53 Famciclo-vir can also be used as suppression therapy to reduce the risk of recurrent genital herpes as well as oral treatment of uncomplicated varicella in HIV-infected patients. The most common adverse effects of famciclovir are headache and nausea.54 Rare adverse events include jaun-dice, rash, pruritus, somnolence, and confusion.54 Acute re-nal failure has occurred in patients taking inappropriately high doses of famciclovir.

FOMIVIRSEN

Fomivirsen is a 21-nucleotide phosphorothionate oligo-nucleotide complementary to messenger RNA (mRNA) of the immediate-early region of CMV.55-57 Its antiviral prop-erty is exerted by antisense inhibition of target gene ex-pression. Other potential mechanisms of antiviral activity include its nonspecific interactions with viral particles that may prevent adsorption or lead to inhibition of enzymes required for viral DNA synthesis. Fomivirsen is given intravitreally. Its main indication is the treatment of CMV retinitis in patients with AIDS who have not benefited from or are intolerant of standard CMV therapies, or whose virus is resistant to ganciclovir and foscarnet.55-57 The main adverse effect of fomivirsen is

increased intraocular pressure and inflammation. Blurred vision, conjunctival hemorrhage, retinal detachment, and retinal edema are other adverse effects.55-57

FOSCARNET

Foscarnet is a nonnucleoside pyrophosphate analogue that is given intravenously for the treatment of herpesviruses.58 Its pharmacokinetic profile is complicated by a high incidence of nephrotoxicity and by its deposition and subsequent grad-ual release from bone.58 Its half-life depends on the duration of therapy; in patients with normal renal function, the plas-ma half-life is about 2 to 4 hours, but terminal half-lives up to about 8 days may occur when it has accumulated in bones. Foscarnet is excreted through glomerular filtration. Foscarnet selectively inhibits pyrophosphate binding on viral DNA polymerases, thus suppressing HSV-1, HSV-2, and CMV replication. It is also active against VZV, HHV-6, and EBV.59 Unlike ganciclovir, foscarnet does not require intracellular conversion to active triphosphate, thus main-taining activity against herpesviruses with TK or UL97 ki-nase mutations.33

Foscarnet is approved for the treatment of CMV ret-initis in patients with AIDS.58 It has been used to treat other CMV diseases in immunocompromised patients, especially those unable to tolerate ganciclovir and those infected with ganciclovir-resistant virus.60,61 Foscarnet is also used for treating acyclovir-resistant mucocutaneous HSV and VZV in immunocompromised patients.58 On rare occasion, it has been used for prevention of CMV in transplant recipients; however, its toxicity limits this clinical indication.60,61

Nephrotoxicity is the most common serious adverse ef-fect of foscarnet, affecting 30% of patients. It is caused by deposition of foscarnet crystals in the glomerular cap-illary lumen.62,63 Foscarnet may cause myelosuppression, with anemia as the most common effect. It can chelate bi-valent metal ions and may lead to reductions in ionized calcium. Other electrolyte disturbances are hypokalemia, hypomagnesemia, and hypophosphatasemia, which could manifest as paresthesias, cardiac dysrhythmias, and neu-rologic symptoms, including seizures.64 Patients should be hydrated to prevent nephrotoxicity, and electrolyte abnor-malities should be corrected to avoid cardiac and neuro-logic complications.

GANCICLOVIR

Ganciclovir is an acyclic 2ʹ-deoxyguanosine analogue for the management of CMV.65 It is available in oral and par-enteral formulations. Oral ganciclovir is poorly absorbed, with a bioavailability of only 5%.65 Management of active CMV disease is therefore with IV ganciclovir or its oral valyl prodrug valganciclovir. Intravitreal ganciclovir im-

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plants are also available, with minimal systemic absorp-tion. Ganciclovir is excreted renally. Ganciclovir undergoes triphosphorylation to become active, with the initial monophosphorylation catalyzed by UL97-encoded kinase and subsequently by cellular kinases. Ganciclovir triphosphate inhibits viral DNA syn-thesis through competitive incorporation during viral DNA synthesis, thereby leading to DNA chain termination. In vitro, it is 10 times more potent than acyclovir against CMV and EBV and is just as effective as acyclovir against HSV-1, HSV-2, and VZV.66 Ganciclovir is active against HHV-6 and HHV-8 but not against HHV-7.67

Ganciclovir is approved for the treatment of CMV retin-itis in patients with AIDS, the treatment of herpes simplex keratitis, and CMV prophylaxis in transplant recipients. In-travenous ganciclovir may also be used to treat other forms of CMV disease, such as colitis or esophagitis. Induction therapy with IV ganciclovir for CMV retinitis in patients with AIDS has an efficacy of 85% to 95% in stabilizing disease.68 Because it is poorly absorbed, oral ganciclovir should not be used for induction treatment of CMV dis-ease.69 Because CMV disease often recurs or progresses in patients with advanced AIDS, oral or IV ganciclovir (or valganciclovir) is given as maintenance therapy until im-mune reconstitution is achieved.69 Intravitreal ganciclovir may also be surgically implanted for the treatment of CMV retinitis, although this treatment should be used together with systemic therapy with IV ganciclovir or oral valganci-clovir therapy. Oral ganciclovir may be used to prevent CMV in pa-tients with AIDS; however, the benefit of this strategy is not as pronounced in the era of highly active antiretroviral therapy. Although IV and oral ganciclovir have also been used to prevent CMV disease in transplant recipients, val-ganciclovir is currently the preferred drug for this indica-tion.60,61,70 Intravenous ganciclovir is also used as a first-line treatment of CMV disease in bone marrow and solid organ transplant recipients.61

Reversible bone marrow suppression is the most com-mon adverse effect of ganciclovir. Other adverse effects of the drug are rash, pruritus, diarrhea, nausea, vomiting, and increased levels of serum creatinine and liver enzymes. Neurotoxicity may occur occasionally. Resistance to ganciclovir occurs most commonly in severely immunocompromised patients with prolonged exposure to the drug. The most common mechanism for ganciclovir resistance is gene mutation71; this mutation leads to deficiency in the viral kinase that is necessary for the initial phosphorylation of ganciclovir into its active form. A less common mechanism is a mu-tation in the gene, which encodes for the CMV DNA polymerase.71

PENCICLOVIR

Penciclovir is an acyclic guanine analogue that is chemi-cally similar to acyclovir. Because it is poorly absorbed from the gastrointestinal tract, it is only available as topi-cal therapy for mucocutaneous herpes. For systemic use, penciclovir has been reformulated into the oral prodrug famciclovir. The antiviral activity of penciclovir is similar to that of acyclovir, with efficacy against HSV-1, HSV-2, and VZV, and, to a lesser extent, against EBV.72 Penciclovir is monophosphorylated by TK and subsequently by cellular kinases into active penciclovir-triphosphate, which inhib-its herpes DNA polymerase activity by serving as a com-petitive inhibitor of deoxyguanosine triphosphate.73 Penci-clovir is approved as topical therapy for recurrent herpes labialis, resulting in a faster healing rate and reduction in pain and viral shedding.74

VALACYCLOVIR

Valacyclovir, an L-valyl ester prodrug of acyclovir,75 pro-vides a higher bioavailability (55%) than oral acyclovir. After absorption, valacyclovir is hydrolyzed almost com-pletely to acyclovir by first-pass intestinal and hepatic me-tabolism. It achieves peak serum concentration in 1 to 3 hours. Serum acyclovir levels are much higher with vala-cyclovir than with oral acyclovir.75

The mechanism of action and spectrum of activity of valacyclovir is identical to those of acyclovir. It is ap-proved for the treatment of initial or recurrent episodes of genital herpes76 and for the treatment of recurrent herpes labialis.4 Treatment is most efficacious when initiated at the earliest onset of symptoms.4 Suppressive therapy with valacyclovir is recommended to prevent recurrent genital herpes76 and has the potential to reduce transmission to sexual partners.4

Valacyclovir is approved for treatment of VZV. Vari-cella often resolves without antiviral therapy in those who are immunocompetent. However, in immunocompromised patients, such as HIV-infected patients and transplant re-cipients, valacyclovir may be used to treat varicella, even if it is uncomplicated.77 Valacyclovir is the most commonly used drug for the treatment of zoster.75,77 In a randomized double-blind trial of older immunocompetent patients, va-lacyclovir was as effective as acyclovir, with similar resolu-tion rates of cutaneous zoster but accelerated resolution of herpetic pain and a lower risk of postherpetic neuralgia.75 The typical course of zoster treatment is 7 days, and the first dose should be started within 48 hours of rash onset. Treatment can be prolonged, continuing until all lesions have crusted, in immunocompromised patients.77

Valacyclovir has also been used to treat acute retinal necrosis and for prevention of CMV disease in kidney

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transplant recipients.78 Although ganciclovir is the back-bone for CMV prevention in transplant recipients, the efficacy of valacyclovir prophylaxis for CMV preven-tion was demonstrated in kidney transplant recipients.78 However, valacyclovir has not been proven effective for preventing CMV in heart, liver, lung, pancreas, and small bowel transplant recipients. The adverse effects of valacyclovir are similar to those of acyclovir. At very high doses, neurotoxicity characterized by confusion, hallucinations, and seizures may occur,78 especially in elderly patients and in those with dehydration and renal disease. The mechanism of resistance for valacyclovir is identical to that of acyclovir (TK mutation); however, achieving higher serum acyclo-vir levels with valacyclovir could reduce the risk of resis-tance compared with oral acyclovir.

VALGANCICLOVIR

Valganciclovir is the L-valyl ester prodrug of ganciclovir. Oral valganciclovir is well absorbed and converted to gan-ciclovir by first-pass intestinal or hepatic metabolism.79 The bioavailability of ganciclovir after valganciclovir adminis-tration is about 60%, and peak plasma concentrations are achieved in 1 to 3 hours.80,81 Valganciclovir is eliminated renally as ganciclovir.80,82

Valganciclovir exerts its antiviral activity in the form of ganciclovir-triphosphate, which inhibits viral replica-tion by serving as a competitive substrate for CMV DNA polymerase. Valganciclovir was first approved by the FDA for treatment of CMV retinitis in patients with AIDS.83 For immediate sight-threatening lesions, valganciclovir is used in combination with an intravitreal ganciclovir implant. Valganciclovir is also used for preventing CMV disease in high-risk CMV donor-positive/recipient-negative recipi-ents of kidney, heart, or kidney-pancreas transplants.61,84 In the United States, valganciclovir is not approved for preventing CMV disease in liver recipients because of a higher incidence of tissue-invasive CMV disease in pa-tients who received valganciclovir vs oral ganciclovir prophylaxis. In other countries, valganciclovir is used for preventing CMV disease in all solid organ transplant re-cipients. It has recently gained approval for the preven-tion of CMV disease in pediatric heart and kidney trans-plant recipients. It can also be used to preemptively treat asymptomatic CMV infection in transplant recipients.85-88 Valganciclovir was recently demonstrated to be as effec-tive as IV ganciclovir for treating mild to moderate CMV disease in transplant recipients.86,87,89

Bone marrow suppression is the most common adverse effect of valganciclovir. Gastrointestinal manifestations, such as diarrhea, nausea, and vomiting, may be observed. Resistance to valganciclovir occurs through mechanisms

identical to those underlying ganciclovir resistance, ie, through mutations in the gene, which encodes for CMV kinase, and the gene, which encodes for CMV DNA polymerase.71

VIDARABINE

Vidarabine, a purine nucleoside obtained from was historically used for treating HSV and

VZV. Acyclovir has since become the preferred drug for these conditions.90 Vidarabine is currently available only as an ophthalmic solution for treating recurrent epithelial keratitis and acute keratoconjunctivitis.90 Once phosphor-ylated into its active form, vidarabine inhibits viral DNA polymerase. Adverse effects of ophthalmic vidarabine in-clude irritation, pain, photophobia, lacrimation, and occlu-sion of the lacrimal duct.90

ANTIVIRAL DRUGS FOR INFLUENZA

M2 INHIBITORS

Amantadine. Amantadine is a symmetric tricyclic amine that inhibits replication of influenza A virus by im-pairing the function of the membrane protein M

2.91 Present

only in influenza A virus, M2 is an acid-activated ion chan-

nel required for nucleocapsid release.91 Amantadine is well absorbed after oral administration. It has an elimination half-life of 11 to 15 hours and is excreted by glomerular filtration and tubular secretion. Amantadine is effective for treating susceptible influ-enza A virus infection.91 It results in a more rapid func-tional recovery and reduces the duration of fever and other symptoms by about 1 day, if given within 48 hours of dis-ease onset.91 Amantadine is effective as prophylaxis for preventing symptomatic influenza A infection in exposed persons.92,93 It is usually given for 14 days or for at least 7 days after the last confirmed illness. Seasonal influenza vaccination, however, remains the preferred method for prevention. Amantadine is generally well tolerated. Among its ad-verse effects are mild neurologic symptoms such as anxi-ety, disorientation, and headache, especially in elderly pa-tients and those taking neuroaffective drugs. Emergence of amantadine resistance has limited its use in the clinical setting.94,95 Amantadine resistance, characterized by amino acid substitutions in the M

2 protein, emerges within 2 to

4 days of treatment. Because of widespread resistance, amantadine is no longer recommended for empiric treat-ment of influenza.94,95 M

2 mutation confers cross-resistance

with rimantadine. Rimantadine. Rimantadine is a symmetric tricyclic amine that inhibits influenza virus.93 It is well absorbed af-ter oral administration, reaching peak plasma concentration

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in 3 to 5 hours. Rimantadine undergoes extensive hepatic metabolism before it is excreted in the urine. The mechanism of action of rimantadine is similar to that of amantadine; it inhibits the ion channel function of M

2, thereby inhibiting viral uncoating. Rimantadine is indi-

cated for prevention and treatment of influenza A virus93; however, its clinical utility is currently limited by drug resistance.96,97 A few trials that compared amantadine and rimantadine suggested similar efficacy; however, neu-rologic adverse events are less severe and frequent with rimantadine.

NEURAMINIDASE INHIBITORS

Oseltamivir. Oseltamivir phosphate is a prodrug of osel-tamivir carboxylate, which is an inhibitor of neuraminidase that is essential in the replication of influenza A and B vi-ruses.98 Oral oseltamivir is well absorbed and reaches peak serum concentrations in 1 hour. Bioavailability of oseltam-ivir phosphate is at least 75%. The prodrug oseltamivir phosphate undergoes extensive hepatic metabolism via ester hydrolysis. More than 99% of active oseltamivir car-boxylate is excreted renally. Oseltamivir carboxylate, the active drug metabolite, selectively blocks viral neuraminidase, thereby preventing the release of virus from infected cells.98 Oseltamivir is ap-proved for the treatment of children (≥1 year) and adults with influenza A or B viral infections.98 Treatment should start within 48 hours of disease onset and continue for 5 days. Oseltamivir is as effective as the other neuraminidase inhibitor, zanamivir, in reducing the febrile period during infection with influenza A (H1N1), influenza A (H3N2), and influenza B virus.99

Oseltamivir is also used for postexposure prophylaxis against influenza A and B, including pandemic strains. For this indication, oseltamivir should be started within 48 hours of exposure and continued daily for at least 10 days or for up to 6 weeks during an outbreak. A systematic review reported no statistically significant difference between osel-tamivir and zanamivir prophylaxis for preventing symptom-atic influenza among immunocompetent adults.100

The most common adverse effects of oseltamivir are nausea, vomiting, diarrhea, abdominal pain, insomnia, and vertigo. Neuropsychiatric adverse effects, including de-lirium, abnormal behavior, and hallucinations, have been reported. Oseltamivir-resistant influenza A virus has been reported.101-103 Mutations in the neuraminidase gene, such as R292K101 and H274Y,98 account for oseltamivir resistance. Surveillance conducted during the 2009 H1N1 influenza pandemic detected sporadic and infrequent incidence of oseltamivir-resistant pandemic (H1N1) 2009 influenza vi-rus. All resistant viruses had neuraminidase mutations (most commonly H275Y mutation) that conferred resistance to

oseltamivir, but not to zanamivir.104 Oseltamivir resistance among influenza B viruses occurs less frequently.105

Zanamivir. Zanamivir is an inhaled neuraminidase in-hibitor that is used for the treatment and prophylaxis of influenza A and B viruses.106 Zanamivir is not available orally since it is poorly absorbed.106 Inhaled zanamivir pro-duces high concentrations in the respiratory tract where in-fluenza virus infection occurs. About 4% to 20% of inhaled zanamivir is absorbed systemically, producing peak serum concentrations at 1 to 2 hours. The absorbed drug is not metabolized and is excreted unchanged in the urine, while the unabsorbed drug is excreted in the feces.106

The mechanism of action of zanamivir is similar to osel-tamivir, by inhibiting neuraminidase, which is essential for release of newly formed viral particles from infected cells.106 For treatment, zanamivir is given by inhalation twice daily for 5 days, with the therapy begun within 48 hours after symptom onset. Zanamivir can be given once daily for 10 days as postexposure prophylaxis of influenza A and B in household or close contacts. Zanamivir pro-phylaxis during community outbreaks may be given for 28 days. Zanamivir has occasionally been given IV to treat critically ill patients with influenza.107,108

Inhaled zanamivir is well tolerated.106 Acute broncho-spasm with decline in respiratory function has been re-ported; a bronchodilator should be available if given as treatment for patients with underlying pulmonary disease. Other adverse effects include headache and gastrointestinal symptoms. Hypersensitivity reactions and neuropsychiat-ric adverse effects occur rarely.109

ANTIVIRAL DRUGS FOR HEPATITIS AND OTHER VIRUSES

INTERFERONS

Interferons (IFNs) are naturally occurring proteins pro-duced in response to viral infection.110 The 3 major classes of IFNs are α, β, and γ; IFN-α and IFN-β are further classi-fied as type I, whereas IFN-γ is type II.110 Available only in parenteral formulation, more than 80% of a subcutaneous (SC) or intramuscular dose of IFN-α is absorbed.110 After an intramuscular injection, peak IFN concentrations occur within 4 to 8 hours and return to baseline levels in 16 to 24 hours.110 Pegylation, which is the process of attachment of IFN to a large inert polyethylene glycol, markedly reduces the rate of absorption and excretion of IFN and therefore increases its plasma concentration.111 For example, after an SC dose of peginterferon α-2b, the peak serum concentra-tion occurs in 15 to 44 hours, high concentrations are main-tained for 48 to 72 hours, and the mean terminal half-life is about 40 hours.110 In contrast, the peak serum concentra-tion of peginterferon α-2a is reached in 72 to 96 hours after

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an SC dose, and the mean terminal half-life is 160 hours.110 Interferon-α undergoes extensive renal catabolism, and negligible amounts of IFN are excreted in the urine. Interferons have multiple overlapping biological activi-ties, including antiviral, antiproliferative, and immunoreg-ulatory functions. After binding to receptors, IFNs initiate a cascade of events that lead to various cellular responses, such as inhibition of virus replication, suppression of cell proliferation, enhancement of the phagocytic activity of macrophages, and augmentation of the specific cytotoxic-ity of lymphocytes for target cells. Interferons have been used in treating multiple viral in-fections and are most commonly used for treating chronic viral hepatitis.112 Interferon-α was the first drug approved for treatment of compensated liver disease due to CHB; it is not approved for treating acute hepatitis B. For CHB, IFN α-2a or α-2b is given parenterally, depending on dos-ing schedule, for 4 to 6 months or up to 48 weeks.112,113 Interferon was most effective in patients with recently acquired hepatitis B virus (HBV), high pretreatment lev-els of alanine aminotransferase (ALT), and low levels of HBV DNA. Subcutaneous peginterferon-α is as effective or slightly more effective than SC IFN-α.114 Likewise, SC peginterferon-α may be more effective than lamivudine in hepatitis B e antigen (HBeAg)–positive and HBeAg-nega-tive patients with CHB,115-117 and the addition of lamivudine to peginterferon-α did not significantly enhance efficacy.118 Interferon-α is effective in patients with HBV and hepati-tis D virus coinfection,119 although they are less responsive than patients infected with HBV alone.120 Guidelines for the management of CHB in HIV-infected patients were recently published121,122; for patients not requiring anti-HIV therapy, peginterferon-α for 12 months is considered a therapeutic option. Lamivudine and the other antiviral nucleos(t)ides for the treatment of HBV often have anti-HIV properties and may result in the development of HIV resistance if giv-en as monotherapy in HBV-HIV coinfected patients. Interferon-α-2a and -2b are approved for the treatment of chronic hepatitis C (CHC); however, they are not ap-proved for acute hepatitis C. A meta-analysis found that IFN-α for at least 12 months had the best risk-benefit ratio for patients with CHC.123 Once-weekly peginterferon-α was more effective than IFN-α given 3 times weekly in patients with CHC.124-126 However, combination therapy with IFN-α and oral ribavirin is more effective than either drug used alone.127 Combining oral ribavirin with peginterferon-α may be more effective than combining it with IFN-α.128,129 Therefore, the British Society for Gastroenterology and the American Association for the Study of Liver Diseases130 recommends once-weekly SC peginterferon-α combined with oral ribavirin as the first line of treatment of CHC. The recommended duration of treatment of CHC in patients not

infected with HIV is 24 weeks (for hepatitis C virus [HCV] genotype 2 or 3) or 48 weeks (for HCV genotype 1). For patients coinfected with HIV and HCV, the rate of intolerance to a combination regimen of IFN-α and riba-virin is higher and the rate of sustained virologic response (SVR) lower than in patients infected with HCV alone.131-133 Use of peginterferon-α resulted in a higher SVR rate than use of IFN-α.131,133 The APRICOT study reported an SVR rate of 40% for patients treated with peginterferon-α plus ribavirin, compared with 20% for those treated with peginterferon-α monotherapy, and 12% for those treated with IFN-α plus ribavirin.132 A lower SVR rate to combi-nation peginterferon-α plus ribavirin therapy was observed in patients coinfected with HCV genotype 1 (29%) than with HCV genotypes 2 and 3 (62%).132,133 Guidelines for the management of HIV and HCV coinfection have been published recently.130 In general, the guidelines recommend combination therapy with peginterferon-α and ribavirin for 48 weeks. Interferons are generally not recommended in acute viral hepatitis, but treatment of acute HCV with IFN-α has resulted in a more rapid resolution of viremia and re-duced progression to chronic hepatitis.134,135 The American Association for the Study of Liver Diseases recommends either IFN-α or peginterferon-α for at least 6 months for acute HCV if infection persists for 2 to 4 months after diagnosis. Interferons are also approved as intralesional therapy for condyloma acuminatum of genital and perianal areas.136 Intralesional injection ensures relatively high concentra-tions of IFN at the local site of infection, but occurrence of systemic adverse effects suggests its absorption from this site. Currently, HSV is generally treated with acyclo-vir, but beneficial responses to topical IFN-α have been re-ported for genital herpes137 and HSV keratitis.90 Beneficial responses to IFN-α have been reported for HIV-associated progressive multifocal leukoencephalopathy138; however, these findings are debatable because IFN-α may not pro-vide added benefits when used with highly active antiretro-viral therapy.139

Most patients receiving IFN may develop flulike symp-toms, which appear to be dose-related, are more likely to occur at the start of treatment, and typically respond to acetaminophen. Among the more serious adverse effects are neuropsychiatric disorders (eg, depression and homi-cidal and suicidal ideation), neurologic disturbances (eg, confusion and seizures), myelosuppression (neutropenia [most commonly] and aplastic anemia [rarely]), cardiovas-cular disorders (eg, arrhythmias), endocrine disorders (eg, thyroid disorders), and pulmonary disorders (eg, dyspnea and pneumonitis).140-142 Patients at risk for developing de-pression are those with preexisting mood and anxiety dis-

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orders, those with a history of major depression, and those receiving higher doses of IFN-α or undergoing long-term treatment regimens. Selective serotonin reuptake inhibi-tors have been used successfully to treat patients with IFN-associated depression, allowing therapy to be con-tinued,143 and as a pretreatment to prevent its occurrence in high-risk patients.144 Other adverse effects are altered liver function,145 renal insufficiency,146 and gastrointesti-nal manifestations.147

RIBAVIRIN

Ribavirin, a synthetic nucleoside analogue of guanine, is available in oral, aerosolized, and IV formulations. Oral ribavirin is absorbed extensively, but its bioavailability is only 65% because of first-pass metabolism. Peak plasma ribavirin concentrations occur within 1 to 2 hours after oral dose.148 Peak plasma concentrations increase over time and are 6 times higher after 4 weeks of treatment. Administra-tion of aerosolized ribavirin leads to high concentrations in the respiratory tract, with some ribavirin absorbed systemi-cally. Ribavirin is mainly excreted in the urine.149

The mechanism of action of ribavirin is known to be diverse but is not completely understood. It may be a com-petitive inhibitor of cellular enzymes because its antiviral activity is reversed by guanosine. Its triphosphorylated form, ribavirin triphosphate, is a potent competitive inhibi-tor of inosine monophosphate dehydrogenase, influenza vi-rus RNA polymerase, and mRNA guanylyltransferase. As a result of this competitive inhibition, intracellular guanosine triphosphate pools are markedly reduced and viral nucleic acid and protein synthesis are inhibited. Ribavirin does not alter viral attachment, penetration, or uncoating, nor does it induce IFN production. Ribavirin inhibits multiple viruses in vitro. Among the susceptible DNA viruses are herpesviruses, adenoviruses, and poxviruses. Susceptible RNA viruses include HCV, Lassa virus, influenza, parainfluenza, measles, mumps, RSV, and HIV. However, no correlation has been found between ribavirin's in vitro activity and its activity against human infections. Oral ribavirin is approved for use, in combination with IFN-α or peginterferon-α, for the treatment of CHC. How-ever, it is not effective when given as monotherapy.150,151 The duration of treatment, and sometimes its dose, may be dic-tated by HCV genotype. Treatment for infections with HCV genotype 1, and probably with genotype 4, should generally continue for 48 weeks, whereas those with genotype 2 or 3 may be treated for 24 weeks. Treatment of HCV in patients coinfected with HIV should be for 48 weeks.150,151

Ribavirin is approved for the treatment of RSV in chil-dren, including hematopoietic stem cell transplant recipi-ents. When used for the treatment of RSV pneumonia, riba-

virin is usually given by the aerosol route, which delivers high concentrations at the site of infection.152 Oral ribavirin has also been used with good outcomes.153 Ribavirin has been used, off-label, for the treatment of HSV, influenza, severe acute respiratory syndrome coronavirus,154,155 La Crosse encephalitis,156 Nipah encephalitis,157 Lassa fever,158 hemorrhagic fever with renal syndrome,159 Crimean-Congo hemorrhagic fever,160,161 Bolivian hemorrhagic fever,162 and hantavirus pulmonary syndrome.163

Aerosolized ribavirin can cause sudden deterioration of respiratory function and cardiovascular effects. Precipi-tation of inhaled ribavirin may occur in ventilatory tub-ings. Hemolytic anemia occurs commonly,154 and ribavirin should not be given to patients with preexisting medical conditions exacerbated by ribavirin-induced hemolysis, including significant cardiac disease or hemoglobinopa-thies. Severe depression, suicidal ideation, and relapse of drug abuse may occur, and ribavirin is contraindicated in patients with a history of, or existing, psychiatric disorders. Significant teratogenic and/or embryocidal effects have been observed in animals exposed to ribavirin. Ribavirin is therefore contraindicated in pregnant women and their male partners, and it is recommended that patients use 2 forms of contraception and avoid pregnancy during therapy and for 6 months thereafter.

NUCLEOS(T)IDE ANALOGUES FOR CHBIn addition to IFN, several nucleos(t)ide analogues are available for the treatment of CHB (Table 2). With the exception of telbivudine, these drugs possess anti-HIV properties, serving as inhibitors of the HIV reverse tran-scriptase inhibitors. The specific mechanism of their anti-HBV property is through competitive inhibition of HBV DNA polymerase. Because of their anti-HIV properties, it is highly recommended that CHB patients considered for treatment with these drugs be tested for HIV infection, and monotherapy with these drugs should be avoided for HIV-infected patients to reduce the risk of HIV resistance. Hepatitis B virus may also develop resistance to these drugs, usually after prolonged exposure, and this risk may be reduced by a strategy of combination antiviral thera-pies. The exact duration of anti-HBV treatment is not de-fined, and HBV relapse often occurs after discontinuation of treatment. Severe exacerbation of hepatitis may also occur on discontinuation of these drugs; hence, monitor-ing for hepatotoxicity should be performed after stopping treatment. Lactic acidosis may occur with nucleos(t)ide analogues, and the drugs should be withdrawn if there is a rapid increase in ALT levels, progressive hepatomegaly or steatosis, or acidosis. Adefovir. Adefovir dipivoxil is an acyclic nucleotide analogue of adenosine monophosphate.164 Oral adefovir

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TABLE 2. Antiviral Nucleos(t)ides for the Treatment of Chronic Hepatitis Ba

Drug name Suggested dosage Drug characteristicsb Toxicityc Resistance

Adefovir 10 mg orally once daily Acyclic nucleotide analogue of Nephrotoxicity rtN236T is most common adenosine monophosphate Lactic acidosis Rebound hepatitis

Emtricitabine 200 mg orally once daily Nucleoside analogue of cytidine Lactic acidosis rtM204V/I provides cross- Very similar to lamivudine Rebound hepatitis resistance with lamivudine Used often in combination with tenofovir

Entecavir 0.5 mg orally once daily for Nucleoside analogue of guanosine Well tolerated High barrier to resistance; treatment-naive patients One of the most potent anti-HBV drugs Lactic acidosis requires 3 mutations for 1 mg orally once daily for Rebound hepatitis phenotype: rtM204V/I treatment-experienced plus rtL180M plus patients and patients with rtT184S/A/I/L or decompensated liver disease rtS202G/C or rtM250L Lamivudine 100 mg orally once daily Nucleoside analogue of cytosine Lactic acidosis rtM204V/I is most frequent Myopathy Rebound hepatitis

Telbivudine 600 mg orally once daily Synthetic thymidine nucleoside analogue Myopathy rtM204I is most frequent No activity against HIV Peripheral neuropathy mutation; others include Lactic acidosis rtL80I/V, rtA181T, Rebound hepatitis rtL180M, and rtL229W/VTenofovir 300 mg orally once daily Acyclic nucleoside phosphonate diester Nephrotoxicity Not well-defined; rtN236T analogue of adenosine monophosphate Lactic acidosis is suggested but not yet One of the most potent anti-HBV drugs Rebound hepatitis confirmed

a HBV = hepatitis B virus; HIV = human immunodeficiency virus. b All drugs inhibit hepatitis B replication by acting as a competitive substrate for the HBV DNA polymerase. All drugs except telbivudine have anti-HBV

properties, and all patients with chronic hepatitis B who are considered for treatment should be screened for HIV.c A common toxicity of the nucleos(t)ide analogues is lactic acidosis, with the potential to cause increases in serum alanine aminotransferase levels and

hepatomegaly.

dipivoxil is rapidly absorbed and converted to adefovir. Its oral bioavailability is about 59%. Excretion of the drug is by glomerular filtration and active tubular secretion. Adefovir is converted intracellularly by cellular kinases to its active metabolite, adefovir diphosphate, which com-petitively inhibits HBV DNA polymerase.165 Although adefovir has the distinction of being the least potent among currently available anti-HBV drugs, it has been used in adults with decompensated liver disease, or with compen-sated liver disease with evidence of active viral replication, persistently elevated ALT levels, and histologic evidence of active inflammation and fibrosis.164

The major adverse effect of adefovir is nephrotoxicity, including proximal renal tubular dysfunction and Fanconi syndrome. Gastrointestinal symptoms, such as nausea, di-arrhea, and abdominal pain, may be observed. Adefovir re-sistance, characterized by the rtN236T mutation, gradually increases over time to 11%, 18%, and 29% at year 3, 4, and 5, respectively.166-169 To minimize the risk of resistance, adefovir is used in combination with other drugs such as lamivudine.165 However, concomitant use with the related drug tenofovir disoproxil fumarate is not recommended be-cause of the augmented risk of nephrotoxicity. Emtricitabine. Emtricitabine is an analogue of cytidine. Although not currently approved for the treatment of CHB, emtricitabine has been used clinically in combination with

tenofovir in HIV/HBV–coinfected patients. Emtricitabine is very similar to lamivudine, and cross-resistance between these drugs is common. Emtricitabine may be more po-tent than lamivudine; however, it should not be used as monotherapy because of high rates of resistance devel-opment.170 The rate of emtricitabine resistance among patients with HBV monoinfection is 18% at 96 weeks.170 Adverse effects are reportedly uncommon and include mild to moderate headache, nausea, diarrhea, and rash.170

Entecavir. Entecavir, a nucleoside guanosine ana-logue,171 is considered one of the most potent agents for the treatment of patients with CHB, including those re-sistant to lamivudine.172 Oral entecavir is extensively absorbed: peak plasma concentrations occur in 30 to 90 minutes, and oral bioavailability is almost 100%. Despite low plasma concentrations, entecavir maintains its poten-cy by the long intracellular half-life of its active metabo-lite entecavir triphosphate. Entecavir is mainly excreted by glomerular filtration and active tubular secretion. The mechanism of action of entecavir is somewhat unique because it inhibits 3 specific functions of the HBV DNA polymerase: priming of the HBV DNA poly-merase, reverse transcription of the negative strand from the pregenomic mRNA, and synthesis of positive-strand HBV DNA.172 Entecavir is approved for the treatment of CHB, at a dose of 0.5 mg orally once daily for nucleoside

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treatment–naive patients, and a dose of 1 mg orally once daily for patients with a history of HBV viremia while receiving lamivudine, those with lamivudine- or telbivu-dine-resistant mutations, and those with decompensated liver disease.173 In randomized trials of HBeAg-positive and HBeAg-negative patients, entecavir demonstrated better outcomes than lamivudine, with improvement in histologic responses, higher percentages of HBV DNA suppression, and normalization or improvement of ALT levels. Adverse effects of entecavir are generally mild and in-clude headache, fatigue, nausea, diarrhea, and insomnia. Entecavir has a high barrier to resistance and requires at least 3 mutations for phenotypic resistance. Entecavir re-sistance requires a baseline rtM204V/I and rtL180M mu-tation plus either rtT184S/A/I/L, rtS202G/C, or rtM250L. Among nucleoside-naive patients, the rate of entecavir resistance is less than 1% after 5 years, but patients with preexisting rtM204V/I have a higher rate of entecavir re-sistance (51%) after 5 years.173

Lamivudine. Lamivudine is a nucleoside analogue of cytosine. Oral lamivudine provides bioavailability of about 85%, and peak serum concentrations occur in 1.0 to 1.5 hours. Hepatic metabolism is low, and up to 70% is ex-creted unchanged by the kidneys.174

Lamivudine is phosphorylated intracellularly into its ac-tive 5´-triphosphate metabolite, lamivudine triphosphate. When the active metabolite is incorporated into viral DNA by HBV polymerase, it results in DNA chain termination. Lamivudine was the first drug to be used as an al-ter native to IFN-α for the treatment of CHB.175,176 In a double-blind study involving about 350 patients with CHB, lamivudine was associated with substantial histologic im-provement, HBeAg antibody seroconversion, and ALT nor-malization.177 However, relapses are common once treat-ment is discontinued.178

The adverse effects of lamivudine are mild and include abdominal pain, nausea, and headache. The clinical utility of lamivudine is limited by the rapid development of anti-viral resistance. Lamivudine shares with the L-nucleosides the primary resistance mutation, rtM204V/I, which occurs easily and confers cross-resistance. After 4 years of lamiv-udine monotherapy, rtM204V/I resistance develops in up to 70% and 90% of patients with HBV monoinfection and HIV/HBV coinfection, respectively. Telbivudine. Telbivudine is a synthetic thymidine nucleoside analogue. Unlike other anti-HBV drugs, tel-bivudine has no activity against HIV. Oral telbivudine is well absorbed and achieves peak plasma concentrations after about 3 hours. It is mainly excreted by glomerular filtration, with a terminal elimination half-life of 30 to 50 hours.179

Telbivudine-triphosphate inhibits HBV by competitive inhibition of viral DNA polymerase. Oral telbivudine is approved for the treatment of CHB in patients with com-pensated liver disease and evidence of active viral replica-tion, persistently increased serum ALT concentrations, and histologic evidence of active liver inflammation and fibro-sis.180,181 It is considered more effective than lamivudine and adefovir.182,183 Compared with lamivudine, telbivudine was associated with a higher degree of reduction in HBV DNA levels; however, no significant differences were found in ALT level normalization, loss of HBeAg, or anti-HBe seroconversion. The most common adverse effects reported for telbivu-dine are dizziness, fatigue, gastrointestinal symptoms, and rash. Unique adverse effects are peripheral neurop-athy and myopathy with elevation in creatine kinase lev-els. Telbivudine treatment should be discontinued if ei-ther peripheral neuropathy or myopathy is diagnosed. The rate of resistance to telbivudine is 25% after 96 weeks of treatment. Tenofovir. Tenofovir disoproxil fumarate, an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate, is considered one of the most potent anti-HBV drugs. In oral form, it is rapidly absorbed and con-verted to tenofovir, reaching peak plasma concentrations in 1 to 2 hours.184 Oral bioavailability, which is only 25% in the fasting state, can be enhanced when taken with a high-fat meal. The terminal elimination half-life of tenofovir is 12 to 18 hours, and it is excreted mainly by active tubular secretion and glomerular filtration.184

Tenofovir disoproxil fumarate is a prodrug that requires diester hydrolysis for conversion to tenofovir. Subsequent phosphorylation by cellular enzymes forms tenofovir diphosphate, which competes with the natural substrate deoxyadenosine 5ʹ-triphosphate for incorporation into the viral DNA strand. Tenofovir is used for the treatment of CHB. In a ran-domized trial comparing tenofovir and adefovir, a higher percentage of patients receiving tenofovir achieved HBV DNA level suppression. In HBeAg-positive patients, the biochemical response was higher with tenofovir; however, the anti-HBe seroconversion rates and histologic responses were similar for adefovir and tenofovir.185-188

The adverse effects of tenofovir include gastrointestinal symptoms, dizziness, fatigue, and headache. Renal toxici-ties, including nephritis, proximal renal tubulopathy (in-cluding Fanconi syndrome), and renal failure, have been associated with tenofovir.189-193

Primary tenofovir resistance mutations have not been well defined. Although viruses with rtN236T are not resis-tant to tenofovir, they have a slower response than do wild-type viruses. One study reported rtA194T as a tenofovir re-

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sistance mutation; however, this pattern was not confirmed in other studies.

PROTEASE INHIBITORS FOR THE TREATMENT OF CHCThe current standard treatment of CHC is peginterferon-α in combination with ribavirin for 24 weeks (for HCV geno-type 2 or 3) or 48 weeks (for HCV genotype 1). The major aim of treatment is to achieve SVR, which is defined as undetectable HCV RNA at 24 weeks after completion of treatment. A combination regimen of peginterferon-α and ribavirin results in SVR rates between 38% and 46%, and the rate is even lower among black patients. Hence, ma-jor efforts have been made to develop novel therapies for CHC. Recently, 2 serine protease inhibitors were approved as novel therapies for CHC due to genotype 1 infection. The addition of serine protease inhibitors to the backbone therapies of peginterferon-α and ribavirin will emerge as the standard of care for the HCV genotype 1 infection, both in treatment-naive and treatment-experienced patients. Boceprevir. Boceprevir is a linear peptidomimetic keto-amide serine protease inhibitor that was recently approved for the treatment of CHC, particularly for genotype 1.194 It is available in oral formulation, and the time to peak concentration after oral administration is 2 hours. Food en-hances its absorption. Boceprevir is metabolized primarily in the liver. It has an elimination half-life of 3 hours and is excreted mostly in the feces.194

Boceprevir exerts anti-HCV properties by binding re-versibly to the HCV nonstructural 3 protein, ultimately inhibiting viral replication. In a recently conducted phase 3 international randomized placebo-controlled trial that en-rolled previously untreated black and nonblack adults with HCV genotype 1 infection (SPRINT-2 [serine protease in-hibitor therapy 2] trial), the addition of boceprevir for 22 weeks or 44 weeks to standard therapy (peginterferon-α-2b and ribavirin) resulted in significantly higher SVR rates compared with standard therapy alone for the nonblack cohort (67% and 68% vs 40%, respectively) and the black cohort (42% and 53% vs 23%, respectively).195 The rela-tive increases in SVR rates for the nonblack cohort were 68% and 70%, respectively, compared with the standard therapy.195

The HCV RESPOND-2 (Retreatment with HCV Ser-ine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) trial evaluated boceprevir for the treatment of patients who had experienced a relapse or who had not achieved SVR to peginterferon-ribavirin treatment.196 In this random-ized open-label trial that enrolled 403 patients, the SVR rates were significantly higher for patients who received peginterferon-ribavirin plus boceprevir treatment for 32 weeks (59%) or 44 weeks (66%) compared with standard peginterferon-ribavirin treatment alone (21%).196 In a mul-

tivariable stepwise logistic regression analysis, the baseline factors associated with SVR were boceprevir use, previous relapse (compared with previous nonresponder), low viral load at baseline, and absence of cirrhosis.196

Boceprevir (800 mg 3 times daily) was approved by the FDA as the first HCV protease inhibitor for the treatment of CHC, specifically for genotype 1; it should be combined with peginterferon and ribavirin. The most common ad-verse effects of boceprevir are flulike illness, fatigue, nau-sea, dysgeusia, and anemia.194 The addition of boceprevir nearly doubled the rate of anemia compared with the use of standard peginterferon and ribavirin therapy, with many patients requiring the use of erythropoietin.195

Telaprevir. Telaprevir is an orally available inhibitor specific to the HCV nonstructural 3/4A serine protease.197 It inhibits HCV replication by binding reversibly to nonstruc-tural 3 serine protease. After oral administration, telaprevir achieves peak plasma concentrations in 4 to 5 hours. It is metabolized primarily in the liver and it has an elimination half-life of 4 to 5 hours. Most of the drug is excreted in the feces. Early-phase studies demonstrated the potent anti-HCV properties of telaprevir.198-200 In a recent phase 3 inter-national randomized double-blind placebo-controlled clinical trial, the addition of telaprevir to the standard treatment of peginterferon-ribavirin was associated with significantly higher SVR rates compared with standard peginterferon-ribavirin alone in a cohort of 1088 patients with previously untreated HCV genotype 1 infections.201 Specifically, the group of patients who received 12 weeks of telaprevir combined with peginterferon-ribavirin, fol-lowed by peginterferon-ribavirin for 12 weeks (if HCV RNA was undetectable at weeks 4 and 12) or 36 weeks (if HCV RNA was still detectable at weeks 4 and 12), had SVR rates of 75% vs 44% with standard therapy.201 The SVR rates were also significantly higher compared with standard therapy among patients who received only 8 weeks of telaprevir combined with peginterferon-ribavirin (69% vs 44%).201 In the second randomized phase 3 trial that evaluated telaprevir in treatment-experienced patients with HCV genotype 1 infection, the addition of telaprevir to the standard treatment regimen of peginterferon-α and ribavirin was associated with significantly higher SVR rates compared with the standard regimen of peginterfer-on-ribavirin alone.202

Collectively, these studies indicate that the addition of telaprevir to standard peginterferon-ribavirin therapy can significantly improve SVR rates in treatment-naive pa-tients infected with HCV genotype 1 and in those who did not benefit from initial treatment with peginterferon-α-2a and ribavirin. As a result of these findings, the FDA ap-proved telaprevir (750 mg 3 times daily) for this treatment

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indication. The most common adverse effects are anemia, neutropenia, leukopenia, and rash.201 In one study, 41% to 60% of patients reported some kind of rash.199 Rashes can be mild to severe, and Stevens-Johnson syndrome and drug rash with eosinophilia and systemic symptoms have been reported. Telaprevir therapy should be discontinued if these dermatologic complications occur, especially in cases of severe rash or even mild to moderate rash if ac-companied by systemic symptoms. The mechanism under-lying rash development is unknown.199 Fatigue, pruritus, and gastrointestinal sympotoms (eg, nausea, diarrhea, and taste disturbance) may also be observed.199

CONCLUSION

This review has highlighted the pharmacokinetics, mecha-nisms of action, clinical indications, and adverse effects of clinically available drugs for the management of viruses other than HIV. The currently available antiviral drugs tar-get 3 main groups of viruses: herpes, hepatitis, and influ-enza viruses. The antiviral therapeutic armamentarium has evolved over the years and is rapidly expanding. Some of the “old” antiviral drugs retain their clinical utility for most infections, such as acyclovir for herpes simplex virus and ganciclovir for CMV. However, other of these “old” anti-viral drugs (eg, amantadine and rimantadine for influenza virus infections) have lost their clinical utility because of the rapid and widespread development of resistance. This serves as a catalyst for the development of novel therapies and, more importantly, should urge the medical community to use these drugs optimally in the clinical setting. Indeed, increased resistance has been observed to the neuramini-dase inhibitors for the treatment of influenza viruses and the nucleos(t)ide analogues for the treatment of CHB. As novel therapies develop (eg, the serine protease inhibitors for the treatment of CHC), care must be taken to optimize their use so that the clinical life span of these drugs is not abbreviated by the development of resistance.

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. 1996;24:778-789. 124. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in pa-tients with chronic hepatitis C. . 2000;343:1666-1672. 125. Perry CM, Jarvis B. Peginterferon-alpha-2a (40 kD): a review of its use in the management of chronic hepatitis C. . 2001;61:2263-2288. 126. Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. . 2000; 343:1673-1680. 127. Brok J, Gluud LL, Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. 2010;(1):CD005445. 128. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. . 2002; 347:975-982. 129. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa- 2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. . 2001;358:958- 965. 130. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. . 2009;49:1335-1374. 131. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV- infected patients: a randomized controlled trial. JAMA. 2004;292:2839-2848.

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132. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. . 2004;351:438-450. 133. Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. . 2004;351:451-459. 134. Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepati-tis C with interferon alfa-2b. . 2001;345:1452-1457. 135. Santantonio T, Fasano M, Sinisi E, et al. Efficacy of a 24-week course of PEG-interferon alpha-2b monotherapy in patients with acute hepatitis C after failure of spontaneous clearance. . 2005;42:329-333. 136. Eron LJ, Judson F, Tucker S, et al. Interferon therapy for condylomata acuminata. . 1986;315:1059-1064. 137. Leung DT, Sacks SL. Current recommendations for the treatment of genital herpes. . 2000;60:1329-1352. 138. Huang SS, Skolasky RL, Dal Pan GJ, Royal W III, McArthur JC. Sur-vival prolongation in HIV-associated progressive multifocal leukoenceph-alopathy treated with alpha-interferon: an observational study. . 1998;4:324-332. 139. Geschwind MD, Skolasky RI, Royal WS, McArthur JC. The rela tive contributions of HAART and alpha-interferon for therapy of progressive mul-tifocal leukoencephalopathy in AIDS. . 2001;7:353-357. 140. Renault PF, Hoofnagle JH, Park Y, et al. Psychiatric complica - tions of long-term interferon alfa therapy. . 1987;147:1577- 1580. 141. Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms as-sociated with hepatitis C and interferon19 alpha: a review. . 2000;157:867-876. 142. Midturi J, Sierra-Hoffman M, Hurley D, Winn R, Beissner R, Carpen-ter J. Spectrum of pulmonary toxicity associated with the use of interferon therapy for hepatitis C: case report and review of the literature. . 2004;39:1724-1729. 143. Levenson JL, Fallon HJ. Fluoxetine treatment of depression caused by interferon-alpha. . 1993;88:760-761. 144. Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the pre-vention of depression induced by high-dose interferon alfa. . 2001;344:961-966. 145. Durand JM, Kaplanski G, Portal I, Scheiner C, Berland Y, Soubey-rand J. Liver failure due to recombinant alpha interferon. . 1991;338:1268-1269. 146. Averbuch SD, Austin HA III, Sherwin SA, Antonovych T, Bunn PA Jr, Longo DL. Acute interstitial nephritis with the nephrotic syndrome following recombinant leukocyte a interferon therapy for mycosis fungoides.

. 1984;310:32-35. 147. Agesta N, Zabala R, Diaz-Perez JL. Alopecia areata during interferon alpha-2b/ribavirin therapy. . 2002;205:300-301. 148. Wade JR, Snoeck E, Duff F, Lamb M, Jorga K. Pharmacokinetics of ribavirin in patients with hepatitis C virus. . 2006;62: 710-714. 149. Kramer TH, Gaar GG, Ray CG, Minnich L, Copeland JG, Connor JD. Hemodialysis clearance of intravenously administered ribavirin.

. 1990;34:489-490. 150. Gish RG. Treating HCV with ribavirin analogues and ribavirin-like molecules. . 2006;57:8-13. 151. Gluud LL, Marchesini E, Iorio A. Peginterferon plus ribavirin for chronic hepatitis C in patients with human immunodeficiency virus.

. 2009;104:2335-2341. 152. Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infec-tion of the lower respiratory tract in infants and young children.

. 2007;CD000181. 153. Pelaez A, Lyon GM, Force SD, et al. Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract in-fection. . 2009;28:67-71. 154. Knowles SR, Phillips EJ, Dresser L, Matukas L. Common adverse events associated with the use of ribavirin for severe acute respiratory syn-drome in Canada. . 2003;37:1139-1142. 155. Muller MP, Dresser L, Raboud J, et al. Adverse events associated with high-dose ribavirin: evidence from the Toronto outbreak of severe acute respi-ratory syndrome. . 2007;27:494-503.

156. McJunkin JE, Khan R, de los Reyes EC, et al. Treatment of severe La Crosse encephalitis with intravenous ribavirin following diagnosis by brain biopsy. . 1997;99:261-267. 157. Chong HT, Kamarulzaman A, Tan CT, et al. Treatment of acute Nipah encephalitis with ribavirin. . 2001;49:810-813. 158. McCormick JB, King IJ, Webb PA, et al. Lassa fever: effective therapy with ribavirin. . 1986;314:20-26. 159. Huggins JW, Hsiang CM, Cosgriff TM, et al. Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin ther - apy of hemorrhagic fever with renal syndrome. . 1991;164:1119- 1127. 160. Fisher-Hoch SP, Khan JA, Rehman S, Mirza S, Khurshid M, McCor-mick JB. Crimean Congo-haemorrhagic fever treated with oral ribavirin.

. 1995;346:472-475. 161. Mardani M, Jahromi MK, Naieni KH, Zeinali M. The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran. Clin

. 2003;36:1613-1618. 162. Kilgore PE, Ksiazek TG, Rollin PE, et al. Treatment of Bolivian hemorrhagic fever with intravenous ribavirin. . 1997;24:718- 722. 163. Prochoda K, Mostow SR, Greenberg K. Hantavirus-associated acute respiratory failure. . 1993;329:1744. 164. Dando T, Plosker G. Adefovir dipivoxil: a review of its use in chronic hepatitis B. . 2003;63:2215-2234. 165. Rivkin AM. Adefovir dipivoxil in the treatment of chronic hepatitis B.

. 2004;38:625-633. 166. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treat-ment of hepatitis B e antigen-positive chronic hepatitis B. . 2003;348:808-816. 167. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipiv-oxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N

. 2003;348:800-807. 168. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term ther-apy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B.

. 2005;352:2673-2681. 169. Delaney WE. Progress in the treatment of chronic hepatitis B: long-term experience with adefovir dipivoxil. . 2007; 59:827-832. 170. Lim SG, Ng TM, Kung N, et al. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. . 2006;166:49- 56. 171. Sims KA, Woodland AM. Entecavir: a new nucleoside analog for the treatment of chronic hepatitis B infection. . 2006;26: 1745-1757. 172. Matthews SJ. Entecavir for the treatment of chronic hepatitis B virus infection. . 2006;28:184-203. 173. Scott LJ, Keating GM. Entecavir: a review of its use in chronic hepatitis B. . 2009;69:1003-1033. 174. Johnson MA, Moore KH, Yuen GJ, Bye A, Pakes GE. Clinical pharma-cokinetics of lamivudine. . 1999;36:41-66. 175. Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection.

. 1995;333:1657-1661. 176. Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as ini-tial treatment for chronic hepatitis B in the United States. . 1999;341:1256-1263. 177. Lai CL, Chien RN, Leung NW, et al; Asia Hepatitis Lamivudine Study Group. A one-year trial of lamivudine for chronic hepatitis B. . 1998;339:61-68. 178. Honkoop P, de Man RA, Heijtink RA, Schalm SW. Hepatitis B reactiva-tion after lamivudine. . 1995;346:1156-1157. 179. Zhou XJ, Ke J, Sallas WM, Farrell C, Mayers DL, Pentikis HS. Pop-ulation pharmacokinetics of telbivudine and determination of dose adjust - ment for patients with renal impairment. . 2009;49:725- 734. 180. Kim JW, Park SH, Louie SG. Telbivudine: a novel nucleoside analog for chronic hepatitis B. . 2006;40:472-478. 181. Jones R, Nelson M. Novel anti-hepatitis B agents: a focus on telbivu-dine. . 2006;60:1295-1299.

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The contributions to the Symposium on Antimicrobial Therapy are a CME activity. For CME credit, see the link on our Web site at mayoclinicproceedings.com.

182. Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. . 2007;357:2576- 2588. 183. Chan HL, Heathcote EJ, Marcellin P, et al. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. . 2007;147:745-754. 184. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate: clini - cal pharmacology and pharmacokinetics. . 2004;43:595- 612. 185. Grim SA, Romanelli F. Tenofovir disoproxil fumarate.

. 2003;37:849-859. 186. Gallant JE, Deresinski S. Tenofovir disoproxil fumarate.

. 2003;37:944-950. 187. Wong SN, Lok AS. Tenofovir disoproxil fumarate: role in hepatitis B treatment. . 2006;44:309-313. 188. Reijnders JG, Janssen HL. Potency of tenofovir in chronic hepatitis B: mono or combination therapy? . 2008;48:383-386. 189. Gitman MD, Hirschwerk D, Baskin CH, Singhal PC. Tenofovir-induced kidney injury. . 2007;6:155-164. 190. Gupta SK. Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. . 2008;22:99- 103. 191. Schmid S, Opravil M, Moddel M, et al. Acute interstitial nephritis of HIV-positive patients under atazanavir and tenofovir therapy in a ret-rospective analysis of kidney biopsies. . 2007;450:665- 670. 192. Kapitsinou PP, Ansari N. Acute renal failure in an AIDS patient on teno-fovir: a case report. . 2008;2:94.

193. Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. . 2006;42:283-290. 194. Foote BC, Spooner LM, Belliveau PP. Boceprevir: a protease inhibitor for the treatment of chronic hepatitis C [Epub ahead of print August 9, 2011].

doi:10.1345/aph.1P744. 195. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. . 2011;364:1195-1206. 196. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. . 2011;364:1207- 1217. 197. Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. . 2007;132: 1979-1998. 198. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus ge-notypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. . 2007;132:1767-1777. 199. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection.

. 2009;360:1827-1838. 200. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. . 2009; 360:1839-1850. 201. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for pre-viously untreated chronic hepatitis C virus infection. . 2011; 364:2405-2416. 202. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. . 2011;364:2417-2428.

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ANTIMICROBIAL STEWARDSHIP



From the Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA.

The authors have no conflict of interest to disclose.

Address correspondence to Shira Doron, MD, Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, 800 Washington St, Boston, MA 02111 ([email protected]). Individual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com.


WHY DO WE NEED ANTIMICROBIAL STEWARDSHIP?

In the early days of antibiotics, booming drug development meant that even when resistance developed, a new drug was always available to treat the increasingly resistant bac-teria. Fourteen new classes of antibiotics were introduced between 1935 and 2003. However, rapid antimicrobial development came with a cost—antimicrobial resistance. In the hospital, resistance to antibiotics and antifungals poses the greatest concern. In 2003, US intensive care units (ICUs) reported to the Centers for Disease Control and Prevention that nearly 60% of isolates were resistant to methicillin.1 Although the rate of invasive methicillin-resistant infections in health care settings was shown to be decreasing in a 2010 Centers for Disease Control and Prevention study,2 isolates inter-mediately or overtly resistant to vancomycin are becom-ing less rare.3 Perhaps even more difficult to manage has been the increase in gram-negative resistance.4 Programs such as the international SMART (Study for Monitoring Antimicrobial Resistance Trend)5 and the SENTRY Anti-microbial Surveillance Program have shown substantial in creases in the rate of resistance to third-gen-eration cephalosporins, extended-spectrum β-lactamase–producing and , and resistant to fluoroquinolones.1,6,7 During the past 30 years, antibiotic development has slowed con-

Antimicrobial Stewardship

Shira Doron, MD, and Lisa E. Davidson, MD

Antimicrobial resistance is increasing; however, antimicrobial drug development is slowing. Now more than ever before, anti-microbial stewardship is of the utmost importance as a way to optimize the use of antimicrobials to prevent the development of resistance and improve patient outcomes. This review describes the why, what, who, how, when, and where of antimicrobial stew-ardship. Techniques of stewardship are summarized, and a plan for implementation of a stewardship program is outlined.

Mayo Clin Proc. 2011;86(11):1113-1123

ASP = antimicrobial stewardship program; CI = confidence interval; DDD = defined daily dose; DOTs = days of therapy; ICU = intensive care unit; OR = odds ratio

siderably, and our options for treating increasingly resis-tant infections are becoming more and more limited. This review aims to describe the why, what, who, how, when, and where of antimicrobial stewardship. Tens of thousands of Americans die of infections caused by antibiotic-resistant pathogens every year. Every day, pa-tients die of bacterial infections for which no active agents are available. Yet since 1998 only 10 new antibiotics have been approved, only 2 of which (linezolid and daptomycin) actually have new targets of action. The reasons for this are simple: drug development is risky and expensive, and drugs to treat infections are not as profitable as those that treat chronic disease. Antibiotics currently in development are in existing classes and are broad spectrum in nature, which means they are likely to further promote the development of resistance if approved and used. In the hospital, an es-timated 50% of antibiotic orders are unnecessary.8 It is in this setting that the broadest-spectrum antibiotics are being used, and rampantly. It is also in this setting that the most dangerous and extreme drug resistance has been seen. All of this has led the Infectious Diseases Society of America’s Bad Bugs, No Drugs task force to call for a global commit-ment from stakeholders to support the development of 10 new drugs in novel classes by the year 2020. This so-called 10 × 20 initiative has been likened to John F. Kennedy’s dream of walking on the moon.

WHAT IS ANTIMICROBIAL STEWARDSHIP?

Until this next giant step is achieved, those of us not devel-oping new drugs have another job: conserve the antibiotics

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we have. In the hospital, antimicrobial stewardship teams are charged with this important initiative. Antimicrobial stewardship has been defined as “the optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and mini-mal impact on subsequent resistance.”9 The goal of antimi-crobial stewardship is 3-fold. The first goal is to work with health care practitioners to help each patient receive the most appropriate antimicrobi-al with the correct dose and duration. Joseph and Rodvold10 wrote about the “4 D’s of optimal antimicrobial therapy”: right Drug, right Dose, De-escalation to pathogen-directed therapy, and right Duration of therapy. The optimal care of an infected patient means treating with the correct, prop-erly dosed antibiotic and one that has the least likelihood of causing collateral damage (ie, leading to resistance in the patient or his or her contacts). An added benefit of programs that aim to optimize antibiotic use is that they generally experience cost savings because fewer doses of antibiotic are used and less expensive antibiotics are cho-sen. Comprehensive programs have demonstrated annual savings of $200,000 to $900,000.11-17

The second goal is to prevent antimicrobial overuse, misuse, and abuse. In both the hospital and the outpatient setting, physicians use antibiotics when they are not neces-sary. Antibiotics are given to patients with viral infections, noninfectious processes (a classic example is the febrile patient with pancreatitis), bacterial infections that do not require antibiotics (such as small skin abscesses that will resolve with incision and drainage), and bacterial coloni-zation (as in the case of a positive urine culture result in a patient with a bladder catheter). Antibiotics are also fre-quently misused, such as in the very common scenario of the use of broad-spectrum antibiotics that cover multidrug-resistant organisms in a patient whose infection was ac-quired in the community or the failure to adjust antibiotics according to culture data, thus maintaining the patient on a regimen to which the organism is not susceptible. of antibiotics is more difficult to define, but the term might be used to describe the use of one particular antibiotic prefer-entially over others by a physician as a result of aggressive detailing by the pharmaceutical representative or worse be-cause of financial interest. The third goal is to minimize the development of resis-tance. Both at the individual patient level and at the com-munity level, antibiotic use changes susceptibility patterns. Patients exposed to antibiotics are at higher risk of becoming colonized or infected by resistant organisms.18-20 The most common cause of the development of diarrhea is exposure to antibiotics.21 Gram-negative resis-tance to carbapenems and cephalosporins has been shown

to increase 10- to 20-fold with exposure to these broad-spectrum antimicrobials.22-24 In a recent systematic review and meta-analyses of outpatient prescribing practices, the use of common antibiotics was associated with significant increased risk of development of antibiotic resistance, up to 12 months after antimicrobial exposure (pooled odds ratio [OR], 1.33; 95% confidence interval [CI], 1.2-1.5).25 More importantly, antimicrobial resistance is associated with in-creased morbidity and mortality. Carbapenem-resistant K

is associated with an increased attributable mortality compared with sensitive (OR, 4.69; 95% CI, 1.9-11.58; P=.001)22 and methicillin-resistant S

bacteremia, relative to methicillin-sensitive bacteremia, has a significantly greater mortality risk

as well (OR, 1.93; 95% CI, 1.54-2.42; P=.001).26 These resistant organisms can become transmitted to other indi-viduals within the hospital or in the patient’s community. Antimicrobial resistance also has significant hospital and societal costs. A recent study by Roberts et al27 estimat-ed that the cost of an antimicrobial-resistant infection is $18,588 to $29,069 per patient, with an excess duration of hospital stay of 6.4 to 12.7 days and attributable mortality of 6.5%.27

WHO: BUILDING THE STEWARDSHIP TEAM

Every hospital should work within its resources to create an effective team given its budget and personnel constraints. The stewardship team does not have to fit a particular mold, and it would be a mistake to delay implementation of a stewardship program because of a lack of availability of one or more of the typical team participants listed subse-quently. Most stewardship teams include either an infec-tious disease physician or a pharmacist (with or without specialized training in infectious disease) or both. Some-times a hospitalist with an interest in infectious disease serves in this role. Often the infection preventionist is an active member of the team. Close collaboration with the staff in the microbiology laboratory, hospital epidemiology, and administration is essential to a well-functioning pro-gram. A working relationship with the information special-ist can be especially helpful. Engaging hospital leadership will open doors to good relationships with other physician groups. Therefore, early involvement of thought leaders from hospital administration and the various practitioner groups will improve acceptance and implementation.

HOW: STEWARDSHIP STRATEGIES

APPROACHES

There are 2 major approaches to antimicrobial stewardship, with the most successful programs generally implementing

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a combination of both. The front-end or preprescription ap-proach to stewardship uses restrictive prescriptive authority. Certain antimicrobials are considered restricted and require prior authorization for use by all except a select group of cli-nicians. Clinicians without authority to prescribe the drug in question must contact the designated antimicrobial steward and obtain approval to order the antimicrobial. The front-end approach has the advantage of targeting specific anti-microbials for specific indications based on local resistance patterns and the hospital formulary. Antimicrobials can be approved for a specific duration, thereby prompting review after culture data have been obtained. Data suggest that pro-grams that use this approach have been able to demonstrate significant reductions in expenditures of the targeted drug but also result in increased use of antimicrobials that are not restricted,28-30 which may or may not be the desired effect. The back-end or postprescription approach to steward-ship uses prospective review and feedback. The antimi-crobial steward reviews current antibiotic orders and pro-vides clinicians with recommendations to continue, adjust, change, or discontinue the therapy based on the available microbiology results and clinical features of the case. Stud-ies of programs that use this approach have shown decreased antimicrobial use, decreased number of new prescriptions of antimicrobials, and improved clinician satisfaction.31,32 The back-end approach has the advantage of being able to focus on de-escalation, a critical aspect of appropriate an-timicrobial use. De-escalation is modification of the initial empiric antimicrobial regimen based on culture data, other laboratory tests, and the clinical status of the patient. De-escalation includes changing a broad-spectrum antibiotic to one with narrower coverage, changing from combina-tion therapy to monotherapy, or stopping antibiotic therapy altogether as it becomes more apparent that these drugs are not needed. The newer rapid molecular diagnostic tests are de-signed to help clinicians de-escalate earlier in the antibiotic course. Peptide nucleic acid technology is widely available in the United States and allows for identification of com-mon organisms from a positive blood culture within 90 minutes. Matrix-assisted laser desorption/ionization tech-nology is gaining popularity in Europe and can be used to identify an increasing number of organisms from positive culture within 60 minutes. In one recent study, rapid poly-merase chain reaction was used to differentiate methicillin-resistant bacteremia from methicillin-sensitive S

in blood culture and the results provided immedi-ately to an infectious disease pharmacist. During the period when this technology was being used, mean length of stay was 6.2 days shorter and mean hospital costs $21,387 less for patients with bacteremia.33 Other technologies are available and in development.

In addition to using one or both of these common ap-proaches, comprehensive antimicrobial stewardship pro-grams (ASPs) use a variety of other strategies and tech-niques to optimize antimicrobial use in the hospital.

TECHNIQUES

Formulary Restriction. Most hospitals have a formu-lary that is somewhat selective and does not include every available antimicrobial. The realities of the process of ne-gotiating with pharmaceutical companies make this neces-sary because the price of the drug depends not only on how much of it the hospital uses but also on how little it uses of the competitor drug. As an example, most hospitals carry only one echinocandin antifungal. Formulary restriction is also a first step toward stewardship because, very simply, making only certain drugs available is a way to steer clini-cians toward the use of those drugs. Formulary restriction can be a challenge for long-term acute care facilities that accept patients from multiple acute care hospitals with dif-ferent formularies because they may feel an obligation to be able to offer the referring hospital continuation of the same antimicrobial the patient was receiving on transfer. Order Sets and Treatment Algorithms. Order sets, whether on paper or as part of a computerized physician order entry system, can be an important tool in the steward-ship team’s efforts to ensure guideline-based appropriate empiric antibiotic ordering. Depending on the level of so-phistication of the paper or electronic order set, the system can prompt the prescriber to make guideline-based anti-biotic choices based on relevant clinical factors, to think about allergies, to remember to adjust for renal function, to consider the cost of therapy, and to order the appropriate tests, monitoring, and consultations. Hermsen et al34 used a surgical prophylaxis order form to improve antibiotic choices. This study demonstrated a significant increase in appropriate antimicrobial use, appropriate weight-based dosing, and appropriate duration of prophylaxis, as well as a decrease in the mean cost of antimicrobial prophylaxis. Treatment algorithms are similar decision tools but lack a direct interface with the ordering process. Some steward-ship teams have even created pocket or online guidebooks for clinicians, which contain empiric antibiotic recom-mendations for common infections, dosing guidelines, and other helpful information. Clinical Guidelines. One of the advantages of guide-line development as part of an ASP is that it provides the opportunity to incorporate many thought leaders within a hospital to develop hospital- or network-specific algo-rithms. Guidelines can use national recommendations but should incorporate local trends in antimicrobial resistance and hospital-specific targets for decreased use. Ibrahim et al35 demonstrated that implementation of ventilator-

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associated pneumonia treatment guidelines during a 2-year period doubled the rate of appropriate initial therapy, while decreasing length of therapy and ventilator-associ-ated pneumonia recurrence. Other studies of guidelines for ventilator-associated pneumonia, including at our own in-stitution, have shown similar results.36-38 After an increase in infections, the province of Quebec, Canada, initiated a global education program to reduce unnecessary antimicrobial use.39 Eleven guidelines were produced by a group of experts, sent to all physicians and pharmacists in Quebec, and posted on a dedicated Web site. Importantly, these guidelines were widely promoted throughout the prov-ince. After the guideline campaign, there were 4.1 fewer prescriptions per 1000 inhabitants (95% CI, −6.6 to −1.6; P<.002) and a decrease in prescription costs of $134.50 per 1000 inhabitants (95% CI, −270.5 to 1.6; P=.054) in Quebec compared with the rest of Canada. These trends persisted 36 months later. One of the advantages of using guidelines and clinical pathways for ASPs is the ability to reach out to frontline professionals who are not specialists in infectious disease. Jenkins et al40 recently published a study on the introduc-tion of empiric therapy guidelines for uncomplicated cellu-litis. The program targeted emergency department and gen-eral medicine physicians. Using this institutional guideline to standardize and streamline the evaluation of inpatient cellulitis resulted in a significant decrease in the use of mi-crobiological and radiologic tests, a decrease in duration of antimicrobial therapy, and significant decreases in the use of broad-spectrum antimicrobials. Education. All successful ASPs include an educational component. Clinicians are educated about the use of an-timicrobials during the process of reading the order sets and treatment algorithms, during telephone conversations with the antimicrobial steward for the purpose of obtaining authorization for use of a restricted antimicrobial, during interaction with the antimicrobial steward conducting con-

current review and feedback, and through formal didactic sessions or Grand Rounds–type lectures. At our institution, an Antimicrobial Management Team Question of the Week is sent by e-mail to all clinicians and has been very well received. In a recent study of pediatricians in Israel, the pri-mary hypothesis was that a multifaceted intervention based on physicians’ engagement with an education process that involved physician, parents, and child would result in long-standing reduction in antimicrobial resistance rates.41 Us-ing a cluster randomized controlled design, the interven-tion group engaged physicians by conducting activities focused on self-developed guidelines, improving parent and physician knowledge, diagnostic skills, and parent-physician communication skills that promoted awareness of antibiotic resistance. Compared with the control group, a significantly greater decrease occurred in annual pre-scription rates in the intervention vs control group (relative risk, 0.89; 95% CI, 0.81-0.98), and the effect was sustained during the 4 following years. Pharmacodynamic Dose Optimization. One steward-ship technique that is being used with increasing frequency is pharmacodynamic dose optimization. Concepts, such as the pharmacodynamic parameter that is correlated with ef-ficacy and knowledge of achievable tissue concentrations, guide the use of specific antimicrobials in previously un-conventional and often off-label ways to optimize micro-bial killing and thus minimize the risk of promoting re-sistance. For β-lactam antibiotics, these dosing strategies maximize the percentage of time that the concentration of the unbound drug is above the minimum inhibitory con-centration of the organism. Some of these dosing regimens are suggested by studies that use Monte Carlo simulation. Examples are given in Table 1. Computer-Assisted Decision Support Programs.The rapidly increasing use of electronic medical records and computerized physician order entry systems provides a critical opportunity for both electronic surveillance of

TABLE 1. Novel Approaches to Antimicrobial Dosing to Combat Resistance

Strategy and drug Pharmacodynamically optimized dose Reference(s)

Prolonged infusion of β-lactams Piperacillin-tazobactam 3.375 g IV every 8 h for 4 h (prolonged infusion) 42 Meropenem 1 g IV for 360 min every 6 h (continuous infusion) 43 Doripenem 500 mg IV every 8 h for 4 h (prolonged infusion) 44Increased frequency dosing of quinolone Ciprofloxacin 400 mg IV every 8 h 45Adjusting antimicrobial dosage to achieve specific recommended blood level Vancomycin Maintain trough above 10 mg/L to prevent 46-48 development of resistance Use of high-dose therapy to overcome high MICs Cefepime 2 g IV every 8 h (3-h infusion) 49

IV = intravenous; MIC = minimum inhibitory concentration.

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antimicrobial-prescribing practices and use of electronic systems to provide guidance to clinicians. Many decision support programs have been developed during the past few years to assist the antimicrobial stewardship team. These programs can identify allergies, inappropriate dosages, and, with the appropriate software and information tech-nology systems, mismatches between drug and suscepti-bility. Evans et al50 demonstrated that one such model was able to provide physician feedback in a timely manner and resulted in significant reductions in the use of antimicrobi-als and length of stay. In a study conducted in Australia, a Web-based monitoring and approval system was used for cephalosporins. This system provided feedback on prescribing patterns to staff. Cephalosporin use decreased from 38.3 to 21.2 defined daily doses (DDDs) per 1000 patient-days after intervention. At the same time, concor-dance with national antibiotic guidelines increased.51 In a pediatric study, a Web-based automated clinical decision support tool provided real-time communication with pre-scribers of antibiotics.52 This system resulted in an 11.6% reduction in doses of antibiotics prescribed during 1 year and an increase in satisfaction of prescribers and pharma-cists. The cost savings using this system was estimated at $370,069. Pharmacist-Driven Intravenous to Oral Switch Pro-grams. Most clinicians cannot remember which medica-tions are highly bioavailable, meaning that the oral formu-lation of these medications will achieve nearly the same blood level as the intravenous. For this reason many hospi-tals empower pharmacists to write orders to switch highly bioavailable antimicrobials (and other medications) from the intravenous to the oral formulation provided the patient meets certain criteria. Patients who are clinically stable and consuming a normal diet and other oral medications are automatically switched by pharmacy to oral drugs, saving money without detriment to the patient. Antimicrobials that are candidates for switch programs are summarized in Table 2. Pharmacy Dosing Programs. In some hospitals, phar-macists are responsible for the dosing and monitoring of vancomycin and/or aminoglycosides. Often using electron-ic dose calculators, pharmacists are able to choose initial doses and adjust dosing based on levels with more accu-racy to achieve appropriate subsequent blood levels com-pared with physicians who often base dose adjustments on techniques of estimation or at best use dosing nomograms. Bond and Raehl53 conducted a study evaluating outcomes in Medicare patients in hospitals with or without phar-macist-managed vancomycin or aminoglycoside dosing protocols. Those hospitals without pharmacist-managed protocols had higher mortality (P<.0001), longer length of stay (P<.0001), increased adverse events (P<.001), and

higher hospital costs (P<.0001). One criticism of this type of program has been that clinicians, particularly resident physicians, will fail to learn or will forget how to dose these antibiotics if not practiced on a regular basis. Antibiotic Cycling. Antibiotic cycling is the scheduled removal and substitution of specific antimicrobials or anti-microbial classes in a given patient care unit. The hypoth-esis is that by removing specific classes of antimicrobials on a regular basis, the development of resistance can be avoided. For example, all patients with suspected ventila-tor-associated pneumonia in a certain ICU might be treated with a fourth-generation cephalosporin in January, an anti - pseudomonal β-lactam/β-lactamase inhibitor in Febru-ary, and an antipseudomonal carbapenem in March; then the cycle is repeated. Studies of antimicrobial cycling are limited and heterogeneous. Several studies in ICU popula-tions have demonstrated a decrease in ventilator-associated pneumonia due to multidrug-resistant infection with cy-cling.54,55 However, these studies also noted that cycling occurred in conjunction with de-escalation and an overall decrease in antimicrobial use. Therefore, it is difficult to ascertain whether the results were attributable to cycling or decreased use. Unfortunately, many trials of antimicrobial cycling are hampered by heterogeneous study populations and large percentages of patients receiving “off-cycle” antimicrobials. A recent systematic review was not able to conclude that cycling was beneficial.56 Because of in-sufficient data, the current Infectious Diseases Society of America guidelines on antimicrobial stewardship8 do not recommend antibiotic cycling. Table 3 lists the most common antimicrobial steward-ship approaches and techniques with their benefits and drawbacks and examples from the literature.

STEPS TO TAKE WHEN IMPLEMENTING AN ASP

UNDERSTAND PROBLEM PATHOGENS AND ANTIMICROBIAL USE AT YOUR INSTITUTION An important first step in building an ASP should be to identify current institutional resistance patterns and an-

TABLE 2. Highly Bioavailable Antimicrobials That Are Good Candidates for Intravenous to Oral Switch Programs

Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) Metronidazole Macrolides (azithromycin, erythromycin) Doxycycline Clindamycin Rifampin Linezolid Fluconazole

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timicrobial use. Not all hospitals need the same level of interventions. Antimicrobial stewardship programs should be tailored to institutional problem pathogens and overuse of particular classes of drugs. Engage your microbiology laboratory, infection control, and pharmacy colleagues.

ASSESS YOUR CURRENT RESOURCE

Before funding can be secured for your ASP, it is crucial to understand what systems are in place that may be accessed to promote stewardship. First and foremost, many institu-tions have or are building electronic medical records and

TABLE 3. Summary of Antimicrobial Stewardship Techniques

Stewardship approaches and strategies Description Advantage Disadvantage Reference(s)

Front-end or The antimicrobial steward reviews the Target antimicrobials that are Unclear impact on anti- 57-59 preprescription order for appropriateness at the time overused, misused, or abused microbial resistance authorization it is written. Specific antimicrobials Encourage use of antimicrobials Some clinicians believe this are restricted to use by certain based on hospital formulary approach threatens their prescribers or units, whereas others Lower antimicrobial costs autonomy must obtain authorization. Anti- Useful in controlling outbreaks Acceptance of recommendation microbial order forms or order sets may vary, depending on who can help prompt clinicians to obtain provides authorization approval Transfer between facilities with different formularies may result in inappropriate antimicrobial therapy Loopholes in the system may allow use of restricted antibiotics without approval

Back-end or The antimicrobial steward reviews Direct interaction and Requires active surveillance by 12, 31, 32, postprescription existing antibiotic orders and provides feedback with prescriber an ASP, which is time- 60, 61 prospective clinicians with direct recommendations Performed by a trained consuming review and to continue, adjust, change, or antimicrobial steward May be difficult to perform feedback discontinue the therapy based on the Frequency of intervention frequently in settings with available microbiology results and can be tailored to size fewer resources clinical features of the case of the institution

Clinical guidelines, Prompt the prescriber to make evidence- Can incorporate feedback Need to educate clinicians to 35-38, 40, 62 order sets, and based antibiotic choices based on local from multidisciplinary team identify patients who are not treatment antimicrobial resistance patterns, Can provide guidance for appropriate for specific algorithms national guidelines, and relevant de-escalation and appropriate guidelines (eg, history of clinical factors length of treatment MDR infection, immunocompromised)

Education Grand Rounds, departmental Direct ASP to practitioner Success depends on support of 39, 41 conferences, house staff teaching, interaction administration, participation e-mail alerts, guidebooks Opportunity for focus on of prescribers and clinical particular ASP topics (CAP, staff VAP, UTI, SSI, SCIP)

Pharmacodynamic Use of PK/PD properties of antimicrobial Optimal use of currently Education of nursing staff 42-45 dose optimization agents to optimize drug efficacy based available antimicrobials may regarding prolonged or on organism, site of infection, and improve outcomes without atypical administration patient characteristics increased risk of toxic effects

Computer-assisted Computer-based algorithm that guides Can be incorporated into Requires significant time and 50-52, 63, 64 decision support a practitioner and makes existing CPOE based on effort from information programs recommendations for antimicrobial drug or suspected infection technology services regimens based on suspected infection, May require additional training patient characteristics, local of ASP team and prescribers microbiology, and optimal drug dosing

Pharmacy-based Algorithms empower pharmacists to Decreased length of stay and Prescribers may quickly lose 53 dosing programs transition bioequivalent drugs from IV early transition to oral comfort with appropriate to PO formulation; dosing and antimicrobials dosing and monitoring of monitoring of vancomycin and Decrease physician error and these potentially nephrotoxic aminoglycosides ordering of unnecessary levels and ototoxic agents

ASP = antimicrobial stewardship program; CAP = community-acquired pneumonia; CPOE = computerized physician order entry; IV = intravenous; MDR = multidrug resistant; PD = pharmacodynamic; PK = pharmacokinetic; PO = oral; SCIP = surgical care improvement program; SSI = skin and soft tissue infection; UTI = urinary tract infection; VAP = ventilator-acquired pneumonia.

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computerized physician order entry systems. These sys-tems may be ideal places to begin development of guide-lines and order sets. Many pharmacy purchasing systems may have the ability to track antimicrobial use and/or to record interventions. Educational forums, such as Grand Rounds or Lunch and Learns, may present opportunities for focus groups to discuss people’s misconceptions and concerns about the idea of restricting antimicrobials. In ad-dition, many national and international resources for stew-ardship have become available in recent months. The Cen-ters for Disease Control and Prevention recently launched the Get Smart for Healthcare Web site and has many excel-lent resources for developing ASPs.65 The Infectious Dis-eases Society of America has guidelines on ASPs and sup-port for clinical physicians developing a business plan.8,66 Many centers that have ASPs have made their resources available online.67

Resources may also include current staffs that have an interest in developing a stewardship program. As noted, there is no set formula to determine who needs to be part of a stewardship program. Support and interest can be found from a wide range of practitioners at your institution.

DETERMINE PRIORITY AREAS AND PLAN FOR INTERVENTIONS

Once you have determined the current state of resistance and antimicrobial use in your institution and your current resources, you can begin to prioritize what areas need to be addressed. You can also begin to determine the most effec-tive way of implementing change, for example, guidelines, order forms, guidebooks, electronic monitoring, and edu-cational detailing. Identify what resources will be needed to fund these endeavors; can existing staff and technology be used or does a business plan need to be developed for funding of this program?

ENGAGE HOSPITAL LEADERS

A key to establishing successful stewardship is the en-gagement of hospital leadership. Determining whether antimicrobial resistance and stewardship is important to hospital administration is a critical first step. If it is not, then you have ample opportunity to demonstrate why stewardship can improve safety and clinical outcomes and decrease antibiotic expenditures. If stewardship has not been a high priority, identifying an administrative “cham-pion” who will support your case in discussion with the administration is extremely important. Antimicrobial re-sistance should be viewed as a quality and safety issue and can tie into many current safety campaigns and bundles, such as those focusing on community-acquired pneumo-nia, antimicrobial prophylaxis for surgery, and asymptom-atic bacteriuria.

DEVELOP A BUSINESS PLAN

Developing a business plan might seem to be the most daunting part of developing an ASP. Start by determining your baseline expenditures. Then examine the attribut-able cost savings associated with the proposed interven-tions based on the literature and your own hospital data. For instance, if use of antibiotics targeting gram-negative bacteria for patients with uncomplicated skin and soft tis-sue infections is a problem at your institution, you can cal-culate the amount of drug saved if you were to implement an algorithm approach similar to that of Jenkins et al40 and assuming similar results. Overall, antimicrobial programs have been shown to be cost-effective.66 Determine the costs associated with the infectious disease diagnosis of interest. Costs may include not only the price of the antimicrobi-als but also those associated with laboratory tests and with adverse events from using the incorrect dose or type of an-timicrobial. As an example, a simple and straightforward goal of any stewardship program can be implementation of a program for conversion of intravenous drugs to oral drugs. Oral drugs are usually less expensive and do not re-quire placement of long-term intravenous catheters, mini-mizing complications from vascular access and enabling earlier discharge from the hospital. Perhaps the biggest barrier to developing a stewardship program is the personnel cost. Many administrators see stewardship as the infectious disease consultant’s job, and yet consultants are unable to bill for stewardship. There is currently no mechanism for direct reimbursement of stewardship programs, and therefore costs must be jus-tified by demonstrating savings to the institution. Also, a widely held perception is that stewardship will result in a decreased number of consultations. In fact, stewardship programs should be aimed at augmenting and supporting the consultative service and may even result in an increased number of referrals.

PUT YOUR PLAN INTO ACTION Determine how you would like to roll out your ASP. Re-member that the most successful plans incorporate educa-tional outreach and physician feedback. If possible, survey hospital staff before and after each step of the program is implemented to determine practitioner satisfaction and room for improvement. Before implementation, identify what outcome data you would like to prospectively col-lect, such as practitioner satisfaction, antimicrobial use, expenditures, and clinical outcome variables, including readmission for specific conditions (eg, cellulitis and community-acquired pneumonia). Pharmacy purchasing systems usually track DDDs or days of therapy (DOTs), which are extremely useful measures of the success of the program.68

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Measure your outcomes and incorporate feedback. It is important to have a predetermined timeline for assessment of goals and launching of each step of your ASP. Feedback on success and failure should be incorporated into the pro-gram on a regular basis. For each process implemented, there should be an outcome goal and measure. Antimicro-bial consumption and expenditures are common outcome measurements, as discussed subsequently, but may not re-flect other important goals, such as improved practitioner satisfaction, decrease in adverse drug events, improvement in adherence to Medicare or other quality measures, or changes in antimicrobial resistance. The 2 most common methods used to evaluate drug consumption are DDD or DOTs. The DDD is calculated as the total number of grams of antimicrobial agent used divided by the number of grams in an average daily dose. The DDD is defined by the World Health Organization.69

The advantage of the DDD is the ability to compare stan-dardized doses among hospitals. The disadvantage is that the DDD does not account for alternative dosing regimens due to renal dysfunction, age, or regimens that optimized pharmacokinetic or pharmacodynamic dosing. Therefore, in many cases the administered dose is different from the DDD recommended by the World Health Organization. This can result in either overestimation or underestimation of drug consumption. An alternative measurement is the number of DOTs. 68 DOTs are expressed as the adminis-tration of a single agent on a given day regardless of the number of doses administered or dosage strength. The ad-vantage is that DOTs are not affected by changes in dosing regimens. DOTs will not reflect actual doses and may not adequately represent antimicrobials that are administered multiple times daily. The DDD may be more helpful when benchmarking institutions or in large studies, whereas DOTs may be more helpful in comparing use of different classes of antimicrobials within an institution. Many institutions begin implementing stewardship as a tiered program to improve practitioner comfort and ac-ceptance. Philmon et al57 used a 3-tiered approach to in-troduce stewardship in a community teaching hospital in Dallas, TX: conversion from intravenous to oral admin-istration for selected highly bioavailable antimicrobials, cessation of perioperative prophylaxis within 24 hours for patients undergoing clean and clean-contaminated sur-gery, and consultation with an infectious disease physician before continuing administration of selected drugs beyond 48 hours. From April 2001 through December 2003, a total of 1426 requests for antimicrobial therapy met cri-teria for intervention. Antimicrobial costs per patient-day decreased by 31%, and total savings in acquisition costs were $1,841,203. Significant decreases were found in

resistance.

Soliciting practitioner feedback is a crucial step in the establishment of a successful stewardship program. We showed that house officer satisfaction with the stewardship program increased significantly between 2008 and 2010 after conducting a survey requesting feedback on the pro-gram and addressing their concerns by making program-matic changes.70

WHERE CAN THINGS GO WRONG: BARRIERS AND PITFALLS

One of the greatest challenges of antimicrobial steward-ship research is demonstrating a clear causal association between implementation of ASPs and decreased rates of antimicrobial resistance. Early studies that achieved de-creased cephalosporin use were successful in controlling the incidence of resistant gram-negative infections to ceph-alosporins but resulted in an increase in carbapenem use and resistance to carbapenems.71 This is an example of the “squeezing the balloon” phenomenon, in which decreasing use of one antimicrobial or class results in increasing use of another, often with associated resistance. Studies of out-breaks of infections have shown improvement in infection rates with decreased use of cephalosporins and fluoroquinolones.72,73 These studies are encouraging in that they suggest that ASPs can impact the rate of infections in hospitals. However, when such interventions come at the cost of increased use of extended-spectrum β-lactam/β-lactamase inhibitors72 and carbapenems, other consequences may be experienced. Studies of the implementation of antimicrobial steward-ship and its effects on resistance are extremely difficult to control and are usually observational. One systematic re-view of the literature attempted to identify “rigorous evalu-ations” of interventions to improve hospital prescribing of antimicrobial drugs. Of the 16 studies that met criteria for inclusion, only 4 provided strong evidence that changes in prescribing antimicrobial drugs to hospital inpatients can decrease antimicrobial resistance.74 Four studies were negative, and the 8 remaining studies were cited as hav-ing flawed designs, allowing for alternative explanations for the outcome. Most studies of antimicrobial stewardship compare individual patient-level data points, such as antibi-otic use and rates of colonization or infection with resistant organisms. Correlating the relationship between antimicro-bial use and resistance over time may be more appropriate. Time-series analyses rely on aggregated, ecologic-level data and attempt to account for such variables as the in-troduction of infection control measures, the variation in use of broad-spectrum classes of drugs, colonization rates, and the lag time between implementation of interventions and development of resistance. In particular, time-series

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analysis is useful in study designs in which infection rates have been ascertained before and after an intervention, but controlling with a nonintervention group may not be prac-tical or ethical. Several time-series analyses of methicillin-resistant and have shown that variations in rates of multidrug-resistant infection may be attributed not only to changes in drug use but also to implementation of infection control practices and rates of colonization with multidrug-resistant bacteria.75-77

From a practical standpoint, implementing a stewardship program can seem like a monumental task. In a nationwide survey of hospitals, of 406 respondents, we found that 51% had what they would consider formal ASPs. Of those who did not, the most commonly cited barriers to implementa-tion were staffing constraints, funding, and lack of time.78

CONCLUSION

As hospitalized patients become more complex to treat, the increasing prevalence of antimicrobial resistance in both health care and community settings represents a daunting challenge. With the increasing complexity of infections and a paucity of new antimicrobials in development, the future of successful antimicrobial therapy looks bleak. Antimicrobial stewardship can provide all practitioners with tools to prevent the overuse of valuable resources and help control the increase in antimicrobial resistance. Although often underappreciated, the increase of antimi-crobial resistance has finally caught the attention of influ-ential international health care organizations. The Institute of Medicine has identified antibiotic resistance79 as one of the key microbial threats to health in the United States and has listed decreasing the inappropriate use of antimicrobi-als as a primary solution to address this threat. The Get Smart campaign, initiated by the Centers for Disease Con-trol and Prevention in 1995, focused on reducing the use of inappropriate antimicrobials in the outpatient setting. In 2010, the Centers for Disease Control and Prevention launched Get Smart for Healthcare, a campaign focused on improving antibiotic use in inpatient health care facili-ties to prevent overuse of antimicrobials and promote the use of antimicrobial stewardship. The 2011 World Health Organization World Health Day focused on international antimicrobial resistance. This World Health Organization campaign has drawn together agencies from all over the world to focus resources and combat the increase in anti-microbial resistance. These organizations are drawing attention to the bat-tles that practitioners face on a daily basis. This attention should be a call to action for insurance providers, national and state governments, and hospital administrators to pro-vide much needed resources to practitioners who incorpo-

rate stewardship practices into everyday patient care. The California Department of Public Health Antimicrobial Stewardship Initiative is an example of how government resources can be used to promote proper antibiotic use in health care facilities. California Department of Pub-lic Health staff assess existing stewardship practices at health care facilities to identify barriers to success and methods to overcome those barriers. They also provide consultative services to help facilities, including long-term care hospitals, where inappropriate antibiotic use is known to be especially common,80 to assist in implemen-tation of stewardship activities and development of for-mal programs. By making antimicrobial stewardship part of our daily practice, we can improve patient safety and care, reduce the unnecessary use of valuable resources, and reduce resistance.

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. 1993;37(5):1073-1081. 46. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. . 2009;66(1):82-98. 47. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Therapeutic monitor-ing of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.

. 2009;29(11):1275-1279. 48. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeu-tic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Phar-macists, and the Society of Infectious Diseases Pharmacists. . 2009;49(3):325-327. 49. Nicasio AM, Ariano RE, Zelenitsky SA, et al. Population pharmacoki-netics of high-dose, prolonged-infusion cefepime in adult critically ill pa-tients with ventilator-associated pneumonia. . 2009;53(4):1476-1481. 50. Evans RS, Pestotnik SL, Classen DC, et al. A computer-assisted man-agement program for antibiotics and other antiinfective agents. . 1998;338(4):232-238. 51. Richards MJ, Robertson MB, Dartnell JG, et al. Impact of a web-based antimicrobial approval system on broad-spectrum cephalosporin use at a teach-ing hospital. . 2003;178(8):386-390. 52. Agwu AL, Lee CK, Jain SK, et al. A World Wide Web-based antimicro-bial stewardship program improves efficiency, communication, and user satis-faction and reduces cost in a tertiary care pediatric medical center.

. 2008;47(6):747-753. 53. Bond CA, Raehl CL. Clinical and economic outcomes of pharmacist-managed antimicrobial prophylaxis in surgical patients.

. 2007;64(18):1935-1942. 54. Raymond DP, Pelletier SJ, Crabtree TD, et al. Impact of a rotating em-piric antibiotic schedule on infectious mortality in an intensive care unit. Crit

. 2001;29(6):1101-1108. 55. Gruson D, Hilbert G, Vargas F, et al. Rotation and restricted use of anti-biotics in a medical intensive care unit: impact on the incidence of ventilator-associated pneumonia caused by antibiotic-resistant gram-negative bacteria.

. 2000;162(3, pt 1):837-843. 56. Brown EM, Nathwani D. Antibiotic cycling or rotation: a systematic review of the evidence of efficacy. . 2005;55(1):6- 9. 57. Philmon C, Smith T, Williamson S, Goodman E. Controlling use of an-timicrobials in a community teaching hospital. . 2006;27(3):239-244.

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58. White AC Jr, Atmar RL, Wilson J, Cate TR, Stager CE, Greenberg SB. Effects of requiring prior authorization for selected antimicrobials: expendi-tures, susceptibilities, and clinical outcomes. . 1997;25(2):230- 239. 59. Gross R, Morgan AS, Kinky DE, Weiner M, Gibson GA, Fishman NO. Impact of a hospital-based antimicrobial management program on clinical and economic outcomes. . 2001;33(3):289-295. 60. Bantar C, Sartori B, Vesco E, et al. A hospitalwide intervention program to optimize the quality of antibiotic use: impact on prescribing practice, an-tibiotic consumption, cost savings, and bacterial resistance. . 2003;37(2):180-186. 61. Cosgrove SE, Patel A, Song X, et al. Impact of different methods of feedback to clinicians after postprescription antimicrobial review based on the Centers For Disease Control and Prevention’s 12 Steps to Prevent Antimicro-bial Resistance Among Hospitalized Adults. . 2007;28(6):641-646. 62. Hermsen ED, Shull SS, Puumala S, Rupp M. Improvement in prescrib-ing habits and economic outcomes associated with the introduction of a stan-dardized approach for surgical antimicrobial prophylaxis.

. 2008;29(5):457-461. 63. McGregor JC, Weekes E, Forrest GN, et al. Impact of a computerized clinical decision support system on reducing inappropriate antimicrobial use: a randomized controlled trial. . 2006;13(4):378- 384. 64. Cook PP, Rizzo S, Gooch M, Jordan M, Fang X, Hudson S. Sustained reduction in antimicrobial use and decrease in methicillin-resistant

and infections following implementation of an electronic medical record at a tertiary-care teaching hospital.

. 2011;66(1):205-209. 65. Centers for Disease Control and Prevention (CDC). Get Smart for Health-care Web site. Resources: state and local stewardship efforts. http://www.cdc.gov /getsmart/healthcare/improve-efforts/resources/index.html. Accessed Septem-ber 7, 2011. 66. McQuillen DP, Petrak RM, Wasserman RB, Nahass RG, Scull JA, Mar-tinelli LP. The value of infectious diseases specialists: non-patient care activi-ties. . 2008;47(8):1051-1063. 67. Pagani L, Gyssens IC, Huttner B, Nathwani D, Harbarth S. Navigating the Web in search of resources on antimicrobial stewardship in health care institutions. . 2009;48(5):626-632. 68. Polk RE, Fox C, Mahoney A, Letcavage J, MacDougall C. Measurement of adult antibacterial drug use in 130 US hospitals: comparison of defined daily dose and days of therapy. . 2007;44(5):664-670.

69. WHO Collaborating Centre for Drug Statistics Methodology. Definitions and general considerations. http://www.whocc.no/ddd/definition_and_general _considera/. Accessed September 7, 2011. 70. Hong SY, Lawrence K, Davidson LE, Taur Y, Nadkarni L, Doron S. Evaluation of programmatic changes to an antimicrobial stewardship program with house officer feedback [abstract 431]. Presented at Infectious Diseases Society of America 48th Annual Meeting; British Columbia, Canada; October 21-24, 2010. http://idsa.confex.com/idsa/2010/webprogram/Paper4082.html. Accessed September 7, 2011. 71. Rahal JJ, Urban C, Horn D, et al. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial . . 1998;280(14):1233-1237. 72. Valiquette L, Cossette B, Garant MP, Diab H, Pepin J. Impact of a re-duction in the use of high-risk antibiotics on the course of an epidemic of

-associated disease caused by the hypervirulent NAP1/027 strain. . 2007;45(suppl 2):S112-S121. 73. Fowler S, Webber A, Cooper BS, et al. Successful use of feedback to im-prove antibiotic prescribing and reduce infection: a con-trolled interrupted time series. . 2007;59(5):990-995. 74. Davey P, Brown E, Fenelon L, et al. Systematic review of antimicrobial drug prescribing in hospitals. . 2006;12(2):211-216. 75. Bosso JA, Mauldin PD. Using interrupted time series analysis to assess associations of fluoroquinolone formulary changes with susceptibility of gram-negative pathogens and isolation rates of methicillin-resistant

. . 2006;50(6):2106-2112. 76. Aldeyab MA, Monnet DL, Lopez-Lozano JM, et al. Modelling the impact of antibiotic use and infection control practices on the incidence of hospital-acquired methicillin-resistant : a time-series analysis. . 2008;62(3):593-600. 77. Vernaz N, Hill K, Leggeat S, et al. Temporal effects of antibiotic use and infections. . 2009;63(6): 1272-1275. 78. Doron SI, Nadkarni LD, Lawrence KR, et al. National Antimicrobial Stewardship Practices—an update [abstract 370]. Presented at Society for Healthcare Epidemiology of America (SHEA) Annual Scientific Meeting; Dal-las, TX; April 1-4, 2011. 79. Institute of Medicine. Microbial threats to health: emergence, detec-tion, and response. Released March 15, 2003. http://iom.edu/Reports/2003 /Microbial-Threats-to-Health-Emergence-Detection-and-Response. Accessed September 7, 2011. 80. Strausbaugh LJ, Joseph CL. The burden of infection in long-term care.

. 2000;21(10):674-679.




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CURRENT CONCEPTS IN ANTIMICROBIAL THERAPY AGAINST SELECT GRAM-POSITIVE ORGANISMS



S causes a broad spectrum of dis-ease. Humans are colonized by this organism mainly in

the nasopharynx and on the skin.1 has the unique propensity to infect and destroy normal healthy tissue, causing skin and wound infections, bloodstream infection (BSI), pneumonia, osteomyelitis, endocarditis, lung ab-scess, and pyomyositis. Manifestations of central venous catheter–related infection include local infection at

Current Concepts in Antimicrobial Therapy Against Select Gram-Positive Organisms: Methicillin-Resistant Staphylococcus aureus,

Penicillin-Resistant Pneumococci, and Vancomycin-Resistant Enterococci

Ana Maria Rivera, MD, and Helen W. Boucher, MD

Gram-positive bacteria cause a broad spectrum of disease in im-munocompetent and immunocompromised hosts. Despite increas-ing knowledge about resistance transmission patterns and new antibiotics, these organisms continue to cause significant morbid-ity and mortality, especially in the health care setting. Methicillin-resistant Staphylococcus aureus poses major problems worldwide as a cause of nosocomial infection and has emerged as a cause of community-acquired infections. This change in epidemiology af-fects choices of empirical antibiotics for skin and skin-structure infections and community-acquired pneumonia in many settings. Throughout the world, the treatment of community-acquired pneu-monia and other respiratory tract infections caused by penicillin-resistant Streptococcus pneumoniae has been complicated by resistance to β-lactam and macrolide antibacterial drugs. Van-comycin-resistant enterococci are a major cause of infection in the hospital setting and remain resistant to treatment with most standard antibiotics. Treatment of diseases caused by resistant gram-positive bacteria requires appropriate use of available anti-biotics and stewardship to prolong their effectiveness. In addition, appropriate and aggressive infection control efforts are vital to help prevent the spread of resistant pathogens.

Mayo Clin Proc. 2011;86(12):1230-1242

BSI = bloodstream infection; CA-MRSA = community-associated methi-cillin-resistant Staphylococcus aureus; CAP = community-acquired pneu-monia; CLSI = Clinical Laboratory Standards Institute; CNS = central nervous system; FDA = Food and Drug Administration; MIC = minimum inhibitory concentration; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-sensitive Staphylococcus aureus; PBP = penicillin-binding protein; PCV7 = pneumococcal conjugate vaccine 7; SSSI = skin and skin-structure infection; UTI = urinary tract infection; VAP = ventilator-associated pneumonia; VRE = vancomycin-resistant enterococci; VISA = vancomycin-intermediate Staphylococcus aureus

the site, thrombophlebitis and tunnel infections, and central venous catheter–related BSI.2 These well-described health care–associated infections continue to challenge physi-cians globally. Community-associated methicillin-resistant (CA-MRSA) has been described in patients with no pre-vious contact with the health care environment. Unlike hospital-associated MRSA, many CA-MRSA strains are susceptible to gentamicin, tetracyclines, lincosamides, and trimethoprim-sulfamethoxazole.1,3 Many of these infections are limited to superficial skin and skin-structure infections (SSSIs). However, CA-MRSA can cause severe systemic infections, including pneumonia and BSI.4 In the United States, the first cases of severe CA-MRSA disease were 4 cases of fatal pneumonia reported to the Centers for Dis-ease Control and Prevention in 1997-1999, all associated with a particular strain of CA-MRSA.5 Several subsequent studies reported community-acquired pneumonia (CAP) with high mortality rates.6,7 In a study of 3 different communities, more than two-thirds had SSSIs, followed by wound infection, urinary tract infection (UTI), sinus infec-tion, and pneumonia as the most common manifestations of their CA-MRSA infection.8 New challenges in treating

Staphylococcus aureus Streptococcus pneumoniae

From the Division of Geographic Medicine and Infectious Diseases, Tufts Uni-versity School of Medicine and Tufts Medical Center, Boston, MA.

Dr Rivera is supported by a grant from the National Institutes of Health (T32AI007438) and has no conflicts of interest to declare. In the past 12 months, Dr Boucher has served as an advisor/consultant to Basilea, Cerexa, Durata, Merck (adjudication committee), Rib-X, Targanta/TMC, TheraDoc/Hospira, and Wyeth/Pfizer (DSMB).

Address correspondence to Helen W. Boucher, MD, FIDSA, Division of Geo-graphic Medicine and Infectious Diseases, Tufts Medical Center, 800 Wash-ington St, Box 238, Boston, MA 02111 ([email protected]). Individual reprints of this article and a bound reprint of the entire Symposium on Antimicrobial Therapy will be available for purchase from our Web site www.mayoclinicproceedings.com.


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infections caused by more resistant organisms include with heteroresistant vancomycin inter-mediate (VISA), vancomycin-resistant , and MRSA resistant to linezolid and daptomycin.9,10 In this article, we provide an overview on MRSA treatment.

METHICILLIN-RESISTANT S AUREUS SSSIs

The spectrum of MRSA SSSIs includes impetigo, follic-ulitis, cellulitis, erysipelas, staphylococcal scalded skin syndrome, toxic shock syndrome, furuncles, carbuncles, and deep skin abscesses.11,12 In a study examining bacterial causes of SSSIs in 11 US emergency departments in 2004, CA-MRSA was the No. 1 cause of endemic SSSIs.13

No clear predictors of CA-MRSA exist, and local trends should be considered when selecting empirical therapy. However, some risk factors include a positive history of contact with CA-MRSA, crowding, contaminated personal objects, compromised skin integrity, and absence of cleanli-ness. Person to person transmission, among men who have sex with men and as the result of heterosexual contact, has been implicated in CA-MRSA epidemiologic trends.14

Although there are several strains of CA-MRSA in the United States, the predominant US strains include the USA300 and USA400 clones. The most common through-out the United States is the USA300 clone, except in Alas-ka.15 In Europe the epidemiology is heterogeneous, but overall the most common clone is the -positive European ST80-MRSA-IV clone.16 Community-acquired MRSA has unique virulence factors, including Panton-Valentin leukocidin, and is frequently associated with in-adequate antibiotic therapy.17-19

AGENTS CURRENTLY AVAILABLE TO TREAT MRSA INFECTION

Some uncomplicated CA-MRSA SSSIs in immunocompe-tent hosts can be treated with incision and drainage, lo-cal debridement, and abscess drainage alone.11 However, in patients with signs of systemic illness or comorbidities, empirical treatment of SSSIs should include antibacte-rial therapy. Unfortunately, clinical predictors of drug resistance are limited, so local rates of CA-MRSA must be considered when treating SSSIs. No large randomized controlled trials have compared oral antibiotics to treat SSSIs, although several ongoing National Institutes of Health studies should help address these questions.20

Observational studies demonstrate successful clinical outcomes with oral antibiotics, including trimethoprim-sulfamethoxazole, doxycycline, and clindamycin. Isolates that test resistant to erythromycin and are susceptible to clindamycin should be tested for inducible clindamycin

resistance (via the D-test) because treatment failures have been reported.21 Linezolid is not recommended to treat un-complicated SSSIs because of the associated toxicity and cost.22

Treatment of SSSIs in patients with comorbidities or signs of systemic disease includes monotherapy with in-travenous antibiotics in addition to prompt and thorough incision and drainage of abscesses, as well as debride-ment of wounds.11 Table 1 lists the systemically available gram-positive antibiotics. Vancomycin may be used at a dosage of 10 to 15 mg/kg intravenously every 12 hours adjusted for renal function.23 Other options include lin-ezolid, 600 mg intravenously every 12 hours, with the limitations mentioned herein, including cost and toxic-ity. Daptomycin is another agent effective for therapy of SSSIs at a dosage of 4 mg/kg daily. New agents for SSSIs include telavancin, approved by the US Food and Drug Administration (FDA) in 2009 at the dosage of 10 mg/kg daily in patients with normal renal function, and cef-taroline, which was FDA approved in 2010 for treatment of acute bacterial SSSIs at the dosage of 600 mg intrave-nously every 12 hours in patients with normal renal func-tion. High cost and risk of toxic effects limit use of these new drugs.23,24 The mechanisms of resistance for MRSA are presented in Table 2.25

THERAPY FOR INVASIVE MRSA INFECTIONS

VANCOMYCIN

Vancomycin remains first-line antimicrobial therapy for serious infections caused by MRSA, including compli-cated SSSIs, pneumonia, and BSI.11 Available in multiple generic formulations, vancomycin is reasonably well toler-ated, associated with a low incidence of adverse effects, and relatively inexpensive. However, despite being the cri-terion standard therapy, the susceptibility of MRSA to this antibiotic may be decreasing, and reports of clinical failure are increasing.26,27

Changes in MRSA vancomycin susceptibility have been observed over time. Increasing minimum inhibitory concentrations (MICs) seem to be related to vancomycin use.28 As the MIC increases, the frequency of heteroresis-tant VISA also has been observed to increase.29 Although most MRSA strains appear susceptible, subpopulations of strains may have VISA selected by vancomycin treat-ment.30 Furthermore, increased vancomycin MIC has cor-related with adverse clinical outcomes in some studies.26,27

However, these data are limited in that they derive from ret-rospective studies, subset analyses, and variations among MIC testing methods.31 In 2006, on the basis of clinical evidence suggesting reduced efficacy in the treatment of isolates with borderline susceptible MICs, the vanco-

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mycin breakpoints were lowered by the Clinical Labora-tory Standards Institute (CLSI). The MRSA vancomycin MIC decreased from 4 μg/mL or less to 2 μg/mL or less for “susceptible,” from 8 to 16 μg/mL to 4 to 8 μg/mL for “intermediate,” and from 32 μg/mL or more to 16 μg/mL or more for the “resistant” designation.32 Despite concerns about evolving resistance, most cases of invasive or severe infections caused by MRSA remain highly susceptible to vancomycin.28,33,34 Nonetheless, recent guidelines suggest treating with higher doses of vancomycin with goal trough values of 15 to 20 μg/mL.23 In patients who do not respond, follow-up cultures should be obtained and, when results are positive, repeat susceptibility testing performed to as-sess for increasing vancomycin MICs. Alternative antibi-otics should be considered when the clinical response is suboptimal.11

Studies evaluating MRSA infections with reduced sus-ceptibility to vancomycin (including VISA and hetero-geneous VISA) suggest that prospective identification of these isolates may have limited value, but the importance of identifying these strains is critical in the context of clini-cal failure of vancomycin therapy.35

In a prospective, multinational cohort study evaluating the outcome of severe infections, higher MIC was associated with an increased mortality at 30 days. The remarkable finding of this study was that high vancomy-cin MIC was associated with worse outcomes in patients with methicillin-sensitive (MSSA)

infections not treated with vancomycin. This finding sug-gests that other factors, presumably related to the bacteria or the host, may be implicated in the worse outcomes. This finding is aligned with current recommendations to con-sider changing from vancomycin therapy in light of clinical response, not MIC alone.36,37

The predictability of vancomycin nephrotoxicity has been demonstrated in a number of studies and is associated with higher vancomycin trough concentrations.38 It has also been associated with underlying renal disease, longer duration of therapy, and use of other nephrotoxic medications.39,40

TEICOPLANIN

Teicoplanin is an antibiotic widely used outside the Unit-ed States for the treatment of infections caused by gram-positive bacteria. It is chemically related to the group of glycopeptides, which also includes vancomycin.41 This an-tibiotic demonstrates bactericidal activity against a broad spectrum of gram-positive organisms, including MRSA and methicillin-resistant coagulase-negative

. It has a longer half-life, higher protein binding, higher bone uptake, and less potential for nephro-toxicity compared with vancomycin.42

In the United Kingdom, the most recent guidelines for the treatment of MRSA infections include teicoplanin as one of the glycopeptides of choice. Local epidemiology and the clinical setting would influence the choice of van-comycin vs teicoplanin. The pharmacokinetics of teicopla-

TABLE 1. Agents for Infections Caused by Resistant Gram-Positive Organisms

Activity against

Resistant Class Route of Drug (mechanism of action) administration MRSA VRE Common toxic effects

Vancomycin Glycopeptide (cell wall IV only All Yes No Renal, cranial nerve VIII, synthesis inhibitor) infusion-related reaction

Daptomycin Lipoglycopeptide (cell IV only SSSI, BSI, No Yes Myopathy, eosinophilic membrane disruption, SARIE, ( pneumonia probably also acts at not pneumonia only) cell wall)

Linezolid Oxazolidonone (protein IV or oral SSSI, No Yes Bone marrow suppression, synthesis inhibitor) pneumonia, lactic acidosis, not BSI peripheral neuropathy

Quinupristin- Streptogramin (protein IV only Salvage No Myalgias, arthralgias dalfupristin synthesis inhibitor)

Telavancin Lipoglycopeptide (cell IV only SSSI, CAP Yes Yes Renal, reproductive wall synthesis inhibitor) toxic effects

Tigecycline Glycylcycline (protein IV only SSSI, CAP, not synthesis inhibitor) HAP/VAP or Yes Yes Nausea, vomiting BSI

Ceftaroline Cephalosporin (cell wall IV only SSSI, CAP Yes No Allergy synthesis inhibitor)

BSI = bloodstream infection; CAP = community-acquired pneumonia; HAP/VAP = hospital-acquired pneumonia/ventilator-associated pneumonia; IV = intravenous; MRSA = methicillin-resistant ; SARIE = right-sided endocarditis; SSSI = skin and skin struc-ture infection; VRE = vancomycin-resistant enterococci.

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nin are unpredictable, and failures have been associated with low levels of the drug.43

LINEZOLID

Linezolid is a bacteriostatic, gram-positive antibiotic that inhibits protein synthesis at the 50S ribosome.44 A synthet-ic oxazolidinone active against MRSA, penicillin-resistant

and vancomycin-resistant en-terococci (VRE), linezolid is currently FDA approved for the treatment of complicated SSSIs and nosocomial pneu-monia. Linezolid is administered at a dosage of 600 mg ev-ery 12 hours orally or intravenously, and dose adjustment is not necessary. Studies have shown higher clinical cure rates and reduced lengths of hospitalization in patients with complicated SSSIs treated with linezolid compared with vancomycin.44 Higher survival rates were found in subset analyses of clinical trials comparing linezolid to vancomy-cin in the treatment of MRSA pneumonia.45 One potential explanation for this effect is that linezolid achieves higher concentration levels in lung tissue.46-48

The role of linezolid in the treatment of MRSA BSI is unclear. Successful treatment of cases of BSI associated with pneumonia or SSSIs have been reported with linezo-lid.49 However, on the basis of the results of a more recent open-label study of catheter-related BSI, linezolid is not recommended for the treatment of BSI.11 An imbalance in deaths among linezolid-treated patients led to early termi-nation of this European study. However, in the published analysis, this imbalance appears to have been driven by deaths among patients with gram-negative BSI or in whom no bacterial cause was elucidated.50

Linezolid is generally well tolerated. Bone marrow sup-pression is generally reversible with discontinuation of li - nezolid therapy. The association with serotonin toxicity and thrombocytopenia may limit its use.51 Linezolid should be administered to patients receiving serotonin reuptake inhibitors with caution, and linezolid therapy should be discontinued if serotonin syndrome is suspected.52 Patients with renal insufficiency have been found to be at a higher

risk of developing thrombocytopenia.53 The most common gastrointestinal adverse effects include nausea, vomiting, and diarrhea. Sporadic cases of lactic acidosis,54 peripheral neuropathy, and optic neuritis have been reported.55 Patients who receive therapy for more than 2 weeks should be moni-tored closely for myelosuppression and other less common toxic effects.

LINEZOLID-RESISTANT S AUREUS

Most strains of are susceptible to linezolid. Resis-tance surveillance data demonstrate that more than 99% of isolates are susceptible.56 The first MRSA isolate resistant to linezolid was reported in 2001 in a patient treated for dialysis-associated peritonitis.57 Since then, the emergence of linezolid-resistant has been reported in recent studies.58 Appropriate monitoring for resistance should be considered during long courses of therapy. As in the case of vancomycin and daptomycin, clinical failure should prompt submission of specimens for culture, susceptibility testing, and MIC determination.59

DAPTOMYCIN

Daptomycin is a cyclic lipopeptide active in vitro against most resistant gram-positive bacteria. This bactericidal agent is thought to cause depolarization of the bacteria via calcium-dependent insertion to the cell membrane.60 Dapto-mycin susceptibility may depend on its ability to penetrate through the cell wall to reach its target.61 Heteroresistant VISA may have an increased daptomycin MIC, probably related to increased cell wall thickness.62 Daptomycin was approved by the FDA for the treatment of serious MRSA infections, including SSSIs, MRSA, and MSSA BSI and right-sided endocarditis, on the basis of the results of pro-spective randomized clinical trials.63,64 The daptomycin dosage is 4 mg/kg intravenously once daily for compli-cated SSSIs and 6 mg/kg intravenously once daily for S

BSIs, including right-sided endocarditis, in patients with normal renal function.64 Daptomycin should not be used to treat pneumonia because it failed in clinical trials

TABLE 2. Mechanism of Resistance in Selected Gram-Positive Pathogens

Species Resistance phenotype Mechanism(s)

β-Lactam Low-affinity penicillin-binding proteins Fluoroquinolone Mutant topoisomerasesMethicillin-resistant Penicillin β-Lactamase

Oxacillin Low-affinity penicillin binding proteins Clindamycin Constitutive erm expression Vancomycin Mechanism unclear

Ampicillin Low-affinity penicillin-binding proteins Vancomycin Altered peptidoglycan precursor Linezolid Mutant ribosomal RNA genes Daptomycin Mechanism unclear

Adapted from 25 with permission.

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and was subsequently found to be inhibited by pulmonary surfactant.65 Resistance developed in several daptomycin-treated patients in the S BSI trial.63 In these cases, clinical failure while receiving daptomycin was related to increased daptomycin MIC from 0.25 or 0.5 μg/mL to 2 or 4 μg/mL. The mechanism is not well understood.9,63

Daptomycin therapy is associated with myopathy. Cre-atine kinase levels should be monitored at baseline and weekly while the patient is undergoing therapy, more often in patients with symptoms of muscle pain or weakness and renal insufficiency or those who receive concomitant statin therapy. Daptomycin therapy should be discontinued for muscle pain or weakness or elevations in creatine kinase levels if the level is 5 to 10 times or more the upper normal limit.64 Acute eosinophilic pneumonia has been reported with daptomycin therapy.66 Although the mechanism of toxicity has not been proven, the release of inflammatory mediators after antigen presentation by macrophages or accumulation in the epithelium after daptomycin binding with surfactant has been implicated.67 It is a diagnosis of exclusion, but physicians should have a low threshold for stopping therapy if daptomycin-induced acute eosinophilic pneumonia is suspected.67

TIGECYCLINE

Tigecycline is a derivative of minocycline and the first drug approved in the class of glycylcyclines.68 A modified side chain binds to the 30S ribosomal subunit, inhibiting pro-tein translation in bacteria.69,70 Tigecycline is active against various drug-resistant pathogens, including MRSA, VRE, and many extended β-lactamase, gram-negative bacteria. Tigecycline has a large volume of distribution and produc-es high concentrations in tissue. However, serum concen-trations decrease rapidly after intravenous administration.71 On the basis of these pharmacokinetic and pharmacody-namic properties, tigecycline should be used with caution in patients with suspected or proven BSI.72 In the United States, this drug is approved for the treatment of compli-cated SSSIs due to MRSA and the treatment of compli-cated intra-abdominal infections caused by MSSA.73 The approved tigecycline dosage is a 100-mg intravenous load-ing dose followed by a 50-mg dose given every 12 hours. Common adverse effects include nausea and vomiting. In a large, randomized, double-blind clinical study of patients with hospital-acquired pneumonia comparing tige-cycline with an imipenem-cilastatin regimen, cure rates were lower in the tigecycline ventilator-associated pneu-monia (VAP) group (67.9%) compared with imipenem (78.2%), whereas in the non-VAP patients tigecycline was noninferior to imipenem. Mortality rates were also higher in the tigecycline group.74 These results may be related to decreased tigecycline concentrations in these critically ill

patients. On the basis of these trends and subsequent obser-vations, the FDA recommends seeking alternatives to tige-cycline to treat patients with severe infections.75 A study is under way to evaluate the role of tigecycline at 2 higher dosages (75 or 100 mg every 12 hours) compared with imipenem-cilastatin in parallel in the treatment of hospital-acquired pneumonia.76

QUINUPRISTIN-DALFOPRISTIN

Quinupristin-dalfopristin is a combination streptogramin agent that is FDA approved for the treatment of SSSIs due to MSSA, streptococci, and the treatment of VRE BSI. This combination antibiotic is bactericidal against via inhibition of protein synthesis. It was studied in patients with MRSA infections who were intolerant of other anti-biotics. In an open-label, emergency use program, quinu-pristin-dalfopristin was successful in treatment of 66.7% of patients, most of whom had SSSIs and osteoarticular infections. Therapy failed in patients with endocarditis.77 Dose-limiting adverse effects include joint pain, muscle pain, and severe pain at the site of infusion.78

TELAVANCIN

Telavancin is a semisynthetic lipoglycopeptide that produces inhibition of cell wall synthesis and disruption of membrane barrier function.79 It has a long half-life of 7 to 9 hours, allow-ing once-daily administration using 7.5 to 10 mg/kg daily. It is a rapidly bactericidal agent, active against MRSA. Tela-vancin was approved by the FDA in 2009 for the treatment of complicated SSSIs caused by gram-positive bacteria, in-cluding MRSA.80 In clinical trials, telavancin was found to be noninferior to vancomycin, with cure rates of 88.3% and 87.1% in the treatment of complicated SSSIs.81

Telavancin was compared with vancomycin in large ran-domized studies in the treatment of hospital-acquired pneu-monia due to gram-positive bacteria, particularly MRSA, and found to be noninferior to vancomycin based on clinical response.82 The most common adverse effects include taste disturbances, nausea, headache, vomiting, constipation, in-somnia, and foamy urine.82 Telavancin therapy was associ-ated with adverse fetal outcomes in animal studies, and the United States package insert includes a warning concerning the potential risk of abnormal fetal development.83 Neph-rotoxicity has been reported with elevation in the serum creatinine levels, which was more likely to occur in patients with underlying diseases that predisposed the patient to kid-ney dysfunction.84

CEFTAROLINE

Ceftaroline is a cephalosporin antibiotic with MRSA ac-tivity. Ceftaroline has high affinity for penicillin-binding protein (PBP) 2a, an MRSA-specific PBP, which correlates

1235



to its low MIC for MRSA. It demonstrates bactericidal, time-dependent killing in vitro and in vivo.85,86 On the basis of randomized clinical trials, ceftaroline was approved by the FDA for SSSIs and CAP in 2010. The drug is dosed ac-cording to renal function and associated with toxic effects similar to other β-lactam antibiotics.50,87 Recommended dosing is 600 mg intravenously every 12 hours or 400 mg intravenously every 12 hours for patients with moderate re-nal dysfunction.88

Activity against other pathogens, including coagulase-negative staphylococci, enterococci, β-hemolytic and viri-dans group streptococci, and some Enterobacteriaceae ( spp, and ), makes ceftaroline a reasonable empirical antibiotic option in the treatment of SSSIs and CAP.89

Ceftaroline was compared with ceftriaxone for the treat-ment of CAP in 2 large randomized, double-blind multi-center studies. Of the patients treated with ceftaroline, 84.3% achieved clinical cure compared with 77.7% in the ceftriaxone group. Ceftaroline demonstrated a safety pro-file similar to ceftriaxone. was iso-lated in 55 (16.5%) of 333 patients treated with ceftaroline in these studies.90

PENICILLIN-RESISTANT PNEUMOCOCCI

is one of the most common pathogens that causes CAP, otitis media, and meningitis.91 Antimicrobial resistance among has in-creased significantly in past decades. Penicillin suscepti-bility breakpoints were established in the late 1970s. Over time, studies in children and adults demonstrated more treatment failures in penicillin-treated patients found to have pneumococcal isolates from meningitis with higher penicillin MICs.92 This observation was not seen among penicillin-treated patients with infecting other areas of the body, including pneumonia and otitis media. However, the clinical impact of antimicrobial re-sistance remains unclear because of the lack of complete correlation between drug susceptibility data and treatment failure.93 The CLSI recently reviewed the breakpoints of S

.94 Using the new meningitis penicillin break-point criteria (≥0.12 μg/mL), resistance prevalence was 34.8% in 2008, but it was found to be 12.3% using the old criteria (>2 μg/mL) for cerebrospinal fluid isolates.95

Risk factors associated with resistance to penicillin include the presence of underlying immuno-suppression and receipt of antibiotics within 3 months.92 Resistance to β-lactam antibiotic drugs is mediated by al-terations in PBPs, decreasing the affinity of the antibiotic to the . Alterations in PBPs occur by trans-formation of genes that can be transferred not only by S

species but also by other groups of strepto-

cocci.96 Macrolide resistance occurs when there is a change in the ribosomal RNA though or . alters the site of macrolide binding through methylation, causing lack of recognition, whereas encodes an ef-flux pump. Resistance to quinolones occurs by alteration of topoisomerases.97 Multidrug resistance is usually spread through resistant genetic material with a small number of predominant clones.98

The impact of the pneumococcal conjugate vaccine 7 (PCV7) was evaluated using data from isolates collected in 2008 as part of the SENTRY surveillance program. The seroprevalence of PCV7 serotypes decreased from 68.5% before the vaccine to 29.3%. Most isolates with drug resis-tance before the vaccine were PCV7 serotypes; however, postvaccine noninvasive, nonvaccine serotypes were found to be increased and are more likely to acquire resistance over time.99 The introduction of the 13-valent pneumococ-cal conjugate vaccine, licensed by the FDA for prevention of invasive pneumococcal disease caused by 13 pneumo-coccal serotypes, could further change the prevalence of isolates in the future.

AGENTS CURRENTLY AVAILABLE FOR TREATMENT OF RESISTANT S PNEUMONIAE INFECTION

Treatment of non–central nervous system (CNS) infection caused by antibacterial-resistant pneumococcal infection still relies on penicillins, aminopenicillins, and third-gen-eration cephalosporins.100 Some of the common mecha-nisms of resistance are listed in Table 2.25 Meningitis is the exception because a combination of vancomycin and a third-generation cephalosporin is recommended due to concerns about emergence of penicillin or cefotaxime non-susceptible pneumococcal isolates.101

There is no consensus on the use of combination therapy for resistant pneumonia and associated BSI.92 Macrolide monotherapy is not recommended as empirical treatment of CAP, especially in geographic areas with high rates of resistant strains.102 Treatment failure with fluoroquinolones has been reported.103 Fluoroquino-lones should be used only when local epidemiology sug-gests high rates of nonsusceptible S strains or in cases of allergy or intolerance to first-line antimicrobial therapy for CAP.104 Although fluoroquinolones allow easy switch from parenteral to oral regimens and have excellent bioavailability, this class of drugs has several drawbacks, in-cluding broad-spectrum activity associated with “collateral damage,” including disturbance of gastrointestinal flora, se-lection of resistance for multiple bacteria (eg, MRSA), drug interactions, and risk of infection.105

Resistance among pneumococci to fluoroquinolones is caused by quinolone resistance–determining regions in

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genes that encode subunits of topoisomerases.106 During 2001-2002, isolates were collected in the United States to determine susceptibility. Testing was per-formed on 1902 isolates. Although the rates of fluoroquin-olone resistance remains low in the United States, 40% were found to have quinolone resistance–determining region mutations, and 35% of levofloxacin-nonsusceptible pneu-mococci were closely related to widespread pneumococcal clones that have spread antibiotic resistance among pneumo-cocci strains in past decades. The authors suggest potential for a rapid increase in resistance associated with clonal dis-semination and the wide use of quinolones worldwide.103

In a European study evaluating the outcome of patients treated for severe pneumococcal CAP, excluding penicil-lin-resistant pneumococci, the combination of levofloxa-cin with a β-lactam was associated with lower mortality rates than ofloxacin or ciprofloxacin. This study had many limitations, including recruitment over a long period and changes in standard antibiotic therapy in the intensive care unit during the study period.107

NEW OPTIONS FOR TREATMENT OF RESISTANT S PNEUMONIAE INFECTION

CEFTAROLINE

Ceftaroline binds to PBPs in , interfering with cell wall synthesis.108 In the international, multicenter, randomized, double-blind clinical trials comparing cef-taroline to ceftriaxone in the treatment of CAP, the cure rate for the ceftaroline group was 85.5% compared with 68.6% for ceftriaxone. However, few pneumococci with high MICs were isolated.90 In the treatment of patients with multidrug-resistant pneumonia, ceftaroline cure rates were numerically higher compared with ceftri-axone. However, the numbers were small, with cure rates of 4 of 4 patients in the ceftaroline group compared with 2 of 9 patients in the ceftriaxone group.109

LINEZOLID

In animal models, linezolid has shown efficacy in the treat-ment of pneumococcal pneumonia. The most important predictor of efficacy is the interval during which drug con-centration exceeds the MIC.110 The role of linezolid in the setting of CAP has been evaluated in several trials. In an open-label trial of 1700 patients comparing intravenous linezolid followed by oral linezolid with ceftriaxone fol-lowed by oral cefpodoxime, the linezolid-treated patients (n=272) had a cure rate of 91% compared with a clinical cure rate of 89% (n=225/254) in patients in the ceftriaxone-cefpodoxime group.111 In a subgroup analysis examining the eradication of and , a subset of 53 patients with blood cultures positive for

had a clinical cure rate of 93% (30 patients) in the linezolid group compared with 70% (23 patients) in the ceftriaxone-cefpodoxime group.111

TELAVANCIN

Telavancin demonstrates in vitro activity against penicil-lin-nonsusceptible .112 In an animal model of meningitis, telavancin was found to be more efficacious than vancomycin plus ceftriaxone against a penicillin-resistant pneumococcal strain.113 We hope that data from future clinical studies will define the role of telavancin in the treatment of clinical infections caused by penicillin-nonsusceptible .

TIGECYCLINE

Although not registered for the treatment of infections with penicillin-nonsusceptible , tigecycline is ac-tive in vitro and might be considered as salvage therapy for these infections.114 A study is currently under way to evaluate the role of tigecycline in the treatment of hospital-acquired pneumonia.76

VANCOMYCIN-RESISTANT ENTEROCOCCI Enterococci are part of normal gastrointestinal tract flora and have relatively low virulence. Most clinical isolates are

and and are less commonly other enterococcal species. The CLSI de-fines vancomycin-susceptible enterococci as having a van-comycin MIC of 4 μg/mL or less and vancomycin-resistant enterococci as having an MIC of 32 μg/mL or more.115 The first cluster of infections due to vancomycin-resistant en-terococci was reported in 22 patients with end-stage renal disease.116 Enterococcal BSIs continue to pose a problem in the hospital setting, causing nosocomial BSIs and post-surgical UTIs.117 , which was much less com-mon clinically than , emerged as an important nosocomial infectious pathogen, with rates of vancomycin resistance of up to 60%.117 Despite this problem there is a paucity of clinical data with the newer antibacterial agents, including linezolid, daptomycin, and tigecycline, in the treatment of this disease.118,119 Moreover, even in the era of these newer agents, patients infected with VRE still need better tolerated alternatives. Antibiotic resistance among enterococci is conferred through mutation and acquisition of genetic material from other species. often has acquired resistance to penicillin by increased expression of low-affinity PBP5 of mutations at this site.120 can have penicillin re-sistance, although it is less common, through a β-lactamase similar to the one found in .121 One mechanism involves plasmid transfer among isolates. Al-though there are 6 phenotypes of vancomycin resistance,

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2 can be harbored on plasmids (VanA and VanB).42 The VanA phenotype is encoded by a gene located in a plasmid transferred to other isolates through conjugation. The VanA phenotype has a vancomycin MIC greater than 256 μg/mL and is teicoplanin resistant. The VanB phenotype codes for resistance to vancomycin and is also transferable to other enterococci; however, these isolates remain susceptible to teicoplanin.122,123 The most common mechanisms of resis-tance in VRE are described in Table 2.25

In a large VRE surveillance program, most resistant iso-lates were (91%) and (7.8%). These rates vary geographically, with a higher prevalence of the VanA phenotype in North America (76%) compared with Europe (40%).124 In the health care setting, multiple factors drive the transmission of VRE, including selective pressure due to antibiotic use, the proportion of patients colonized with VRE vs susceptible enterococci, and adherence to pre-vention measures.125-127

Infection with VRE affects patients in intensive care units and those with intravascular or bladder catheter de-vices. Immunosuppressed patients, particularly recipients of liver and other solid organ transplants and hematopoietic stem cell transplants, remain vulnerable to VRE infections. Prolonged hospitalization, residence in long-term care fa-cilities, and exposure to antibiotics are also implicated in VRE infections.128

Clinical outcome is worse and mortality rates higher in patients with VRE infections compared with those with infections caused by vancomycin-susceptible enterococci. One of the main challenges for physicians treating VRE is the intrinsic resistance to many antibiotics, including β-lactams, aminoglycosides, lincosamides, and trimetho-prim-sulfamethoxazole.129 Vancomycin-resistant is usually susceptible to β-lactams.130

One of the most important decisions to make when pre-sented with a positive microbiological report of VRE is to identify whether the isolate represents infection or coloni-zation. Commonly, VRE isolates can be reported from su-perficial wounds, removed catheters, urine cultures, and ab-dominal drains. Positive blood cultures, as well as cultures of normally sterile sites, represent VRE infection. Catheters should be removed in the setting of VRE infection. Man-agement and debridement of wounds and surgical manage-ment for source control should be performed as a first rule in the management of localized infections.131

AGENTS CURRENTLY AVAILABLE FOR TREATMENT OF VRE INFECTION

Infections due to VRE include urinary tract, wound infec-tions, BSI, endocarditis, and meningitis. Efficacy data for agents used in the management of VRE infections are lim-

ited. Often based on anecdotal report, most of these drugs are not approved by the FDA for the treatment of VRE infections.132 Tetracycline, doxycycline, oral novobiocin with ciprofloxacin, and doxycycline have been reported as effective in treating VRE infections. However, there are no clinical studies to support these therapies.133

For treatment of lower UTIs, nitrofurantoin may be effec-tive because this agent is excreted into the urine.134 Fosfo-mycin can be used for treatment of uncomplicated UTIs.135 Invasive VRE infection, including BSI, endocarditis, and meningitis, warrants therapy with a bactericidal agent. Syner-gistic activity of a cell wall–active agent and aminoglycoside is used in the setting of endocarditis and/or critical illness. For serious enterococcal infections, including meningitis and endocarditis, treatment includes a cell wall–active agent and an aminoglycoside to produce a synergistic effect.130,136

FOSFOMYCIN

Fosfomycin is a phosphonic acid derivate that was first iso-lated from cultures of species in 1969.137 In the United States it is approved for the treatment of uncompli-cated UTIs caused by E coli and , but it is used widely intravenously, particularly in Europe. Fosfomycin has activity against gram-positive and gram-negative bacte-ria. Fosfomycin is active in vitro against ,

, , and ,138 as well as against a number of gram-negative organisms.139 In a review of 1311 potentially relevant trials, 63 studies of fosfomycin for the treatment of infections caused by gram-positive and gram-negative bacteria were reviewed. The most common gram-positive organism was . Most patients received fos-fomycin in combination with other antibiotics. The diversity and heterogeneity of the studies make it difficult to draw conclusions, but fosfomycin may be considered an antibiotic option for the treatment of infections caused by multidrug-resistant pathogens. Further studies should be performed to assess a possible role for intravenous fosfomycin.140

QUINUPRISTIN-DALFOPRISTIN

Quinupristin-dalfopristin is a protein synthesis–inhibiting antibiotic that has potent in vitro activity against but poor activity against .141 In a large study of 396 patients with vancomycin-resistant infection, the overall efficacy of quinupristin-dalfopristin was 66%.142 The most common sites of infection were intra-abdominal, BSI, UTI, catheter-related BSI, and SSSI.142 Severe myalgias, ar-thralgias, and gastrointestinal adverse effects limit its use.78

LINEZOLID

Linezolid has potent in vitro and in vivo activity against vancomycin-resistant strains of and Initial data, obtained through compassionate use stud-

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ies, demonstrated resolution of infection in 63% to 81% of cases and led to FDA approval of linezolid in 2000.143 Although linezolid has not been approved specifically for the treatment of enterococcal endocarditis, it has been used in this setting. In a large study of 796 patients who were treated for endocarditis, linezolid was used in patients who were intolerant to vancomycin or did not respond to it or were intolerant to quinupristin-dalfopristin therapy. Among these patients, 32 were re-treated, 59.9% had in-fection caused by VRE, and 19.4% had infection caused by MRSA. Overall, patients with vancomycin-resistant

had a clinical cure rate of 81.4%, those with MRSA infection had a cure rate of 66.1%, and therapy failed in 12.8%.144

DAPTOMYCIN

Daptomycin is bactericidal in vitro against most gram-positive organisms, including VRE. Although daptomycin has not been approved for infections, it has been recommended for treatment based on in vitro data and few clinical studies.145-147 Daptomycin MICs for are higher than for . There are no FDA-approved daptomycin MIC breakpoints for , but the CLSI suggests that a daptomycin MIC greater than 4 μg/mL is nonsusceptible. The approved dosing is 4 mg/kg intrave-nously once daily for complicated SSSIs. For BSI, the approved dosage is 6 mg/kg intravenously daily. Some experts favor higher dosages of 8 mg/kg intrave-nously once daily.148 Patients receiving daptomycin therapy should be monitored regularly for the development of myo-pathy with serum creatine kinase values measured at least weekly and careful monitoring for development of muscle pain or weakness.

TIGECYCLINE

Tigecycline is approved for the treatment of complicated SSSIs and intra-abdominal infections, including those caused by vancomycin-susceptible On the ba-sis of in vitro and animal data, VRE appears susceptible to tigecycline. Further studies are needed to define the role of tigecycline in the treatment of VRE infections.75,149,150

Published studies of antibacterial therapy for deep eye infections and CNS infections caused by resistant gram-positive bacteria are limited. Animal models suggest that daptomycin may have some advantages compared with vancomycin due to its bactericidal activity.151 There are also some data examining linezolid in animal infection models. In a clinical study evaluating the possible role of linezolid in the treatment of acute postoperative endophthalmitis, 21 patients undergoing cataract surgery were included. Li-nezolid concentration intraocularly was measured after in-travenous administration of 600 mg of linezolid. This study

demonstrated acceptable aqueous humor concentrations of linezolid. We hope that further studies will help elucidate its role in acute postoperative endophthalmitis.152

In an open-label, prospective study evaluating linezolid in the management of neurosurgical infections, eradication of causative bacteria was documented in 2 patients with CNS infections and in 1 patient with staphylococcal bacte-remia. The outcome for these 2 patients was favorable after 14 days of therapy. Twelve patients were treated prophy-lactically with linezolid, 1 of whom had a positive blood culture with .153

A study in Germany with 10 patients with poor response to other treatments demonstrated improvement in 6 patients with linezolid; however, some patients had abscesses and there were multiple organisms, including atypical mycobac-teria.154 Another study evaluated the use of linezolid for the management of nosocomial CNS infections; however, the study was limited because it was retrospective and the group was heterogenous, including differences in indwelling de-vices and intracranial collections in some patients.155

Although the data seem to be limited to case reports and small reports of CNS infections treated with linezolid, this antibiotic should be considered for the management of se-rious CNS infections that may not be responsive to other first-line antibiotics or in cases of failure to other antibi-otics, but further clinical randomized prospective studies should be performed to clarify its role.

CONCLUSION

Resistant gram-positive bacteria cause significant morbid-ity and mortality. Methicillin-resistant continues to cause a variety of clinical syndromes worldwide. Van-comycin remains the mainstay treatment, but with the emergence of less susceptible strains other therapeutic options should be considered, depending on the clinical setting. Both MRSA BSI and endocarditis may be treated with daptomycin, but daptomycin should not be used for pneumonia. Linezolid is recommended for MRSA pneu-monia and skin infection but not as first-line therapy for BSI. Tigecycline provides an alternative for MRSA SSSIs. Quinupristin-dalfopristin should be reserved for refractory cases of invasive MRSA because its use is limited by its adverse effects. Telavancin was approved for the treatment of SSSIs, but concerns of toxicity preclude its use in this indication; we hope to learn more about its potential role in VAP in the near term. Ceftaroline is the newest agent ap-proved for MRSA SSSIs and CAP. Penicillin-resistant pneumococcal strains vary in dif-ferent countries and regions. Linezolid and telavancin have shown in vitro activity, but further studies are needed to clarify their role. These agents may be considered in the

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context of intolerance or resistance to β-lactams. β-Lactam antibiotics remain first-line therapy. However, knowledge of local epidemiology and resistance patterns may help in-form empirical management of infections caused by these bacteria. Vancomycin plus a third-generation cephalosporin is recommended in the treatment of CNS in-fection because of the concern of emergence of resistance. Ceftaroline represents a novel class of cephalosporins and may be a new option for treatment of penicillin-resistant S

Vancomycin-resistant enterococci have emerged as concerning pathogens in the hospital setting with a high rate of BSI and other nosocomial infection. Nitrofuran-toin and fosfomycin are options for the management of uncomplicated VRE UTI. Other agents, including tetra-cycline, novobiocin, and doxycycline, have been used to treat VRE infections, but supportive clinical trial data are lacking. Newer VRE therapies include quinupristin-dalfopristin, linezolid, and daptomycin. Quinupristin-dalfopristin and linezolid therapy are limited by tolerabil-ity and toxicity concerns; a paucity of efficacy data and uncertainty regarding optimal dose limit daptomycin use. We hope that new agents will be developed to address these challenges. Improved knowledge of mechanisms of resistance con-tinues to inform development of new antimicrobial thera-pies. These medicines are but one part of a comprehensive approach to the problem of antimicrobial resistance. Physi-cians must use existing antimicrobial drugs prudently and practice impeccable infection control in health care facili-ties if we are to control the spread of resistant bacteria.

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bacteremia. . 2008;46(suppl 5):S386-S393. 60. Laganas V, Alder J, Silverman JA. In vitro bactericidal activities of daptomycin against and are not mediated by inhibition of lipoteichoic acid biosynthesis.

. 2003;47(8):2682-2684. 61. Cui L, Tominaga E, Neoh H, Hiramatsu K. Correlation between re-duced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate . 2006; 50(3):1079-1082. 62. Skiest DJ. Treatment failure resulting from resistance of

to daptomycin. . 2006;44(2):655-656. 63. Fowler V Jr, Boucher H, Corey G, et al. Endocarditis and Bac-teremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by . . 2006;355(7): 653-665. 64. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. . 2004;38(12):1673-1681. 65. Pertel PE, Bernardo P, Fogarty C, et al. Effects of prior effective therapy on the efficacy of daptomycin and ceftriaxone for the treatment of community-acquired pneumonia. . 2008;46(8):1142-1151. 66. Hayes D Jr, Anstead MI, Kuhn RJ. Eosinophilic pneumonia induced by daptomycin. . 2007;54(4):e211-e213. 67. Miller BA, Gray A, LeBlanc TW, Sexton DJ, Martin AR, Slama TG. Acute eosinophilic pneumonia secondary to daptomycin: a report of three cases. . 2010;50(11):e63-e68. 68. Petersen PJ, Jacobus NV, Weiss WJ, Sum PE, Testa RT. In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycyl-amido derivative of minocycline (GAR-936). . 1999;43(4):738-744. 69. Rose WE, Rybak MJ. Tigecycline: first of a new class of antimicrobial agents. . 2006;26(8):1099-1110. 70. Stein GE, Craig WA. Tigecycline: a critical analysis. . 2006;43(4):518-524. 71. Rodvold KA, Gotfried MH, Cwik M, Korth-Bradley JM, Dukart G, Ellis-Grosse EJ. Serum, tissue and body fluid concentrations of tigecy - cline after a single 100 mg dose. . 2006;58(6):1221- 1229. 72. Meagher AK, Ambrose PG, Grasela TH, Grosse JE. The pharmacokinet-ic and pharmacodynamic profile of tigecycline. . 2005;41(suppl 5):S333-S340. 73. Breedt J, Teras J, Gardovskis J, et al. Safety and efficacy of tigecycline in treatment of skin and skin structure infections: results of a double-blind phase 3 comparison study with vancomycin-aztreonam.

. 2005;49(11):4658-4666. 74. Freire AT, Melnyk V, Kim MJ, et al. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia.

. 2010;68(2):140-151. 75. Curcio D. Tigecycline for severe infections: the gap between the warn-ing and the necessity. . 2011;66(2):454-456.

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76. Study evaluating safety and efficacy of tigecycline versus imipenem/cilastatin subjects with hospital-acquired pneumonia. ClinicalTrials.gov Web site. http://www.clinicaltrials.gov/ct2/show/NCT00707239?term=tigecycline +pneumonia&rank=1. Accessed October 24, 2011. 77. Drew RH, Perfect JR, Srinath L, Kurkimilis E, Dowzicky M, Talbot GH. Treatment of methicillin-resistant infections with quinupristin–dalfopristin in patients intolerant of or failing prior therapy.

. 2000;46(5):775-784. 78. Olsen KM, Rebuck JA, Rupp ME. Arthralgias and myalgias related to quinupristin-dalfopristin administration. . 2001;32(4):e83-e86. 79. Kanafani ZA. Telavancin: a new lipoglycopeptide with multiple mecha-nisms of action. . 2006;4(5):743-749. 80. Saravolatz LD, Stein GE, Johnson LB. Telavancin: a novel lipoglyco-peptide. . 2009;49(12):1908-1914. 81. Stryjewski ME, O’Riordan WD, Lau WK, et al. Telavancin versus stan-dard therapy for treatment of complicated skin and soft-tissue infections due to gram-positive bacteria. . 2005;40(11):1601-1607. 82. Shaw JP, Seroogy J, Kaniga K, Higgins DL, Kitt M, Barriere S. Phar-macokinetics, serum inhibitory and bactericidal activity, and safety of telavan-cin in healthy subjects. . 2005;49(1):195-201. 83. Bonkowski J, Daniels AR, Peppard WJ. Role of telavancin in treat-ment of skin and skin structure infections. . 2010;3:127-133. 84. Stryjewski ME, Chu VH, O’Riordan WD, et al. Telavancin versus stan-dard therapy for treatment of complicated skin and skin structure infections caused by gram-positive bacteria: FAST 2 study.

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. 2007;51(9):3397-3400. 86. Ge Y, Biek D, Talbot GH, Sahm DF. In vitro profiling of ceftaroline against a collection of recent bacterial clinical isolates from across the United States. r. 2008;52(9):3398-3407. 87. Wilcox MH. Future gazing in the management of multiply drug-resis-tant gram-positive infection. . 2009;59(suppl 1):S75-S80. 88. Zhanel GG, Sniezek G, Schweizer F, et al. Ceftaroline. . 2009; 69(7):809-831. 89. Biek D, Critchley IA, Riccobene TA, Thye DA. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-gram-positive activ-ity. . 2010;65(suppl 4):iv9-iv16. 90. File TM Jr, Low DE, Eckburg PB, et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. . 2010;51(12):1395-1405. 91. Musher DM. Infections caused by : clini-cal spectrum, pathogenesis, immunity, and treatment. . 1992; 14(4):801-807. 92. Yu VL, Chiou CC, Feldman C, et al. An international prospective study of : correlation with in vitro resistance, antibiotics administered, and clinical outcome. . 2003;37(2):230-237. 93. Bowden RA, Ljungman P, Snydman DR. 3rd ed. New York, NY: Lippincott Williams & Wilkins; 2010. 94. Weinstein MP, Klugman KP, Jones RN. Rationale for revised penicil-lin susceptibility breakpoints versus : coping with antimicrobial susceptibility in an era of resistance. . 2009; 48(11):1596-1600. 95. Mera RM, Miller LA, Amrine-Madsen H, Sahm DF. Impact of new clinical laboratory standards institute penicillin susceptibility testing breakpoints on reported resistance changes over time.

. 2011;17(1):47-52. 96. Hakenbeck R, Briese T, Chalkley L, et al. Antigenic variation of peni-cillin-binding proteins from penicillin-resistant clinical strains of

. . 1991;164(2):313-319. 97. Canu A, Malbruny B, Coquemont M, Davies TA, Appelbaum PC, Leclercq R. Diversity of ribosomal mutations conferring resistance to mac-rolides, clindamycin, streptogramin, and telithromycin in

. . 2002;46(1):125-131. 98. Reinert RR, Jacobs MR, Appelbaum PC, et al. Relationship between the original multiply resistant South African isolates of from 1977 to 1978 and contemporary international resistant clones.

. 2005;43(12):6035-6041.

99. Mera RM, Miller LA, Amrine-Madsen H, Sahm DF. The impact of the pneumococcal conjugate vaccine on antimicrobial resistance in the United States since 1996: evidence for a significant rebound by 2007 in many classes of antibiotics. . 2009;15(4):261-268. 100. Cunha BA. Antimicrobial therapy of multidrug-resistant

, vancomycin-resistant enterococci, and methicillin- resistant . . 2006;90(6):1165-1182. 101. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. . 2004;39(9):1267- 1284. 102. Garau J. Treatment of drug-resistant pneumococcal pneumonia.

. 2002;2(7):404-415. 103. Fuller JD, Low DE. A review of infection treatment failures associated with fluoroquinolone resistance. . 2005;41(1):118-121. 104. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society Consensus guidelines on the management of community-acquired pneumonia in adults. . 2007;44(suppl 2):S27-S72. 105. Owens RC, Ambrose PG. Antimicrobial safety: focus on fluoroquinolo-nes. . 2005;41(suppl 2):S144-S157. 106. Eliopoulos GM. Quinolone resistance mechanisms in pneumococci.

. 2004;38(suppl 4):S350-S356. 107. Olive D, Georges H, Devos P, et al. Severe pneumococcal pneumonia: impact of new quinolones on prognosis. . 2011;11(1):66. 108. Kosowska-Shick K, McGhee P, Appelbaum P. Affinity of ceftaroline and other β-lactams for penicillin-binding proteins from

and . . 2010; 54(5):1670-1677. 109. Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cepha-losporin with activity against methicillin-resistant . Clin

. 2011;52(9):1156-1163. 110. Gentry-Nielsen MJ, Olsen KM, Preheim LC. Pharmacodynamic activ-ity and efficacy of linezolid in a rat model of pneumococcal pneumonia.

. 2002;46(5):1345. 111. Cammarata SK, San Pedro GS, Timm JA, et al. Comparison of linezolid versus ceftriaxone/cefpodoxime in the treatment of hospitalized patients with community-acquired pneumonia [abstract]. In:

. Stockholm, Sweden: 2000. 112. Krause KM, Renelli M, Difuntorum S, Wu TX, Debabov DV, Benton BM. In vitro activity of telavancin against resistant gram-positive bacteria.

. 2008:52(7): 2642-2647. 113. Stucki A, Gerber P, Acosta F, Cottagnoud M, Cottagnoud P. Efficacy of telavancin against penicillin-resistant pneumococci and

in a rabbit meningitis model and determination of kinetic parameters. . 2006;50(2):770-773.

114. Fritsche TR, Sader HS, Stilwell MG, Dowzicky MJ, Jones RN. Antimi-crobial activity of tigecycline tested against organisms causing community-ac-quired respiratory tract infection and nosocomial pneumonia.

. 2005;52(3):187-193. 115. Clinical and Laboratory Standards Institute. Methods for Dilution Anti-microbial Susceptibility Tests for Bacteria That Grow Aerobically: Approved Standard —Eighth Edition. Wayne, PA: Clinical and Laboratory Standards Institute; 2009. http://www.clsi.org/source/orders/free/m07-a8.pdf. Accessed November 16, 2011. 116. Uttley A, Collins C, Naidoo J, George R. Vancomycin-resistant entero-cocci. . 1988;1(8575):57-58. 117. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Ed-mond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. . 2004;39(3):309-317. 118. Erlandson KM, Sun J, Iwen PC, Rupp ME. Impact of the more-potent antibiotics quinupristin-dalfopristin and linezolid on outcome measure of pa-tients with vancomycin-resistant bacteremia. . 2008;46(1):30-36. 119. Segreti JA, Crank CW, Finney MS. Daptomycin for the treatment of gram-positive bacteremia and infective endocarditis: a retrospective case series of 31 patients. . 2006;26(3):347-352. 120. Rybkine T, Mainardi JL, Sougakoff W, Collatz E, Gutmann L. Peni-cillin-binding protein 5 sequence alterations in clinical isolates of

with different levels of β-lactam resistance. . 1998; 178(1):159-163.

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121. Zscheck K, Murray B. Genes involved in the regulation of β-lactamase production in enterococci and staphylococci. . 1993;37(9):1966-1970. 122. Noble W, Virani Z, Cree RGA. Co-transfer of vancomycin and other resistance genes from NCTC 12201 to

. . 1992;93(2):195-198. 123. Arthur M, Courvalin P. Genetics and mechanisms of glycopeptide resis-tance in enterococci. . 1993;37(8):1563-1571. 124. Deshpande LM, Fritsche TR, Moet GJ, Biedenbach DJ, Jones RN. Antimicrobial resistance and molecular epidemiology of vancomycin-resistant enterococci from North America and Europe: a report from the SENTRY antimicrobial surveillance program. . 2007;58(2):163-170. 125. Bonten MJM, Slaughter S, Ambergen AW, et al. The role of “coloniza-tion pressure” in the spread of vancomycin-resistant enterococci: an important infection control variable. . 1998;158(10):1127-1132. 126. Fridkin SK, Edwards JR, Courval JM, et al. The effect of vanco-mycin and third-generation cephalosporins on prevalence of vancomycin-resistant enterococci in 126 US adult intensive care units. . 2001;135(3):175-183. 127. Paterson DL. “Collateral damage” from cephalosporin or quinolone an-tibiotic therapy. . 2004;38(suppl 4):S341-S345. 128. Ostrowsky BE, Trick WE, Sohn AH, et al. Control of vancomycin-resistant in health care facilities in a region. . 2001;344(19):1427-1433. 129. Gold HS, Moellering RC Jr. Antimicrobial-drug resistance.

. 1996;335(19):1445-1453. 130. Gold HS. Vancomycin-resistant enterococci: mechanisms and clinical observations. . 2001;33(2):210-219. 131. Linden PK. Treatment options for vancomycin-resistant enterococcal infections. . 2002;62(3):425-441. 132. Howe RA, Robson M, Oakhill A, Cornish JM, Millar MR. Successful use of tetracycline as therapy of an immunocompromised patient with septicae-mia caused by a vancomycin-resistant . . 1997;40(1):144-145. 133. Linden PK, Miller CB. Vancomycin-resistant enterococci: the clini-cal effect of a common nosocomial pathogen. . 1999;33(2):113-120. 134. Linden P, Coley K, Kusne S. Bacteriologic efficacy of nitrofurantoin for urinary tract infection due to vancomycin-resistant [abstract 208]. . 1999;29(4):999. 135. Swaminathan S, Alangaden GJ. Treatment of resistant enterococcal uri-nary tract infections. . 2010;12(6):455-464. 136. Moellering R. Antimicrobial susceptibility of enterococci: in vitro stud-ies of the action of antibiotics alone and in combination. In:

New York, NY: Grune & Stratton; 1981:81-96. 137. Hendlin D, Stapley EO, Jackson M, et al. Phosphonomycin, a new antibiotic produced by strains of . . 1969;166(901):122- 123. 138. Barry A, Brown S. Antibacterial spectrum of fosfomycin trometamol.

. 1995;35(1):228-230. 139. Okazaki M, Suzuki K, Asano N, et al. Effectiveness of fosfomycin com-bined with other antimicrobial agents against multidrug-resistant

isolates using the efficacy time index assay. . 2002;8(1):37-42.

140. Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfo-mycin for the treatment of infections caused by multidrug-resistant non-fer-menting gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. . 2009;34(2):111-120. 141. Jones RN, Ballow CH, Biedenbach DJ, Deinhart JA, Schentag JJ. An-timicrobial activity of quinupristin-dalfopristin (RP 59500, synercid®) tested against over 28,000 recent clinical isolates from 200 medical centers in the United States and Canada. . 1998;31(3):437-451. 142. Moellering RC, Linden PK, Reinhardt J, Blumberg EA, Bompart F, Tal-bot GH; Synercid Emergency-Use Study Group. The efficacy and safety of qui-nupristin/dalfopristin for the treatment of infections caused by vancomycin-re-sistant . . 1999;44(2):251-261. 143. Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. . 2003;36(2):159-168. 144. Babcock HM, Ritchie DJ, Christiansen E, Starlin R, Little R, Stanley S. Successful treatment of vancomycin-resistant endocarditis with oral linezolid. . 2001;32(9):1373-1375. 145. Rybak MJ, Hershberger E, Moldovan T, Grucz RG. In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against staphylococci and enterococci, including vancomycin-intermediate and-resis-tant strains. . 2000;44(4):1062-1066. 146. Pankey G, Ashcraft D, Patel N. In vitro synergy of daptomycin plus rifampin against resistant to both linezolid and vanco-mycin. . 2005;49(12):5166-5168. 147. Poutsiaka DD, Skiffington S, Miller KB, Hadley S, Snydman DR. Dap-tomycin in the treatment of vancomycin-resistant bacte-remia in neutropenic patients. . 2007;54(6):567-571. 148. Figueroa D, Mangini E, Amodio-Groton M, et al. Safety of high-dose intravenous daptomycin treatment: three-year cumulative experience in a clini-cal program. . 2009;49(2):177-180. 149. Florescu I, Beuran M, Dimov R, et al. Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant or vancomycin-resistant en-terococci: a phase 3, multicentre, double-blind, randomized study.

. 2008;62(suppl 1):17-28. 150. Gardiner D, Dukart G, Cooper A, Babinchak T. Safety and efficacy of intravenous tigecycline in subjects with secondary bacteremia: pooled results from 8 phase III clinical trials. . 2010;50(2):229-238. 151. Gerber P, Stucki A, Acosta F, Cottagnoud M, Cottagnoud P. Dapto-mycin is more efficacious than vancomycin against a methicillin-susceptible

in experimental meningitis. . 2006;57(4):720-723. 152. Vázquez EG, Mensa J, López Y, et al. Penetration of linezolid into the anterior chamber (aqueous humor) of the human eye after intravenous admin-istration. . 2004;48(2):670-672. 153. Myrianthefs P, Markantonis SL, Vlachos K, et al. Serum and cerebro-spinal fluid concentrations of linezolid in neurosurgical patients.

. 2006;50(12):3971-3976. 154. Rupprecht TA, Pfister HW. Clinical experience with linezolid for the treat-ment of central nervous system infections. . 2005;12(7):536-542. 155. Maure B, Martinez-Vazquez C, Perez-Veloso M, Rodriguez Fer-nandez M, Sopena B. Linezolid in postneurosurgical infections. . 2008;36(1):82-83.




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Questions About Current Concepts in Antimicrobial Therapy Against Select Gram-Positive Organisms

1. A 60-year-old man recently underwent hemodialysis for end-stage kidney disease associated with poorly controlled diabetes mellitus. He is evaluated in the hospital after de-velopment of fever during dialysis. The patient was hospi-talized 3 months ago for placement of an atrioventricular fistula and receives dialysis through a Hickman catheter. On physical examination, his temperature is 39.3°C, blood pressure is 100/70 mm Hg, pulse rate is 100/min, and re-spiratory rate is 22/min. There is tenderness at the cath-eter insertion site and a new grade 3/6 holosystolic mur-mur that increases with inspiration, heard at the left lower sternal border. Multiple blood cultures reveal growth of methicillin-resistant Transthoracic echocardiography reveals a 0.5-cm vegetation on the tri-cuspid valve and moderate tricuspid insufficiency. The pa-tient has a history of documented urticaria, bronchospasm, and hypotension associated with vancomycin use.

?a. Vancomycinb. Daptomycinc. Linezolidd. Ceftarolinee. Tigecycline

2. A 55-year-old woman developed a fever during her third week of hospitalization in the cardiac care unit af-ter she had a myocardial infarction and experienced car-diogenic shock. Initially, broad-spectrum antibiotics were prescribed, including vancomycin and cefepime; use of these agents was discontinued after 72 hours, when it was clear that her hypotension and shock were related to her cardiac status. The patient has been in acute renal failure, with a creatinine level ranging from 5.0 to 8.0 mg/dL in the past week. Soon after admission, her glomerular filtration rate was less than 10 mL/min. She is now febrile, with a temperature of 39.1°C. You are called by the microbiolo-gist after blood cultures from the patient’s central catheter yielded vancomycin-resistant

?

a. Start antibiotics only if cultures remain positive after removal of the catheterb. Quinopristin-dalfopristin c. Daptomycind. Linezolid

e. Ciprofloxacin

3. A 24-year-old male athlete is hospitalized after fever de-veloped associated with an infected turf burn. He noticed some redness in the area 2 days ago but now has some pu-rulent drainage and swelling. Cultures obtained from the drainage yielded , which is resistant to oxacillin but susceptible to vancomycin and linezolid.

a. Dicloxacillinb. Linezolidc. Trimethoprim-sulfamethoxazoled. Tetracyclinee. Clindamycin 4. A 65-year-old woman with a medical history notable for diabetes mellitus and chronic obstructive pulmonary disease is admitted for symptoms consistent with possible exacerbation of chronic obstructive pulmonary disease and pneumonia. She has received azithromycin treatment many times in the past as an outpatient and again recently before this hospitalization. The patient is seeking treatment now because she is not improving with azithromycin therapy.

Streptococcus pneumoniae

?a. Alteration of topoisomerasesb. Presence of the or genesc. Decreased permeability of the outer cell enveloped. Plasmid acquisitione. Presence of the gene

5.

S aureus nosocomial pneumonia? a. Linezolidb. Daptomycinc. Ceftarolind. Tigecyclinee. Telavancin

Correct answers:1. b, 2. d, 3. a, 4. b, 5. a


Mechanisms of Resistance and ClinicalRelevance of Resistance to �-Lactams,

Glycopeptides, and Fluoroquinolones

Louis B. Rice, MD

Abstract

The widespread use of antibiotics has resulted in a growing problem of antimicrobial resistance in the community andhospital settings. Antimicrobial classes for which resistance has become a major problem include the �-lactams, theglycopeptides, and the fluoroquinolones. In gram-positive bacteria, �-lactam resistance most commonly results fromexpression of intrinsic low-affinity penicillin-binding proteins. In gram-negative bacteria, expression of acquired�-lactamases presents a particular challenge owing to some natural spectra that include virtually all �-lactam classes.Glycopeptide resistance has been largely restricted to nosocomial Enterococcus faecium strains, the spread of which ispromoted by ineffective infection control mechanisms for fecal organisms and the widespread use of colonization-promoting antimicrobials (especially cephalosporins and antianaerobic antibiotics). Fluoroquinolone resistance incommunity-associated strains of Escherichia coli, many of which also express �-lactamases that confer cephalosporinresistance, is increasingly prevalent. Economic and regulatory forces have served to discourage large pharmaceuticalcompanies from developing new antibiotics, suggesting that the antibiotics currently on the market may be all that willbe available for the coming decade. As such, it is critical that we devise, test, and implement antimicrobial stewardshipstrategies that are effective at constraining and, ideally, reducing resistance in human pathogenic bacteria.

CME Activity

Target Audience: The target audience for Mayo Clinic Proceedings is pri-marily internal medicine physicians and other clinicians who wish to advancetheir current knowledge of clinical medicine; and who wish to stay abreastof advances in medical research.Statement of Need: General internists and primary care providers mustmaintain an extensive knowledge base on a wide variety of topics coveringall body systems as well as common and uncommon disorders. Mayo ClinicProceedings aims to leverage the expertise of its authors to help physiciansunderstand best practices in diagnosis and management of conditions en-countered in the clinical setting.Accreditation: College of Medicine, Mayo Clinic is accredited by the Ac-creditation Council for Continuing Medical Education to provide continuingmedical education for physicians.Credit Statement: College of Medicine, Mayo Clinic designates thisJournalbased CME activity for a maximum of 1.0 AMA PRA Category 1Credit(s).™ Physicians should claim only the credit commensurate with theextent of their participation in the activity.Learning Objectives: Educational objectives. On completion of this article,readers should be able to: (1) identify the major mechanisms of resistance to�–lactams, glycopeptides, and fluoroquinolones used by human pathogenicbacteria; (2) identify major relationships between the use of antibiotics and theemergence of resistance to �–lactams, glycopeptides, and fluoroquinolones;and (3) evaluate a minimum inhibitory concentration in the context of theclinical infection and the achievable concentrations of antibiotics.Disclosures: As a provider accredited by ACCME, College of Medicine,Mayo Clinic (Mayo School of Continuous Professional Development) mustensure balance, independence, objectivity and scientific rigor in its educa-tional activities. Course Director(s), Planning Committee Members, Faculty,and all others who are in a position to control the content of this educa-tional activity are required to disclose all relevant financial relationships with

any commercial interest related to the subject matter of the educationalactivity. Safeguards against commercial bias have been put in place. Facultyalso will disclose any off label and/or investigational use of pharmaceuticalsor instruments discussed in their presentation. Disclosure of this informationwill be published in course materials so those participants in the activity mayformulate their own judgments regarding the presentation.In their editorial and administrative roles, William L. Lanier, Jr., MD, Scott C.Litin, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA,have control of the content of this program but have no relevant financialrelationship(s) with industry.Dr Rice is on the scientific advisory boards of Tetraphase, Novartis, Astra-Zeneca, and T2 Biosystems and the Clinical Editorial Board of TheraDoc.He has received speaking fees from Taisho Toyama and Cubist.Method of Participation: In order to claim credit, participants must com-plete the following:1. Read the activity.2. Complete the online CME Test and Evaluation. Participants must achieve

a score of 80% on the CME Test. One retake is allowed.Participants should locate the link to the activity desired at http://bit.ly/A5vSzq. Upon successful completion of the online test and evaluation, youcan instantly download and print your certificate of credit.Estimated Time: The estimated time to complete each article is approxi-mately 1 hour.Hardware/Software: PC or MAC with Internet access.Date of Release: 2/1/2012Expiration date: 1/31/2014 (Credit can no longer be offered after it haspassed the expiration date.)Privacy Policy: http://www.mayoclinic.org/global/privacy.htmlQuestions? Contact [email protected].

© 2012 Mayo Foundation for Medical Education and Research � Mayo Clin Proc. 2012;87(2):198-208

Medical School of BrownUniversity, Providence, RI.

198 Mayo Clin Proc. �

T he problem of antimicrobial resistance inbacterial pathogens has been fairly de-scribed as a growing global crisis. Rates of

reported resistance in common pathogens are reach-

February 2012;87(2):198-208 � doi:10.1016/j.mayocp.2011.12.003 �

ing levels in many corners of the world that precludethe empirical use of many of our most potent andreliable antimicrobial agents. In addition to the tra-

From the Department ofMedicine, Warren Alpert

ditional settings of hospital intensive care units and

© 2012 Mayo Foundation for Medical Education and Researchwww.mayoclinicproceedings.org

https://bit.ly/A5vSzq

https://bit.ly/A5vSzq

http://www.mayoclinic.org/global/privacy.html

mailto:[email protected]

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ANTIMICROBIAL RESISTANCE

specialized units, resistance is becoming increas-ingly common in the community setting, leading tosubstantial changes in our typical prescribing prac-tices. The use of �-lactam antibiotics to empiricallytreat soft tissue infections in many regions of theworld has been compromised by the widespreadisolation of community-acquired methicillin-resis-tant Staphylococcus aureus (CA-MRSA).1 Similarly,the emergence and spread of Escherichia coli strainsresistant to both fluoroquinolones and extended-spectrum cephalosporins has driven the greater useof carbapenems for the treatment of urinary tractinfections.2 Perhaps as a consequence, the emer-gence of carbapenem resistance in previously sus-ceptible species has been identified around theworld.3

For most of the antibiotic era (roughly from themid-1940s forward), concerns about resistancewere tempered by the knowledge that newer, morepotent agents were being developed by the dozensof companies in the business of making antibiotics.We no longer have the luxury of anticipating theimminent introduction of the solution to our resis-tance problems. The number of large pharmaceuti-cal corporations actively engaged in antibiotic dis-covery has dwindled to the single digits, and thenumber of new antimicrobial agents introduced hasbeen reduced to a trickle over the past decade.4 Nu-merous explanations for the retreat from antimicro-bial discovery have been proffered.5 Concern hasbeen raised that the criteria for clinical developmentpromoted by the US Food and Drug Administrationis increasing the cost of drug development. Alongthe same lines, pharmaceutical companies preferen-tially develop drug classes with greater potential forprofit (net asset value) than that obtained with anti-biotics. These concerns can be addressed by publicpolicy modifications. Perhaps the most problematicchallenge to developing new antibiotics that are ac-tive against currently resistant pathogens is that,given the multiresistant nature of modern pathogensand the varied (sometimes nonspecific) mechanismsof resistance, identifying and developing safe newagents with broad activity is extremely difficult. Assuch, it has never been more important for practi-tioners to develop better strategies for using antibi-otics to minimize the emergence and spread of re-sistance. This review focuses on resistance to 3classes of antibiotics (�-lactams, glycopeptides, andfluoroquinolones), reviewing mechanisms andpointing out some of the challenges in employingantimicrobial usage strategies to curb growingresistance.

DEFINING RESISTANCEAntimicrobial resistance and susceptibility in the
clinical setting take many forms that are not predict- t
Mayo Clin Proc. � February 2012;87(2):198-208 � doi:10.1016/j.maywww.mayoclinicproceedings.org

able by in vitro susceptibility testing. For example,susceptible bacteria deep inside an abscess may notbe accessible to antibiotics and therefore behave as ifthey are resistant. A fully susceptible organism mayalso act resistant if present in a biofilm attached to aforeign body. Conversely, species often consideredresistant to specific antibiotics (eg, Pseudomonasaeruginosa and tetracycline) may be treated success-fully if the infection occurs in the lower urinarytract,6 where the antibiotic can be concentrated

eavily and the density of bacteria is generally low.hus, the advisability of using an antimicrobialgent in a particular situation depends on a carefulonsideration of the in vitro susceptibility of theacterial strain, the drug concentrations achievablet the site of infection, and the metabolic state of thenfecting bacteria. Standard-setting organizationsthe US Food and Drug Administration, the Euro-ean Committee on Antimicrobial Susceptibilityesting, the Clinical and Laboratory Standards In-titute) establish susceptible, intermediate, and re-istance standards based on a careful analysis ofchievable serum levels, susceptibilities of bacteria,esults of animal experiments, and human clinicalrials. Given the variability of individual clinical cir-umstances, it is clear that these designations muste considered educated guides rather than firmronouncements.

Resistance can be achieved either through geneutation or through the acquisition of exogenous

esistance determinants. Mechanisms by which re-istance genes are acquired vary. Transferable plas-ids may be very large (�150 kb) and contain a

ariety of resistance gene.7 Plasmids may formointegrates with transposons that incorporate oner more resistance genes. Some plasmids encodeheir own transfer machinery, whereas others can beobilized by a coresident transferable plasmid.hromosomal elements may also transfer on theirwn or be mobilized by transferable plasmids. Su-erb recent work by Manson et al8 has shown that

large chromosomal transfers among Enterococcusfaecalis result from mobilization of segments of thechromosome by conjugative plasmids throughcointegration across identical insertion sequenceslocated on both replicons. These findings suggestthat virtually any part of the genome can be mobi-lized, emphasizing the fluidity of many bacterialgenomes.

RESISTANCE TO SPECIFIC ANTIMICROBIALCLASSES

Resistance to �-Lactams�-Lactam antibiotics act by binding to cell wall syn-hesis enzymes known as penicillin-binding pro-
eins (PBPs), thereby inhibiting peptidoglycan syn-
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thesis.9 Inhibition of PBPs weakens the cell wall,resulting in inhibition of cell growth and frequentlyin cell death. The 3 mechanisms of �-lactam resis-tance are reduced access to the PBPs, reduced PBPbinding affinity, and destruction of the antibioticthrough the expression of �-lactamase (enzymesthat bind and hydrolyze �-lactams) (Table).10 Ingram-positive bacteria, antibiotics have free accessto the bacterial cytoplasmic membrane, where thePBPs are located. In gram-negative bacteria, the bac-terial outer membrane (absent in gram-positive bac-teria) can both restrict �-lactam entry and concen-trate �-lactamase molecules. If �-lactam moleculesare sufficiently excluded from this periplasmic spaceby either reduced entry or increased efflux, and if�-lactamase molecules are heavily concentrated,even a relatively weak �-lactamase can confer highlevels of resistance.11

Resistance to �-Lactams in Gram-Positive Bacteria.With the exception of staphylococci (which pro-duce a narrow-spectrum penicillinase), clinicallyimportant �-lactam resistance in gram-positive spe-cies occurs almost exclusively through the expres-sion of PBPs that bind �-lactams with low affinity. InS aureus, resistance to methicillin results from theexpression of low-affinity PBP2a.12 Penicillin-bind-ing protein 2a is encoded by the mec determinant,which is found exclusively in mobile chromosomalelements referred to as staphylococcal chromosomal

TABLE. Named �-Lactamases From ClinicalIsolates, by Ambler Classa

Ambler classb (No.)

A B C D

TEM (190) IMP (30) CMY (73) OXA (224)

SHV (141) VIM (3) FOX (10)

CTX-M (120) IND (8) ACT (9)

GES (17) NDM (6) DHA (8)

KPC (11) MOX (8)

PER (7) MIR (5)

VEB (7) ACC (4)

SME (3) CFE (1)

PC1 (1)c LAT (1)

a Based on information obtained from Lahey Clinic Web site(http://www.lahey.org/studies/) on July 25, 2011.b Ambler classification is based on DNA sequence similarityand does not directly correlate with function or spectrum.c PC1 is the only �-lactamase of clinical importance found ingram-positive bacteria. At this time, it is virtually uniformlypresent in pathogenic staphylococcal species and has neverbeen shown to extend its spectrum to include broad-spec-

strum cephalosporins.

Mayo Clin Proc. � Fe

cassette mec (SCCmec).13 It is presumed that theransfer of these elements between staphylococcaltrains has contributed to the spread of MRSA, al-hough such transfer has not been documented initro. The sizes of the SCCmec elements vary, withecent CA-MRSA isolates demonstrating a smaller,ore compact element devoid of other resistanceeterminants (partially explaining the greater sus-eptibility of the community-acquired strains thanheir nosocomial counterparts).14 Genotyping datauggest that relatively few CA-MRSA clones are cir-ulating around the world, although more recentata using genome-wide single nucleotide polymor-hisms suggest that there may have been multipleransfers of the element into clinical strains withimilar genotypes.15

Expression of methicillin resistance in S aureuss complex, involving the participation of severalther loci that have become known as fem (factorsssential for methicillin resistance) or aux (auxiliary)actors.12 Many of these loci encode functions in-olved in the development of precursors of the cellall. Their inactivation generally results in reduced

evels of resistance, suggesting that PBP2a is limitedn its ability to process cell wall precursors differingrom the norm. As a class B PBP, PBP2 does not have

functional glycosyltransferase region, so it mustork in concert with the glycosyltransferase of PBP2

o make peptidoglycan. Consequently, deletion ofBP2 renders PBP2a unable to confer resistance to

�-lactam antibiotics.16

The chromosomal location of the SCCmec de-erminants and the small size of the more recentlydentified regions suggest that the metabolic costs ofetaining these determinants may be insignificant.oreover, �-lactam antibiotics do not achieve suffi-

cient concentrations at sites of S aureus colonizationto convincingly select for colonization by resistantstrains. As such, strategies to limit MRSA by reduc-ing consumption of �-lactam antibiotics have had,at best, mixed results. Strategies designed to limitthe spread of MRSA through infection control inter-ventions have been more effective.

Compelling data suggest that �-lactam antibi-tics are superior to vancomycin for the treatmentf methicillin-susceptible S aureus.17 Until the re-

cent introduction of ceftobiprole and ceftaro-line,18 expression of PBP2a was considered toconfer resistance to all �-lactam antibiotics.

hether the superiority of �-lactams will extendo MRSA now that these agents are available re-ains to be determined.

The widespread resistance of Enterococcus fae-ium to ampicillin is attributable to the expression ofow-affinity PBP5, which though apparently intrin-ic to the species, is transferable between E faecium
trains.19,20 The spread of ampicillin-resistant E fae-
bruary 2012;87(2):198-208 � doi:10.1016/j.mayocp.2011.12.003www.mayoclinicproceedings.org

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cium throughout the world has been attributed toclonal complex 17,21 a loosely associated group ofstrains that have undergone significant gene acqui-sition. Recent work suggests that E faecium of thisclonal complex has acquired lower-affinity PBP5 onseveral occasions.22 The extent to which genetic ex-change and recombination23 occur in E faeciumstrains seriously complicates attempts to establishspecific genetic lineages.

Clinical studies and a series of animal experi-ments suggest that cephalosporins, especially thosethat enter the gastrointestinal tract in high concen-trations, are powerful selectors for high-level gutcolonization by ampicillin-resistant E faecium.24-27

Whether systematic attempts to reduce overall useof these agents will result in reductions in ampicil-lin-resistant E faecium colonization remains to bedetermined.

Streptococcus pneumoniae takes advantage of itscapacity to take up DNA to become resistant to�-lactams.28 Resistant strains exhibit a variety of“mosaic” genes derived from recombination be-tween native pneumococcal PBP genes and thosefrom less susceptible viridans streptococci. Resis-tance achievable by this mechanism is limited by thelevels of resistance expressed by the native PBPs thatcontribute to the mosaic and generally remains atlow levels that affect the efficacy of intravenous an-tibiotics only in the cerebrospinal fluid. Other nat-urally transformable species, such as Neisseria gon-orrhoeae,29 also exhibit mosaic PBP genes. Recently,the first gonococcal strain exhibiting high-level re-sistance to cephalosporins was shown to mediateresistance through a mosaic PBP gene.30

It stands to reason that a mosaic gene would beless “efficient” at performing its function than thenative gene and that therefore reductions in the se-lective pressure favoring persistence of these genes(ie, reduction in use of �-lactam antibiotics) wouldresult in reduced prevalence of resistance. System-atic attempts to reduce use of antibiotics in the com-munity have been associated with reductions in Spneumoniae resistance31; however, specific correla-tions between reductions in use of �-lactams (asopposed to erythomycin or trimethoprim-sulfame-thoxazole) and penicillin resistance have been diffi-cult to demonstrate. Moreover, antimicrobial usageanalyses have been complicated by the widespreaduse of the 7-valent pneumococcal conjugate vac-cine, which has played a major role in reducing ratesof penicillin resistance in S pneumoniae32 by target-ing serotypes with a high prevalence of resistance.

Resistance to �-Lactams in Gram-Negative Bacteria.Resistance to �-lactams in gram-negative bacteriaoccurs overwhelmingly by expression of �-lactama-
ses. The combination of proliferation of �-lactam

ntibiotics and the widespread access to moleculariological techniques has led to an explosion in theumber of named �-lactamases in the past decade.s of July 25, 2011, the number of named �-lacta-

mases listed on the authoritative Web site managedby George Jacoby at Lahey Clinic (http://www.lahey.org/studies/) was 927 from 24 different �-lac-tamase classes (Table). The sheer number of en-zymes makes a coherent discussion of specific en-zymes virtually impossible unless it occurs betweenexperts, so I will try to simplify the discussion in away that emphasizes the most recent and clinicallyimportant aspects of the problem.

To understand the problem of �-lactamase–me-iated resistance in gram-negative bacteria, it is besto view it as having occurred in 4 waves (Figure 1).he first wave included a few different narrow-pectrum penicillinases that emerged in associa-ion with the use of ampicillin to treat gram-neg-tive infections. The growing prevalence of strainslaborating these enzymes, such as TEM-1 of E colind SHV-1 of Klebsiella pneumoniae, prompted theevelopment of newer �-lactam classes (such as the

cephalosporins, carbapenems, and aztreonam) thatwere resistant to hydrolysis. The second wave ofclinical importance occurred in the 1980s and in-volved the emergence of resistance to extended-spectrum cephalosporins.33 This resistance was fo-cused primarily in K pneumoniae and resulted fromhe accumulation of point mutations within TEM-r SHV-type enzymes.33 The accumulation ofnough point mutations, usually in combinationith increased expression due to promoter changes

nd reduced �-lactam access to the periplasmicpace from reductions in porin expression, resultedn expression of high-level resistance to extended-pectrum cephalosporins.34,35

There are 3 important points to make about thisecond wave of �-lactamases. The first is that mostf the mutations resulted in an “opening up” of thenzyme-active site. This opening up allowed the ac-ommodation of the bulky extended-spectrumephalosporins, but at the cost of weakening activitygainst ampicillin.33 The second is that, with few

exceptions, the mutations resulted in increasedsusceptibility to clinically available �-lactamasenhibitors (although the clinical strains were gen-rally resistant to the �-lactam–�-lactamase in-ibitor combinations because they made multiplenzymes in high quantity).36 Finally, these extended-pectrum �-lactamases were inactive against carbapen-

ems, resulting in carbapenems being used more fre-quently in settings in which they were prevalent.37 The

eakening of the �-lactamases against penicillins,their hypersusceptibility to inhibition, and their uni-versal susceptibility to carbapenems suggested that re-
ductions of cephalosporin use in favor of either in-
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hibitor combinations or carbapenems would resultin reductions in their prevalence. Several institu-tions reported reductions in extended-spectrum�-lactamase prevalence in association with reducedcephalosporin use during this period.37-39

The third wave overlapped with the second andinvolved the emergence and spread of the CTX-Mfamily of �-lactamases.40 Derived from the chromo-somal enzyme of Kluyvera spp, these enzymes arenatural cephalosporinases. They have penetratedwidely into many different species, including Kpneumoniae. In contrast to the first wave, CTX-Menzymes are also widely prevalent in pathogenic Ecoli.41 Worldwide spread of sequence type ST131 Ecoli expressing both CTX-M–type enzymes and fluo-roquinolone resistance has seriously complicatedthe empirical treatment of community-acquired uri-nary tract infections in many regions.42,43 Whetherreductions in cephalosporin use will lead to reducedprevalence of these strains is unclear, as they are cepha-losporinases by nature (ie, they will not likely be over-taken by narrow-spectrum variants). Moreover, thenearly universal association with fluoroquinolone re-sistance makes coselection a significant problem.

The fourth wave of �-lactamase–mediated resis-

FIGURE 1. Time line showing the use of differentarticle describing resistance (or a new class of �antibiotics in a previously susceptible organism. Itfollows closely on the heels of clinical introductiotamase. Data from records of US Food and Drug

tance is the emergence and spread of carbapen- q


mases.44 The carbapenems are broadly active pre-cisely because they resist hydrolysis by a wide rangeof �-lactamases and are often a “last line” of effectivetherapy for serious infections caused by gram-nega-tive bacteria. There are 3 broad categories of carbap-enemases. The first is the KPC (K pneumoniae car-apenemase) class, which is found primarily, butot exclusively, in K pneumoniae.45 Strains express-

ing these enzymes have spread worldwide and arecharacteristically resistant to all �-lactam antibioticss well as resistant to inhibition by currently avail-ble �-lactamase inhibitors. In vitro expression ofesistance to carbapenems is variable and may beependent on difficult-to-discern factors like plas-id copy number or porin reduction,46 making

hese strains difficult to detect at times. The KPCnzymes are often encoded on a mobile transposonesignated Tn440147 and can be transferred to dif-erent species on transferable plasmids. Originallyoncentrated in K pneumoniae in the United States,PC genes have now been identified in a wide vari-ty of different gram-negative species and have beenound throughout the world.45

The second major class of carbapenemasesre the metalloenzymes, so-named because they re-

ses of antibiotics and the publication of the firsttamases conferring resistance) to that class ofbe seen that emergence of resistance generallyantibiotics. ESBL � extended-spectrum �-lac-

ministration approvals and PubMed.

clas-laccann ofAd

uire the presence of a metal (usually zinc) as a


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cofactor for activity. A number of different “groups”of metalloenzymes have been described. Originallyconcentrated in Japan (where the number of carbap-enems and their use was greatest in the 1980s and1990s), they have now been identified worldwide.45

The mechanism by which they hydrolyze �-lactamsdiffers in important ways from the other types of�-lactamases, and therefore they are not subject toinhibition by any of the clinically available �-lactamaseinhibitors.48 Although metalloenzymes in general hy-drolyze aztreonam poorly, and therefore their pres-ence can be suggested by carbapenem resistance in thesetting of aztreonam susceptibility,49 the frequent co-expression of more common extended-spectrum�-lactamases in conjunction with metalloenzymes re-sults in clinical strains that express resistance to bothclasses. Although a number of different types of met-alloenzymes have been described, enzymes designatedVIM-1 and NDM-1 have been implicated in recent in-ternational outbreaks and in rising endemicity in dif-ferent regions.45

The third major class of carbapenemases are theOXA-type enzymes. More than 100 such enzymeshave been described in a number of gram-negativespecies. Only a few are associated with carbapenemresistance. These enzymes are responsible for mostof the carbapenem resistance observed in Acineto-bacter species.50 Like the other carbapenemases,they are not susceptible to inhibition by currentlyavailable �-lactamase inhibitors.

In many instances, in vitro analysis of carbap-enem hydrolysis by carbapenemases demonstratesrelatively weak activity. Clinical resistance resultsfrom the frequent presence of auxiliary mechanismsthat augment �-lactamase–mediated resistance,such as increased expression of �-lactamase (generallythrough the acquisition of stronger promoters) and re-duced �-lactam access to the periplasmic spacethrough porin mutations or pump activations.50

The broad activity of carbapenemases compro-mises both therapy for individual patients and strat-egies designed to modify antimicrobial selectivepressures. There are no classes of �-lactams thathave predictable activity against strains producingcarbapenemases, and many carbapenem-resistantstrains also express resistance to fluoroquinolonesand aminoglycosides. Thus, clinicians must fre-quently turn to second-line agents such as colistin ortigecycline. Given concerns about toxicity, efficacy,and spectrum that accompany use of these agents, itis hard to envision circumstances in which their useas empirical agents would be welcomed.

Resistance to GlycopeptidesGlycopeptides (vancomycin is the only glycopep-tide licensed for use in the United States) are of suf-
ficient size to preclude their passage through the

porins that allow entry into the periplasmic space ofgram-negative bacteria, so they are active onlyagainst gram-positive bacteria. Glycopeptides act bybinding to the terminal D-alanine present on thepentapeptide stem of peptidoglycan precursors,thereby inhibiting the transpeptidation step re-quired for peptidoglycan cross-linking. High-levelresistance to glycopeptides results from the acquisi-tion and expression of operons that substitute a ter-minal D-lactate or D-serine for the D-alanine,thereby reducing the vancomycin binding affinity.51

Expression of these operons is regulated by responseregulators encoded by the same transposons thatencode resistance, so the cost of having them is min-imized. Vancomycin-resistant enterococci (VRE)(predominantly E faecium) emerged in the 1980s,most likely in response to the widespread use oforally administered (and nonabsorbed) glycopep-tides in humans with gastrointestinal infection dueto Clostridium difficile (in the United States) and tothe use of orally administered glycopeptides to ani-mals as a feed additive (in Europe). Although a largenumber of different glycopeptide resistance operonshave now been described (VanA, B, C, D, E, F, G, L,M), VanA and VanB remain the most clinically rele-vant. Both have been identified on transposons thatare presumed to be the mechanisms that facilitatetheir dissemination.52,53 For reasons that remainunexplained, the acquired glycopeptide resistancedeterminants have remained concentrated in E fae-cium. Vancomycin-resistant E faecalis generally rep-resents a minority of isolates but may be particularlyimportant in the rare transfer of these operons to Saureus.54

Of great concern more than a decade ago washe possibility that the glycopeptide resistance de-erminants prevalent in E faecium would becomeidespread in MRSA, many strains of which were

usceptible only to glycopeptides. The level of con-ern over this possibility has diminished in the inter-ening years for 2 reasons. The first is that several newgents (quinupristin-dalfopristin, linezolid, daptomy-in, tigecycline, telavancin, ceftaroline) have been in-roduced that have activity against MRSA. The secondeason is the S aureus strains expressing the knownancomycin resistance determinants have been ex-eedingly rare.55 To date, roughly a dozen such strains

have been reported, and there is no compelling evi-dence for any clonal spread.

A more common type of reduced vancomycinsusceptibility observed in S aureus is a stepwise, in-termediate resistance that raises the minimum inhib-itory concentration (MIC) marginally (to 4-8 �g/mL) butenough to compromise treatment of clinical staph-ylococcal infection by vancomycin.56 This type ofintermediate resistance (vancomycin-intermediate S
aureus, or VISA) appears to be an intrinsic adapta-
ocp.2011.12.003 203

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204

tion of certain S aureus strains that occurs undercircumstances of persistent vancomycin selectivepressure.57 Although the mechanisms underlyingthe intermediate phenotype remain unclear, mostappear to involve a thickening of the cell wall in away that contains increased numbers of unlinkedpeptidoglycan precursors.57 These unlinked pre-cursors are thought to bind the glycopeptides beforethey can interact with peptidoglycan precursors atthe cytoplasmic membrane, essentially soaking upthe antibiotic before it can bind to the cell wall pre-cursors. The intermediate phenotype is often unsta-ble in the absence of persistent glycopeptide selec-tive pressure, and clonal spread of these strains hasnot been observed.

A potentially more troublesome development inS aureus has been what some have noted as “MICcreep.” Clinical failures have been observed morecommonly with S aureus strains having MICs of2 �g/mL or higher. Consequently, the most recentrecommendation from the Infectious Diseases Soci-ety of America for treatment of serious S aureus in-fections is that alternative therapeutic agents shouldbe used for patients whose isolate MICs are equal toor greater than 2 �g/mL.58 The extent to which Saureus MIC creep truly exists is debatable. One re-cent study indicated that the creep identified over a10-year period was methodology dependent andmost pronounced with the use of E-test strips.59 Itremains good advice to follow up patients closelyand, if the clinical progress dictates, switch to a non-glycopeptide for the treatment of serious S aureusinfections. Some experts recommend targetinghigher trough concentrations in dosing regimens.However, a recent multicenter study concluded thata 3-fold increased risk of renal dysfunction was as-sociated with vancomycin regimens in which thetrough concentration exceeded 15 �g/mL.60

The mutational evolution to vancomycin resis-tance in S aureus appears to be a phenomenon that isonly advantageous in the setting of continued van-comycin selective pressure, probably because thick-walled S aureus cocci are not favored in the naturalenvironment. But what of the vancomycin resistanceoperons? Is it likely that reduced vancomycin usewill reduce their prevalence in E faecium? Probablynot. Associations between vancomycin use in theclinical setting and VRE colonization have oftenbeen tenuous. The potential connection betweenoral vancomycin use and VRE colonization was rec-ognized early, leading to recommendations thatmetronidazole, rather than oral vancomycin, beused to treat C difficile colitis. Unfortunately, it wassoon recognized that exposure to potent antianaero-bic antibiotics, including metronidazole, was a sig-nificant risk factor for VRE colonization.61 Recent
data indicate that reductions of use of oral glycopep-

tides in European feed animals have dramaticallydecreased animal colonization with VRE.62 How-ver, reduction of parenteral vancomycin use in hu-ans is unlikely to have a major impact on hospitalrevalence, since little vancomycin enters the gas-rointestinal tract when it is administered parenter-lly. The strongest selective pressure for VRE colo-ization and infection most likely comes from these of extended-spectrum cephalosporins,63 which

select for ampicillin-resistant E faecium (the vast ma-jority of VRE are ampicillin-resistant E faecium).Whether systematic efforts to reduce cephalosporinuse will reduce VRE prevalence remains to bedetermined.

Resistance to FluoroquinolonesHigh levels of resistance to fluoroquinolones in bothgram-positive and gram-negative bacteria are attrib-utable to the accumulation of point mutations ingenes encoding cellular topoisomerases (enzymesthat act to coil and uncoil complementary DNAstrands) along with acquisition of auxiliary mecha-nisms that serve to augment the level of resistanceexpressed.64 These point mutations occur primarilyin the quinolone resistance–determining regions,the areas of the topoisomerases involved in quino-lone binding. The level of resistance to a specificfluoroquinolone associated with a mutation de-pends on the nature of the mutation and whether itis located in the gene encoding the primary target forthat fluoroquinolone (gyrA or parC, for example). Ingeneral, single point mutations confer only modestlevels of resistance. This observation has led to theidea that a “mutant prevention concentration”65

(MPC) can be identified that prevents the clinicalemergence of resistant strains from susceptible pop-ulations. In other words, keeping the concentrationof a fluoroquinolone persistently above the level ofresistance expressed by a first-order mutant effec-tively suppresses that mutant from emerging. Invitro and some animal studies support the effective-ness of this strategy.66-68

Unfortunately, in the clinical environment, theelationship between antimicrobial administrationnd the emergence of resistance is not simple. Therere several mechanisms by which bacteria, espe-ially gram-negative bacteria, can move closer to thereakpoint for resistance without actually becominglinically resistant. Mechanisms facilitating such in-reases include the increased expression or acquisi-ion of a number of efflux pumps, the acquisition oflasmids that encode “protection enzymes” (Qnr),r the acquisition of plasmids encoding enzymeshat inactivate the fluoroquinolone [aac(6=)-Ib-cr]Figure 2). In one study, the presence of qnrA in an

E coli strain increased the MPC 8-fold, from 1 to
8 �g/mL, pushing it beyond clinically achievable


concentrations.69 Moreover, the concentrations offluoroquinolone achieved throughout the body arenot uniform. The concentration in the lung may beconsiderably higher than in the bowel (where manymutants are waiting to emerge). Finally, the MPC formoxifloxacin against S pneumoniae is considerablydifferent than the moxifloxacin MPC against Paeruginosa. Consequently, concentrations that sup-press the emergence of fluoroquinolone-resistantmutants in S pneumoniae may promote their emer-gence in P aeruginosa in the same patient. In thecurrent environment, in which fluoroquinolone-resistant variants of common pathogens are com-monplace, use of these agents invites colonizationby resistant strains. It is therefore unlikely that anystrategies designed to try to suppress the emergence

FIGURE 2. Representative graph (not based on ations of various fluoroquinolone resistance mechancase, the baseline susceptible species (Escherichiaconcentration (MIC) in the absence of any resistaperformed during the development of a fluoroquprevention concentration (MPC) (the concentraemergence of single-step mutants) to be 1 �g/mLresult from a single gyrA amino acid substitution (clinical use of the agent, auxiliary mechanisms of ror acquisition of qnr genes or modifying enzyme gethe MIC but not to a level that would be considauxiliary genes present, the 8-fold increase in MICresults in a strain that has an MIC above the preMPC). Under these circumstances, a previously dresult in selection of resistant mutants.

of resistance by using higher concentrations of fluo-


roquinolones will be successful in the clinicalsetting.

CONCLUSIONAlthough the emergence of antimicrobial resistanceis invariably associated with antimicrobial use, themultiple mechanisms of resistance, the frequency ofgene exchange in the natural environment, and thenonspecific nature of many resistance mechanismsmake developing resistance-specific strategies to re-duce individual resistance phenotypes complicatedand fraught with potential deleterious unintendedconsequences. Efforts to reduce overall antimicro-bial exposure, for example, through organized ef-forts to identify appropriate minimal lengths of ther-

l data) of the individual and combined contribu-to clinical resistance to fluoroquinolones. In this

for example) would have a minimum inhibitorymechanism of 0.06 �g/mL. In vitro experimentsne, for example, would determine the mutantof antimicrobial agent that will suppress thene doubling dilution above the MIC that wouldh confers a 3-fold increase in resistance). With

ance, such as activation of intrinsic efflux pumpsac(6=)-Ib-cr, are acquired by strains and increaseclinically resistant. With one or more of these

ociated with a single amino acid change in gyrAsly defined MPC (ie, 1 �g/mL is no longer theed MPC is inaccurate and misleading and may

ctuaismscoli,nceinolotion, or owhicesistne a

eredass

viouefin

apy, hold greater promise for reducing the burden of

ocp.2011.12.003 205

1

1

1

1


206

resistance. Reductions in the use of antibiotics (eg,the fluoroquinolones) that promote the emergenceof broad-spectrum mechanisms of resistance mayhave greater benefits in reducing the prevalence ofresistance to a variety of troublesome nosocomialpathogens.

Correspondence: Address to Louis B. Rice, MD, RhodeIsland Hospital, 593 Eddy St, Providence, RI 02903([email protected]). Individual reprints of this article and abound reprint of the entire Symposium on AntimicrobialTherapy will be available for purchase from our Web sitewww.mayoclinicproceedings.org.

The Symposium on Antimicrobial Therapy will continuein an upcoming issue.

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4. Deurenberg RH, Stobberingh EE. The evolution of Staphylo-coccus aureus. Infect Genet Evol. 2008;8(6):747-763.

5. Basset P, Senn L, Vogel V, Zanetti G, Blanc DS. Diversity ofstaphylococcal cassette chromosome mec elements in pre-dominant methicillin-resistant Staphylococcus aureus clones in asmall geographic area. Antimicrob Agents Chemother. 2010;54(11):4589-4595.

6. Pinho MG, de Lencastre H, Tomasz A. An acquired and anative penicillin-binding protein cooperate in building the cellwall of drug-resistant staphylococci. Proc Nat Acad Sci USA.2001;98(19):10886-10891.

7. Chang FY, Peacock JE, Jr., Musher DM, et al. Staphylococcusaureus bacteremia: recurrence and the impact of antibiotictreatment in a prospective multicenter study. Medicine (Balti-more). 2003;82(5):333-339.

18. Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antibiotics:doripenem, ceftobiprole, ceftaroline, and cefepime. Med ClinNorth Am. 2011;95(4):743-760, viii.

19. Rice LB, Carias LL, Hutton-Thomas R, et al. Penicillin-bindingprotein 5 and expression of ampicillin resistance in Enterococ-cus faecium. Antimicrob Agents Chemother. 2001;45(5):1480-1486.

20. Rice LB, Carias LL, Rudin S, et al. Enterococcus faecium low-affinity pbp5 is a transferable determinant. Antimicrob AgentsChemother. 2005;49(12):5007-5012.

21. Top J, Willems R, Bonten M. Emergence of CC17 Enterococcusfaecium: from commensal to hospital-adapted pathogen. FEMSImmunol Med Microbiol. 2008;52(3):297-308.

22. Galloway-Pena JR, Rice LB, Murray BE. Analysis of PBP5 ofearly U.S. isolates of Enterococcus faecium: sequence variationalone does not explain increasing ampicillin resistance overtime. Antimicrob Agents Chemother. 2011;55(7):3272-3277.

23. Willems RJ, Hanage WP, Bessen DE, Feil EJ. Population biologyof Gram-positive pathogens: high-risk clones for disseminationof antibiotic resistance. FEMS Microbiol Rev. 2011;35(5):872-900.

24. Donskey CJ, Hanrahan JA, Hutton RA, Rice LB. Effect ofparenteral antibiotic administration on persistence of vanco-mycin-resistant Enterococcus faecium in the mouse gastrointes-tinal tract. J Infect Dis. 1999;180(2):384-390.

25. Donskey CJ, Hanrahan JA, Hutton RA, Rice LB. Effect ofparenteral antibiotic administration on establishment of colo-nization with vancomycin-resistant Enterococcus faecium in themouse gastrointestinal tract. J Infect Dis. 2000;181(5):1830-1833.

26. Donskey CJ, Schreiber JR, Jacobs MR, et al. A polyclonaloutbreak of predominantly VanB vancomycin-resistant entero-cocci in Northeast Ohio. Clin Infect Dis. 1999;29:573-579.

27. Rice LB. Antibiotics and gastrointestinal colonization by van-comycin-resistant enterococci. Eur J Clin Microbiol. 2005;24(12):804-814.

28. Coffey TJ, Dowson CG, Daniels M, et al. Horizontal transfer ofmultiple penicillin-binding protein genes, and capsular biosyn-thetic genes, in natural populations of Streptococcus pneu-moniae. Mol Microbiol. 1991;5(9):2255-2260.

29. Spratt BG. Hybrid penicillin-binding proteins in penicillin-resis-tant strains of Neisseria gonorrhoeae. Nature (London). 1988;332:173-176.

30. Ohnishi M, Golparian D, Shimuta K, et al. Is Neisseria gonor-rhoeae initiating a future era of untreatable gonorrhea?: de-tailed characterization of the first strain with high-level resis-tance to ceftriaxone. Antimicrob Agents Chemother. 2011;55(7):
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32. Talbot TR, Poehling KA, Hartert TV, et al. Reduction in highrates of antibiotic-nonsusceptible invasive pneumococcal dis-ease in tennessee after introduction of the pneumococcalconjugate vaccine. Clin Infect Dis. 2004;39(5):641-648.

33. Jacoby GA, Medeiros AA. More extended-spectrum �-lacta-mases. Antimicrob Agents Chemother. 1991;35(9):1697-1704.

34. Hernandez-Alles S, Alberti S, Alvarez D, et al. Porin expressionin clinical isolates of Klebsiella pneumoniae. Microbiology. 1999;145 ( Pt 3):673-679.

35. Rice LB, Carias LL, Hujer AM, et al. High-level expression ofchromosomally encoded SHV-1 �-lactamase and an outermembrane protein change confer resistance to ceftazidimeand piperacillin-tazobactam in a clinical isolate of Klebsiellapneumoniae. Antimicrob Agents Chemother. 2000;44(2):362-367.

36. Ardanuy C, Linares J, Dominguez MA, et al. Outer membraneprofiles of clonally related Klebsiella pneumoniae isolates fromclinical samples and activities of cephalosporins and carbapenems.Antimicrob Agents Chemother. 1998;42(7):1636-1640.

37. Rahal JJ, Urban C, Horn D, et al. Class restriction of cephalo-sporin use to control total cephalosporin resistance in noso-comial Klebsiella. JAMA. 1998;280(4):1233-1237.

38. Peña C, Pujol M, Ardanuy C, et al. Epidemiology and successfulcontrol of a large outbreak due to Klebsiella pneumoniaeproducing extended-spectrum �-lactamases. AntimicrobAgents Chemother. 1998;42(1):53-58.

39. Rice LB, Eckstein EC, DeVente J, Shlaes DM. Ceftazidime-resistant Klebsiella pneumoniae isolates recovered at theCleveland Department of Veterans Affairs Medical Center.Clin Infect Dis. 1996;23(1):118-124.

40. Tzouvelekis LS, Tzelepi E, Tassios PT, Legakis NJ. CTX-M-typebeta-lactamases: an emerging group of extended-spectrumenzymes. Int J Antimicrob Agents. 2000;14(2):137-142.

41. Qi C, Pilla V, Yu JH, Reed K. Changing prevalence of Escherichiacoli with CTX-M-type extended-spectrum beta-lactamases inoutpatient urinary E. coli between 2003 and 2008. Diagn MicrobiolInfect Dis. 2010;67(1):87-91.

42. Johnson JR, Johnston B, Clabots C, Kuskowski MA, CastanheiraM. Escherichia coli sequence type ST131 as the major cause ofserious multidrug-resistant E. coli infections in the UnitedStates. Clin Infect Dis. 2010;51(3):286-294.

43. Nicolas-Chanoine MH, Blanco J, Leflon-Guibout V, et al. In-tercontinental emergence of Escherichia coli clone O25:H4-ST131 producing CTX-M-15. J Antimicrob Chemother. 2008;61(2):273-281.

44. Queenan AM, Bush K. Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev. 2007;20(3):440-458, table ofcontents.

45. Walsh TR. Emerging carbapenemases: a global perspective. Int JAntimicrob Agents. 2010;36 Suppl 3:S8-14.

46. Landman D, Bratu S, Quale J. Contribution of OmpK36 tocarbapenem susceptibility in KPC-producing Klebsiella pneu-moniae. J Med Microbiol. 2009;58(10):1303-1308.

47. Cuzon G, Naas T, Nordmann P. Functional characterization ofTn4401, a Tn3-based transposon involved in blaKPC genemobilization. Antimicrob Agents Chemother. 2011.

48. Lisa MN, Hemmingsen L, Vila AJ. Catalytic role of the metalion in the metallo-beta-lactamase GOB. J Biol Chem. 2010;
285(7):4570-4577.

49. Lolans K, Queenan AM, Bush K, Sahud A, Quinn JP. Firstnosocomial outbreak of Pseudomonas aeruginosa producing anintegron-borne metallo-beta-lactamase (VIM-2) in the UnitedStates. Antimicrob Agents Chemother. 2005;49(8):3538-3540.

50. Heritier C, Poirel L, Lambert T, Nordmann P. Contribution ofacquired carbapenem-hydrolyzing oxacillinases to carbapenemresistance in Acinetobacter baumannii. Antimicrob Agents Che-mother. 2005;49(8):3198-3202.

1. Gold HS. Vancomycin-resistant enterococci: mechanisms andclinical observations. Clin Infect Dis. 2001;33(2):210-219.

2. Arthur M, Molinas C, Depardieu F, Courvalin P. Characteriza-tion of Tn1546, a Tn3-related transposon conferring glyco-peptide resistance by synthesis of depsipeptide peptidoglycanprecursors in Enterococcus faecium BM4147. J Bacteriol. 1993;175(1):117-127.

53. Carias LL, Rudin SD, Donskey CJ, Rice LB. Genetic linkage andcotransfer of a novel, vanB-containing transposon (Tn5382)and a low-affinity penicillin-binding protein 5 gene in a clinicalvancomycin-resistant Enterococcus faecium isolate. J Bacteriol.1998;180(17):4426-4434.

54. Flannagan SE, Chow JW, Donabedian SM, et al. Plasmid con-tent of a vancomycin-resistant Enterococcus faecalis isolatefrom a patient also colonized by Staphylococcus aureus with aVanA phenotype. Antimicrob Agents Chemother. 2003;47(12):3954-3959.

55. Perichon B, Courvalin P. VanA-type vancomycin-resistantStaphylococcus aureus. Antimicrob Agents Chemother. 2009;53(11):4580-4587.

56. Sakoulas G, Moise-Broder PA, Schentag J, et al. Relationship ofMIC and bactericidal activity to efficacy of vancomycin fortreatment of methicillin-resistant Staphylococcus aureus bacter-emia. J Clin Microbiol. 2004;42(6):2398-2402.

7. Sieradzki K, Tomasz A. Gradual alterations in cell wall structureand metabolism in vancomycin-resistant mutants of Staphylo-coccus aureus. J Bacteriol. 1999;181(24):7566-7570.

8. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelinesby the infectious diseases society of america for the treatmentof methicillin-resistant Staphylococcus aureus infections inadults and children: executive summary. Clin Infect Dis. 2011;52(3):285-292.

9. van Hal SJ, Barbagiannakos T, Jones M, et al. Methicillin-resis-tant Staphylococcus aureus vancomycin susceptibility testing:methodology correlations, temporal trends and clonal pat-terns. J Antimicrob Chemother. 2011.

0. Bosso JA, Nappi J, Rudisill C, et al. Relationship betweenvancomycin trough concentrations and nephrotoxicity: a pro-spective multicenter trial. Antimicrob Agents Chemother.2011;55(12):5475-5479.

1. Donskey CJ, Chowdhry TK, Hecker MT, et al. Effect of anti-biotic therapy on the density of vancomycin-resistant entero-cocci in the stool of colonized patients. N Engl J Med. 2000;343(26):1925-1932.

2. Johnsen PJ, Townsend JP, Bohn T, et al. Factors affecting thereversal of antimicrobial-drug resistance. Lancet Infect Dis.2009;9(6):357-364.

3. Rice LB, Hutton-Thomas R, Lakticova V, Helfand MS, DonskeyCJ. Beta -lactam antibiotics and gastrointestinal colonizationwith vancomycin-resistant enterococci. J Infect Dis. 2004;189(6):1113-1118.

4. Hooper DC. Emerging mechanisms of fluoroquinolone resis-tance. Emerg Infect Dis. 2001;7(2):337-341.

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67. Tam VH, Louie A, Fritsche TR, et al. Impact of drug-exposure intensity and duration of therapy on the emer-gence of Staphylococcus aureus resistance to a quinoloneantimicrobial. J Infect Dis. 2007;195(12):1818-1827.

68. Tam VH, Louie A, Deziel MR, Liu W, Drusano GL. The
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amplification is characterized by an inverted U: a newparadigm for optimizing pharmacodynamics to counter-select resistance. Antimicrob Agents Chemother. 2007;51(2):744-747.

9. Briales A, Rodriguez-Martinez JM, Velasco C, et al. In vitroeffect of qnrA1, qnrB1, and qnrS1 genes on fluoroquinoloneactivity against isogenic Escherichia coli isolates with mutationsin gyrA and parC. Antimicrob Agents Chemother. 2011;55(3):
1266-1269.


Current Concepts in Laboratory Testing toGuide Antimicrobial Therapy

Stephen G. Jenkins, PhD, and Audrey N. Schuetz, MD, MPH

Abstract

Antimicrobial susceptibility testing (AST) is indicated for pathogens contributing to an infectious process that warrantsantimicrobial therapy if susceptibility to antimicrobials cannot be predicted reliably based on knowledge of their identity.Such tests are most frequently used when the etiologic agents are members of species capable of demonstrating resistance tocommonly prescribed antibiotics. Some organisms have predictable susceptibility to antimicrobial agents (ie, Streptococcuspyogenes to penicillin), and empirical therapy for these organisms is typically used. Therefore, AST for such pathogens isseldom required or performed. In addition, AST is valuable in evaluating the activity of new and experimental compoundsand investigating the epidemiology of antimicrobial resistant pathogens. Several laboratory methods are available to charac-terize the in vitro susceptibility of bacteria to antimicrobial agents. When the nature of the infection is unclear and the cultureyields mixed growth or usual microbiota (wherein the isolates usually bear little relationship to the actual infectious process),AST is usually unnecessary and results may, in fact, be dangerously misleading. Phenotypic methods for detection of specificantimicrobial resistance mechanisms are increasingly being used to complement AST (ie, inducible clindamycin resistanceamong several gram-positive bacteria) and to provide clinicians with preliminary direction for antibiotic selection pendingresults generated from standardized AST (ie, �-lactamase tests). In addition, molecular methods are being developed andincorporated by microbiology laboratories into resistance detection algorithms for rapid, sensitive assessment of carriagestates of epidemiologically and clinically important pathogens, often directly from clinical specimens (ie, presence of vanco-mycin-resistant enterococci in fecal specimens).

CME Activity

Target Audience: The target audience for Mayo Clinic Proceedings is pri-marily internal medicine physicians and other clinicians who wish to advancetheir current knowledge of clinical medicine; and who wish to stay abreastof advances in medical research.Statement of Need: General internists and primary care providers mustmaintain an extensive knowledge base on a wide variety of topics coveringall body systems as well as common and uncommon disorders. Mayo ClinicProceedings aims to leverage the expertise of its authors to help physiciansunderstand best practices in diagnosis and management of conditions en-countered in the clinical setting.Accreditation: College of Medicine, Mayo Clinic is accredited by the Ac-creditation Council for Continuing Medical Education to provide continuingmedical education for physicians.Credit Statement: College of Medicine, Mayo Clinic designates this Jour-nal-based CME activity for a maximum of 1.0 AMA PRA Category 1Credit(s).™ Physicians should claim only the credit commensurate withthe extent of their participation in the activity.Learning Objectives: Educational objectives. On completion of this article,readers should be able to: (1) interpret the results generated by the variousstandardized methods of antimicrobial susceptibility testing commonly em-ployed by clinical microbiology laboratories; (2) evaluate findings generatedfrom phenotypic methods used for detection of antimicrobial resistance;and (3) explain the rationale for use of molecular methods for detection andcharacterization of antimicrobial resistance determinants.Disclosures: As a provider accredited by ACCME, College of Medicine,Mayo Clinic (Mayo School of Continuous Professional Development) mustensure balance, independence, objectivity and scientific rigor in its educa-tional activities. Course Director(s), Planning Committee Members, Faculty,and all others who are in a position to control the content of this educa-tional activity are required to disclose all relevant financial relationships with

any commercial interest related to the subject matter of the educationalactivity. Safeguards against commercial bias have been put in place. Facultyalso will disclose any off label and/or investigational use of pharmaceuticalsor instruments discussed in their presentation. Disclosure of this informationwill be published in course materials so those participants in the activity mayformulate their own judgments regarding the presentation.In their editorial and administrative roles, William L. Lanier, Jr., MD, Scott C.Litin, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA,have control of the content of this program but have no relevant financialrelationship(s) with industry.Drs Jenkins and Schuetz have no financial disclosures relevant to thismanuscript. Two drugs mentioned in the article are off-label use for anti-microbial therapy.Method of Participation: In order to claim credit, participants must com-plete the following:1. Read the activity.2. Complete the online CME Test and Evaluation. Participants must achieve

a score of 80% on the CME Test. One retake is allowed.Participants should locate the link to the activity desired at http://bit.ly/zchWvb. Upon successful completion of the online test and evaluation, youcan instantly download and print your certificate of credit.Estimated Time: The estimated time to complete each article is approxi-mately 1 hour.Hardware/Software: PC or MAC with Internet access.Date of Release: 3/1/2012Expiration date: 2/28/2014 (Credit can no longer be offered after it haspassed the expiration date.)Privacy Policy: http://www.mayoclinic.org/global/privacy.htmlQuestions? Contact [email protected].


asdYork, NY.

290 Mayo Clin Proc.

A ssessment of the antimicrobial suscepti-bility patterns of significant bacterial iso-lates is among the primary responsibili-

ties of the clinical microbiology laboratory. From i

� March 2012;87(3):290-308 � doi:10.1016/j.mayocp.2012.01.007 �

practical perspective, clinicians often perceiveuch test results to be at least as important asetermination of the etiologic agents of patients’

From the Department ofPathology, Weill CornellMedical College, New

nfections. In the face of ever-escalating antimi-

© 2012 Mayo Foundation for Medical Education and Researchwww.mayoclinicproceedings.org

http://bit.ly/zchWvb

http://bit.ly/zchWvb



LABORATORY TESTING TO GUIDE ANTIMICROBIAL THERAPY

crobial resistance and the frequent need for treat-ment with newer, often more expensive antibiot-ics, antibacterial susceptibility testing (AST)results take on an increasingly important role.1

DILUTION METHODS FOR ASTAgar and broth dilution methods may be used todetermine the minimum concentrations of antibiot-ics that are required to inhibit or kill microorgan-isms. Drugs under study are typically tested at2-fold doubling (log2) serial dilutions (eg, 4, 8, 16�g/mL, and so on), with the lowest concentration ofeach antibiotic that inhibits visible growth of organ-isms designated as the minimum inhibitory concen-tration (MIC). In the United States, results are usu-ally reported in micrograms per milliliter, whereasin some other parts of the world results may be re-ported in milligrams per liter. The concentrationranges tested vary with the antimicrobial agent, thepathogen under study, and the infection site. Rangesshould encompass the concentrations used to definethe interpretive categories (susceptible, intermedi-ate, and resistant) of the antimicrobial agent and theranges of expected MICs for reference quality con-trol organisms. Alternative dilution methods mayinclude only a single or a selected few concentra-tions of antibiotics, such as breakpoint AST and sin-gle-drug concentration screening. Dilution methodsoffer flexibility in that the standard Mueller-Hintonmedium used for the testing of frequently en-countered pathogens (eg, members of the familyEnterobacteriaceae, staphylococci, enterococci,and some nonfermentative gram-negative bacilli,such as Acinetobacter baumannii and Pseudomonasaeruginosa) may be supplemented or, in somecases, replaced by another medium, allowing foraccurate testing of many fastidious organisms forwhich standardized methods are not availablefor reliable disk diffusion testing. Dilution meth-ods are also amenable for use in automated anti-biotic susceptibility testing systems.

Breakpoints derived by regulatory bodies andprofessional groups are frequently similar. For ex-ample, there are relatively small numbers of discor-dant breakpoints between the US Food and DrugAdministration (FDA) and the Clinical and Labora-tory Standards Institute (CLSI), and those discrep-ancies are under active review by both organiza-tions. By comparison, there are sometimes sizabledifferences in the interpretive criteria used in differ-ent countries or regions of the world for the sameantibiotics. Such disparities are sometimes a func-tion of the fact that different dosages and/or admin-istration intervals are used for the same antimicro-bial agents. In addition, some breakpoint-settingorganizations are more conservative than others in
assessing susceptibility to anti-infectives, placing
Mayo Clin Proc. � March 2012;87(3):290-308 � doi:10.1016/j.mayocwww.mayoclinicproceedings.org

more emphasis on detection of emerging resistancebased on examination of microorganism popula-tion distributions. Technical factors, including in-cubation temperature and atmosphere, inoculumsize, and test medium formulation, can also affectzone diameters and MICs, justifying differentbreakpoints.

Agar Dilution MethodMueller-Hinton agar is the medium recommendedfor routine testing of most rapidly growing aerobicand facultatively anaerobic bacterial pathogens. Thesolvents and diluents that are required to preparestock solutions of antibiotics and the methodsused to perform such testing are defined in theCLSI standard on dilution AST.2 The agar dilutionapproach to susceptibility testing is both wellstandardized and reproducible and may be usedas a reference method in the evaluation of otherdilution assays. This method facilitates the con-comitant and efficient testing of large numbers oforganisms. In addition, population heterogeneity(ie, resistant subpopulations of organisms) and in-oculum contamination (ie, “mixed” cultures) aremore easily detected by agar than by broth testing.The primary disadvantages of this testing approachare the labor-intensive, time-consuming steps re-quired to prepare testing plates, particularly whenthe number of compounds to be tested is high orwhen only a limited number of bacteria are to bestudied, or both. For these reasons, most clinicalmicrobiology laboratories do not use this approachfor routine AST.

Broth Dilution MethodsGeneral approaches to broth dilution testing includeboth macrodilution, wherein volumes of broth intest tubes for each dilution typically equal or exceed1 mL, and broth microdilution (BMD), in whichantimicrobial concentrations are most frequently ofsmaller volumes in 96-well microtiter plates. Thebroth macrodilution approach is both reliable andwell standardized and is of particular utility in re-search studies and in testing of a single antimicrobialagent for 1 bacterial isolate. The method is, how-ever, both laborious and time intensive and, becauseof the ready commercial availability of convenientmicrodilution systems, is not generally consideredpractical for routine use in clinical microbiologylaboratories.

The convenience afforded by BMD has led to itswidespread use in both clinical and reference labo-ratories. This approach is, in fact, now consideredthe reference international testing method.3 Plastic,disposable plates containing a panel of several anti-
biotics to be tested concomitantly may be prepared
p.2012.01.007 291

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within the laboratory or, alternatively, purchasedfrom commercial vendors either as freeze-dried orfrozen trays. The BMD technique is also well stan-dardized and reliable. The inoculation and readingprocedures readily lend themselves to the simulta-neous testing of several antibiotics with single bac-terial isolates. Although most commercially avail-able systems use multipoint inoculating devices orautomated inoculation instruments, plates may alsobe inoculated with multichannel pipettors. Testingresults may be determined either visually or throughthe use of semiautomated or automated instru-ments. An example of a commercially availablemanual BMD is Sensititre (TREK Diagnostic Sys-tems, Cleveland, OH). Examples of automated BMDplatforms include the BD Phoenix (Becton Dickin-son, Franklin Lakes, NJ), Microscan (SiemensHealthcare Diagnostics, Deerfield, IL), and Vitek(bioMérieux, Marcy l’Etoile, France).

AGAR DISK DIFFUSION TESTINGIn many clinical microbiology laboratories an agardisk diffusion method is routinely used for the test-ing of common, rapidly growing, and some fastidi-ous bacterial pathogens, allowing categorization ofmost such isolates as susceptible, intermediate, orresistant to a wide range of antimicrobial agents.This approach is particularly common in resource-limited settings and when performed according tostandardized methods, such as those published bythe CLSI, provides accurate direction to cliniciansmaking therapeutic antibiotic decisions.4 With thistesting approach, commercially prepared filter pa-per disks impregnated with specified predeterminedconcentrations of the antibiotics to be assessed areapplied to the surface of a defined agar mediumpreviously inoculated with the challenge bacterialpathogen. The antimicrobial agents then diffusefrom the disks through the agar, and as the distancefrom the disks increases, the drug concentrationsdecrease in a logarithmic fashion, creating gradientsof drug concentrations in the medium around thedisks. Simultaneously with the diffusion of thedrugs, the bacteria inoculated to the agar surface notinhibited by the concentrations of the antibiotics inthe agar multiply, creating a visible lawn of growth.In areas where the test organism is inhibited by theantimicrobial agents, growth fails to occur, resultingin zones of inhibition around each active drug. Theinhibitory zone diameters are influenced by the dif-fusion rates of the various antimicrobial agentsthrough the agar, a function of the molecular sizesand hydrophilicities of the compounds. The zonesizes are inversely proportional to the logarithms ofthe antibiotic MICs. After incubation at recom-mended temperatures, atmospheric conditions, and
times, depending on the pathogen under study, the i
Mayo Clin Proc. �

diameters of the zones of inhibition are measured inmillimeters and interpreted based on publishedstandards. The most recent criteria for interpretingzone diameters of inhibition for antibiotics ap-proved for use by the FDA are listed in Table 3 of adocument updated annually by the CLSI.5

Such disk diffusion interpretive criteria (break-oints) are chosen after the establishment of MICreakpoints, which is accomplished by plotting the

nhibition zone diameters against the MICs derivedrom the testing of a large number of strains of var-ous species. A statistical approach using a linearegression formula may be used to calculate the ap-ropriate zone diameter intercepts for previouslyetermined MIC breakpoints. An alternative, prac-ical approach to deriving disk diffusion interpretiveriteria is the use of the error rate–bounded methody which the zone diameter breakpoints are selectedased on the minimization of disk interpretive er-ors, particularly very major errors.6,7 This most re-ent CLSI approach focuses on the rate of interpre-ive errors near the proposed breakpoint vs errorates for MICs greater than a single log2 dilution

from the MIC breakpoints.8 The concept of this ap-roach is that errors occurring with organisms forhich MICs closely approximate the MIC break-oints are less of a clinical concern than errors forore highly susceptible or resistant isolates.

The disk diffusion approach for AST has beentandardized primarily for commonly encountered,apidly growing bacterial pathogens and is applica-le to neither anaerobes nor fastidious species thatemonstrate marked variability in growth rate fromtrain to strain.9 The disk diffusion test approachas been modified, though, to allow for reliable test-

ng of several species of fastidious bacteria, includ-ng Haemophilus influenzae and Neisseria gonor-hoeae. There are several advantages to the diskiffusion approach to AST, including the following:1) it is technically easy to perform and results areeproducible, (2) the reagents and supplies are in-xpensive, (3) it does not require the use of expen-ive equipment, (4) it generates categorical interpre-ive results well understood by clinicians, and (5) itllows for considerable flexibility in the selection ofntibiotics for testing. However, this method alsoas a number of drawbacks. For example, only a

imited number of bacterial species can be testedsing this approach. In addition, the disk diffusionest is inadequate for detection of vancomycin-inter-ediate Staphylococcus aureus. Of importance, itrovides only a qualitative result, whereas a quanti-ative MIC result that indicates the degree of suscep-ibility may in some cases be required (eg, whenrolonged or continuous infusion of specific antimi-robial agents is being considered for treatment of
nfections caused by relatively resistant bacteria).
March 2012;87(3):290-308 � doi:10.1016/j.mayocp.2012.01.007www.mayoclinicproceedings.org

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GRADIENT DIFFUSION METHODSThe M.I.C.Evaluator (Oxoid, Cambridge, UK) andEtest (bioMérieux, Durham, NC), are commerciallyavailable gradient diffusion systems for quantitativeAST. Both systems use preformed antimicrobial gra-dients applied to 1 face of a plastic strip to generatediffusion of drug into an agar-based medium. Theassays are performed in a manner similar to that fordisk diffusion using a suspension of test organismequivalent in turbidity to that of a 0.5 McFarlandstandard to inoculate the surface of an agar plate.Following recommendations for incubation temper-atures, times, and atmospheric conditions, the MICis read directly from a preprinted scale on the top ofthe strip at the point at which the ellipse of organismgrowth inhibition intercepts the strip. An exampleof an isolate tested for antimicrobial susceptibilityby both Etest and disk diffusion is shown in theFigure. Several strips containing different antimi-crobial agents may be applied in a radial arrange-ment to the surface of large round plates, or theymay be placed in opposite directions on large rect-angular plates. Minimum inhibitory concentrationsgenerated by these methods generally agree wellwith those obtained using standard agar and brothdilution methods.10-12 Such gradient methods aresimilar in flexibility and simplicity to the disk diffu-sion approach, but they enable one to determinequantitative MICs. Significant advantages of the agargradient diffusion systems include the ability to gen-erate quantitative MIC results for infrequently testedantimicrobial agents and the option to test fastidiousand anaerobic organisms, for which reliable diskdiffusion methods and/or commercial systems are

FIGURE. Manual susceptibility testing of Pseu-domonas aeruginosa by Etest and disk diffusion.Various patterns of susceptibility and resis-tance are seen.

not available, through the use of specific enriched M


media. Gradient diffusion strips are, however, con-siderably more expensive than the paper disks usedfor diffusion testing.

METHODS FOR FASTIDIOUS BACTERIAMany fastidious bacterial species do not grow satis-factorily using standard in vitro susceptibility test-ing approaches with unsupplemented media. Forseveral of the more frequently encountered patho-gens (eg, Streptococcus pneumoniae and Streptococcusspp other than S pneumoniae, N gonorrhoeae, and

eisseria meningitidis, and H influenzae and Hae-ophilus parainfluenzae), modifications have beenade to the standard CLSI MIC and disk diffusionethods to allow laboratories to perform reliableST. Such modifications typically involve the use of

est media with supplemental nutrients, prolongedncubation times, and/or incubation in an atmo-phere with an increased concentration of carbonioxide. Specific MIC and zone diameter break-oints have been established by the CLSI for suchrganisms, as have recommended acceptable rangesor the testing of applicable quality control strains.he CLSI has also published guidelines for AST of

he fastidious and/or infrequently recovered bacteriaisted in the Table.13 Methods for the standardizedesting of potential agents of bioterrorism (eg, Bacil-us anthracis, Francisella tularensis, Brucella spp, Yer-inia pestis, and Burkholderia pseudomallei) have alsoeen developed, and specific conditions for theiresting are defined in Table 2 of the CLSI M45-A2ocument.13 Currently, specific recommendations

for several other fastidious bacteria, including Legion-ella and Bordetella spp, do not exist, partially becauseinfections caused by these species typically respondwell to the recommended drugs of choice, they arerelatively uncommon isolates in clinical laborato-ries, and they require special complex media for re-covery in vitro, presenting unique problems in thedevelopment of AST assays.

For the most part, breakpoints for these bacteriawere predicated on interpretive criteria establishedfor other organisms as published in CLSI standardsand adapted based on published literature and theexperience of the authors of the document. This is insharp contrast to the extensive body of clinical mi-crobiologic, pharmacokinetic, and pharmacody-namic information typically used for the establish-ment of breakpoints as published in other CLSIstandards. Because of the limited testing and natureof the potential agents of bioterrorism and Helico-bacter pylori, the interpretive recommendations andtesting approaches for these organisms were re-cently transferred from the standard CLSI M100documents to the M45 guideline.13

As mentioned, in addition to standard disk and
IC methods, many species of fastidious bacteria
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may be tested by a gradient agar technique. TheEtest method permits placement of strips on mediaoptimal for the growth of the organism being testedand allows the use of various incubation conditions.A major limitation, however, to such an approach islack of approval for such testing by the FDA.When FDA clearance has not been awarded, theresults of such testing should be interpreted withcaution, and an applicable qualifying commentshould be an integral component of any resultantpatient report.

SUSCEPTIBILITY TESTING OF ANAEROBICBACTERIAThe importance of anaerobic bacteria as participantsin and causes of significant infections and the needfor specific antibiotic therapy for bacteremia andsurgical prophylaxis against anaerobes are welldocumented.14-19 As a rule, AST is considered anecessity for effective guidance of antibiotic ther-apy, but how and when susceptibility testing ofanaerobic bacteria should be performed havebeen topics of debate, in part owing to a numberof misconceptions and confounding factors.20-24

Specimens collected from infections in which anaer-obes are involved are typically polymicrobic, ren-dering isolation and identification of individual or-ganisms slow and the results of AST too delayed tohave a consistent positive effect on individual pa-tient outcomes. For clinicians, the combination ofsurgical intervention and broad-spectrum antibiot-ics has limited the correlation of potential antibac-terial resistance with outcome, directing many clin-

TABLE. Clinical and Standards Laboratory Institute PTesting of Fastidious and/or Infrequently Recovered B

Abiotrophia and Granulicatella spp (once referred to as tstreptococci)

Aeromonas spp

Bacillus spp other than Bacillus anthracis

Campylobacter coli and Campylobacter jejuni

Corynebacterium spp

Erysipelothrix rhusiopathiae

The group of bacteria previously referred to as the HAAggregatibacter aphrophilus, Cardiobacterium hominis,

Facultatively anaerobic Lactobacillus spp

Leuconostoc spp

Listeria monocytogenes

Moraxella catarrhalis

Pasteurella spp

Pediococcus spp

Plesiomonas shigelloides

ical microbiology laboratories away from the routine

Mayo Clin Proc. �

performance of anaerobic susceptibility testing.There is considerable evidence, though, that antibi-otic resistance is common among many anaerobicspecies and that patient treatment with inactiveagents results in poor clinical responses and in-creased rates of mortality.14,16,19,25,26 Results ofAST have also indicated that substantial differencesexist in resistance patterns among hospitals on a lo-cal, regional, and national basis, suggesting that onemedical center’s patterns may not be applicable tothose of other facilities.27-30 Therefore, the need fornaerobic AST is of far more importance today thann the past.

If practical, individual hospitals should estab-ish antibiograms for the more frequently recoverednaerobes on a periodic basis and test individualatient isolates as needed to assist in patient care.or purposes of presenting cumulative antimicro-ial susceptibility data, an attempt should be madeo include the results from 80 to 100 anaerobic iso-ates with recognized important resistance mecha-isms (eg, clindamycin resistance among membersf the Bacteroides fragilis group). Ideally, following

CLSI guidelines for preparation of antibiograms, 30isolates for each genus or species should be in-cluded.31 When this is not possible, an effort shoulde made to present data for 30 isolates from the B

ragilis group and at least 10 strains for other genera.ntibiotics in the report should reflect the hospital

ormulary. A recent CLSI document included an an-ibiogram for members of the B fragilis group gener-

ated from the results of testing of isolates collectedat many health care facilities across the United

hed Guidelines for Antimicrobial Susceptibilityria

ependent, pyridoxal-dependent, or nutritionally variant

organisms (Aggregatibacter actinomycetemcomitans,ella corrodens, and Kingella kingae)

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may refer to this document when prescribing em-pirical therapy for suspected or proven B fragilisgroup infections in settings in which anaerobicAST is not available.

To assist in management, anaerobic susceptibil-ity testing should be performed when (1) the selec-tion of an antibiotic to which the isolate is suscepti-ble is critical for treatment of the patient, (2) long-term therapy is under consideration, (3) anaerobesare recovered from specific, usually sterile, bodysites (eg, bone, blood, joint, or brain), or (4) treat-ment with an antimicrobial agent typically activeagainst the organism has failed.

The agar dilution susceptibility testing ap-proach, which uses Brucella blood agar as the me-dium, has been designated the reference method bythe CLSI anaerobe working group.33 Because of thetime-consuming, labor-intensive nature of thismethod, it is not generally considered practical forroutine use in most clinical microbiology laborato-ries but serves as the reference method to whichother more practical testing approaches can be com-pared. Alternative testing methods currently usedinclude BMD (only standardized for members of theB fragilis group), limited agar dilution, and gradientstrip diffusion assays, such as Etest. Disk diffusionand broth disk elution testing should not be usedbecause the results generated from such methodsdo not correlate with the CLSI reference agar di-lution method.33 Although of limited use, �-lac-tamase testing may be of value for some organismsif therapy with ampicillin or penicillin is beingconsidered.

METHODS FOR SUSCEPTIBILITY TESTINGOF NOCARDIA SPP AND OTHER AEROBICACTINOMYCETESSusceptibility testing of Nocardia spp and other aer-obic actinomycetes (Rhodococcus spp, Streptomycesspp, Gordonia spp, and Tsukamurella spp) should beperformed on clinically significant isolates. Suscep-tibility testing results serve to guide initial therapeu-tic choices and may document emergence of drugresistance. No commercially available broth sys-tems have yet been cleared by the FDA for Nocar-dia spp or other aerobic actinomycetes. The CLSIBMD is the reference method for testing.34 Rec-ommended drugs for primary testing are amika-cin, amoxicillin-clavulanate, ceftriaxone, cipro-floxacin, clarithromycin, imipenem, linezolid,minocycline, moxifloxacin, trimethoprim-sulfa-methoxazole, and tobramycin. Second-line drugsfor testing include cefepime, cefotaxime, and doxy-cycline. Vancomycin and rifampin results shouldalso be reported on isolates of Rhodococcus equi be-cause these drugs are particularly useful therapeuti-
cally. Microbiological breakpoints were established

in 2003 and are available for Nocardia spp only.34

When aerobic actinomycetes other than Nocardiaspp are tested, the susceptibility categories shouldbe listed as tentative. The breakpoints for S aureusshould be adapted as provided in the current CLSIM100 document (M100-S21) for R equi, but theyshould also be reported as tentative. Susceptibilitytesting results for most aerobic actinomycetes areavailable within 3 to 5 days, whereas results for Requi and some isolates of Tsukamurella spp may beread at 24 or 48 hours.

Challenges in the identification and AST of No-cardia spp have become apparent within the past 10years. Before the year 2000, conventional pheno-typic methods were largely used to identify Nocardiaspp; however, molecular identification is now thepreferred means of reliable identification to the spe-cies level.35 Both 16s ribosomal RNA sequencingnd matrix-assisted laser desorption/ionization-time ofight are among the techniques currently used, but

imitations exist.36 Because routine molecular test-ng is difficult to implement in many clinical micro-iology laboratories, isolates typically must be sento a reference laboratory for identification. To ad-ress this issue, Wallace et al37 proposed a series of

various susceptibility patterns that could predictplacement of Nocardia spp within particular groups,but, as new strains are identified, these groupingshave not proved to be valid, particularly for the No-cardia nova complex.

The method for susceptibility testing of Nocar-ia spp also presents a challenge to many clinicalicrobiology laboratories because BMD is some-hat impractical owing to cost, availability of sup-lies, and expertise needed to perform and interprethe results. Moreover, false resistance with BMD haseen noted for ceftriaxone when testing Nocardiarasiliensis and imipenem when testing Nocardia far-

cinica.34 In addition, sulfonamide results are incon-sistent when using BMD; for this compound, diskdiffusion testing with sulfisoxazole may be per-formed concurrently. Investigators have evaluateduse of the Etest method compared with BMD, withvarying results.38 However, both lack of agreementwith BMD and the absence of standardized methodshave restricted routine use of the Etest. The CLSI hasproposed that the agar proportion method be usedto confirm questionable results from commercialbroth systems and to test additional antibiotics orconcentrations of drugs.

The major taxonomic revisions within the last10 years have further complicated testing becauseclinical and epidemiological differences existamong species. Furthermore, resistance to trim-ethoprim-sulfamethoxazole and other antimicro-
bials is increasing among various species; thus,
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identification of isolates to the species level re-mains imperative.39

METHODS FOR SUSCEPTIBILITY TESTINGOF MYCOBACTERIAAccording to the most recent Centers for DiseaseControl and Prevention mycobacterial suscepti-bility testing guidelines, initial isolates from pa-tients with tuberculosis should be tested for sus-ceptibility to isoniazid, rifampin, ethambutol, andpyrazinamide.40 This guidance overrides the priorpractice of performing susceptibility testing for only3 drugs (isoniazid, rifampin, and ethambutol) andthen only when a pulmonary or infectious diseaseclinician requested it. Current guidelines also statethat susceptibility testing should be repeated after 3months if the patient remains culture-positive de-spite appropriate therapy. However, susceptibilitytesting may be performed earlier if the patient ap-pears to be failing to respond to therapy or if in-tolerance to the drug regimen is evident. First-linesusceptibility test results should be available forisolates of the Mycobacterium tuberculosis complexwithin 15 to 30 days of original receipt of thespecimen in the laboratory.41 However, ideally,susceptibility results should be available within 7to 14 days of specimen receipt.34 If resistance toany of the 4 initially tested agents is discovered,testing of secondary drugs should be performedas soon as possible. If the isolate is resistant onlyto pyrazinamide, Mycobacterium bovis should beruled out because most M tuberculosis isolates aresusceptible to pyrazinamide. Further specificguidelines regarding secondary drug testing andfollow-up are outlined in CLSI M24-A2.34

The agar proportion approach has traditionallybeen considered the standard method for antimyco-bacterial susceptibility testing, but as an agar-basedsystem, the time to result reporting is lengthy (ap-proximately 3 weeks).42 Both the agar proportionmethod and the radiometric method define resis-tance as growth of more than 1% of the inoculum ofbacterial cells in the presence of an antituberculardrug. The antitubercular drugs are inoculated atspecific in vitro concentrations, the values ofwhich correlate to clinical responsiveness. If morethan 1% of the bacterial population grows in thepresence of a drug, that particular drug will not beof therapeutic utility.42 The agar proportionmethod is used primarily to confirm results fromcommercial liquid broth systems and to test addi-tional drugs that may not be available for testingusing other systems. The FDA-cleared broth sys-tems for M tuberculosis testing have shorter incu-bation times than the agar proportion method;however, these commercial testing systems are
only cleared for certain drugs.43 a
Mayo Clin Proc. �

There are several molecular assays that haveeen developed for the detection of mutations asso-iated with drug resistance in M tuberculosis, includ-ng both real-time polymerase chain reaction (PCR)

ethods and line probe assays.44 Molecular-basedethods for detection of M tuberculosis drug resis-

ance are more rapid than traditional methods ofusceptibility testing. Mutations associated with re-istance to isoniazid or rifampin are typically de-ected by such methods. These tests may be runsing growth from positive cultures but may also beerformed directly on acid-fast smear-positive spec-

mens if the patient is highly suspected of havingrug-resistant tuberculosis. It is currently suggestedhat molecular testing of drug susceptibility beacked up by culture, with performance of pheno-ypic culture-based drug susceptibility testing whenhe isolate is retrieved from culture.34

Susceptibility testing of nontuberculous myco-acteria (NTM) should be performed on isolatesonsidered clinically significant. The American Tho-acic Society criteria for clinical significance of NTMre positive cultures from at least 2 sputum speci-ens or 1 bronchial wash or bronchial lavage spec-

men. Alternatively, a transbronchial or lung biopsyith histopathologic findings consistent with myco-acteria and positive on culture for NTM is suffi-ient to be interpreted as clinically significant. Inddition, NTM isolates from usually sterile bodyites, such as cerebrospinal fluid, are consideredlinically significant. However, routine susceptibil-ty testing need not be performed on Mycobacteriumarinum because acquired resistance is uncommonith this organism.34 Initial susceptibility testing of

Mycobacterium kansasii to isoniazid, rifampin, andethambutol need not be performed but can be of-fered if treatment has failed.

The standard susceptibility testing method forNTM is BMD. The American Thoracic Society andCLSI guidelines exist for susceptibility testing ofmembers of the Mycobacterium avium complex, Mkansasii, M marinum, and the rapidly growing my-cobacteria.34 However, accurate susceptibility predic-tions for other slowly growing mycobacteria cannot bemade. The macrolides are the only antimicrobial agentsthat should be tested against M avium complex be-cause they are the only agents for which correlationshave been demonstrated between in vitro suscepti-bility tests and clinical response.45 Because the mu-ation leading to resistance is the same for clarithro-ycin and azithromycin, only 1 drug need be

ested. Generally, clarithromycin is tested becausezithromycin demonstrates poor solubility. If thesolate is macrolide resistant, testing for susceptibil-ty to the secondary agents moxifloxacin and lin-zolid may be considered. Susceptibility testing of M
vium complex may also be performed if the patient

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relapsed while undergoing macrolide therapy. Inaddition, susceptibility testing should be repeatedafter 3 months of therapy for patients with dissem-inated M avium complex disease and after 6months of therapy for patients with chronic pul-monary disease caused by M avium complex.Commercially available broth systems have notyet been cleared by the FDA for slowly growingNTM.

PHENOTYPIC AND GENOTYPIC METHODS FORDETECTION OF ANTIMICROBIAL RESISTANCEA number of phenotypic tests are available to theclinical microbiology laboratory to characterize apathogen’s susceptibility to an antibiotic by screen-ing for a specific resistance mechanism or pheno-type. Although such screening tests do not result indetermination of an MIC, some have sufficient spec-ificity and sensitivity that confirmatory testing is notrequired and the screening test result can be re-ported without further testing. Other assays requireadditional or confirmatory testing. For example, testsfor inducible clindamycin resistance among staphylo-cocci and screening tests for high-level gentamicinand streptomycin resistance in enterococci are gen-erally considered to be comparable to standardmethods for the detection of clinically significantresistance, and they do not require confirmatorytesting. By comparison, laboratories that use ertap-enem resistance as a surrogate marker for carbapen-emase production among certain species of Entero-bacteriaceae must confirm resistance to meropenem,imipenem, or doripenem by another more standard-ized approach because ertapenem-resistant strains arenot always resistant to these other agents.

In addition, methods for the direct detection ofantibiotic-resistant bacteria in clinical samples haveprogressed rapidly in recent years, largely because ofthe continued evolution and spread of multidrug-resistant pathogens, such as methicillin-resistant Saureus (MRSA). The development of commercial as-says that facilitate rapid detection of such pathogensdirectly from clinical specimens, often generatingresults in a few hours or less, has positively en-hanced surveillance efforts and patient manage-ment. Other genotypic assays for detection of spe-cific antimicrobial resistance genes in gram-negativebacteria (eg, blaKPC-containing Klebsiella pneu-moniae) have the potential to improve therapeuticpatient decisions and assist in epidemiological in-vestigations of resistance gene dissemination in thehospital and community setting.

�-LACTAMASE TESTSA positive �-lactamase test result indicates that the
organism is resistant to applicable �-lactam agents,

ut a negative reaction is inconclusive because otherechanisms of resistance to the �-lactams may ex-

st. For example, a positive �-lactamase test resultfor a strain of N gonorrhoeae means that the isolate isresistant to penicillin, ampicillin, and amoxicillinand that these drugs would not be appropriate ther-apeutic choices. However, a �-lactamase test onlydetects one form of penicillin resistance in N gonor-rhoeae. Strains with chromosomally mediated resis-tance with penicillin-binding protein modificationscan only be detected by the disk diffusion or the agardilution MIC method.46,47

Three direct �-lactamase tests—the acidomet-ic, iodometric, and chromogenic methods—haveeen widely used. All 3 methods involve the testingf isolates grown on nonselective media, and resultsre typically available within 1 to 60 minutes. Al-hough some bacteria (eg, N gonorrhoeae and H in-

fluenzae) produce �-lactamase constitutively, oth-ers (eg, staphylococci) may produce detectablelevels of enzyme only after exposure to an induc-ing agent, typically a �-lactam.48 Even after induc-tion, though, direct �-lactamase tests may not beufficiently sensitive to detect �-lactamase produc-ion in all staphylococci.49 Therefore, for serious in-ections that require penicillin therapy, clinical mi-robiology laboratories should perform both MICnd induced �-lactamase tests on all subsequent iso-

lates from the same patient. In addition, PCR testingof the isolate for the presence of the blaZ �-lacta-

ase gene may also be an option.

ETECTION OF METHICILLIN RESISTANCEN STAPHYLOCOCCUS SPPThe most common currently used method for thedetection of MRSA is culture.50 Traditional MRSAdetection methods consist of culture from a selectiveliquid or solid medium. Recently, chromogenicagars have shown improved sensitivity and specific-ity over nonchromogenic media for detection ofMRSA.51 Chromogenic agars contain selective anti-biotic(s) and various chromogenic substrates, whichprovide easy visual identification of colonies. An ad-ditional advantage of chromogenic agar is the fastertime to detection of the organism. MRSA is oftendetected within 20 to 48 hours on chromogenic me-dia, with a high percentage of cases identified within24 hours.52 Several chromogenic media are avail-ble from different manufacturers.

The use of an overnight preenrichment stepith selective broth medium before inoculation of

he agar has been shown to increase sensitivity of theesting by 15% to 30%.53 However, the delay in

detection of an additional 18 to 24 hours and thecost of the selective broth medium represent
disadvantages.
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Early diagnosis of MRSA in the laboratory is cru-cial in guiding appropriate antimicrobial therapy.Rapid molecular methods of MRSA detection areincreasingly used and are available for testing from avariety of sources.54 Traditional detection of MRSAfrom automated blood culture instruments is time-consuming because 24 to 72 hours are required forsubculture, biochemical identification, and AST ofthe isolate once the result turns positive. Severaltechniques are available for identification of MRSAdirectly from blood culture bottles that have flaggedas positive for growth when gram-positive cocci inclusters are seen on Gram stain.55 Several commer-cial molecular methods are available, including nu-cleic acid amplification and hybridization assays.51

A commercial penicillin-binding protein 2a latex ag-glutination kit, which facilitates the detection ofthe protein product expressed by the mecA gene,is available for detection of MRSA directly fromblood culture.56 Other systems are currently un-der investigation.50

HIGH-LEVEL AMINOGLYCOSIDE RESISTANCEIN ENTEROCOCCISuccessful treatment of enterococcal endocarditisand other serious enterococcal infections requiresthe use of an aminoglycoside with a cell wall–activeagent, such as ampicillin, penicillin, or vancomycin.All enterococci demonstrate innate low-level resis-tance to aminoglycosides because of their facultativeanaerobic metabolism, which reduces transmem-brane potential, thereby limiting drug uptake. How-ever, the bactericidal combination of an aminogly-coside and a cell wall–active antimicrobial, whichallows for markedly enhanced uptake of the amino-glycoside, leads to enhanced killing of the organismin the absence of high-level aminoglycoside resis-tance (HLAR).

The CLSI recommends HLAR screening of en-terococci with both gentamicin and streptomycinfrom blood cultures or other specimens submittedfor the evaluation of endocarditis, such as heartvalve tissue. The BMD may be performed by assess-ing growth of the organism in the presence of 1000�g/mL of streptomycin or 500 �g/mL of gentamicinin brain heart infusion broth.5 The recommendedscreening concentrations for streptomycin andgentamicin using other methods are also cov-ered.57 Performance data of commercially avail-able media and systems for HLAR screening havebeen reviewed.58

In enterococci, HLAR is mediated by aminogly-coside-modifying enzymes (AMEs), which modifythe aminoglycoside by acetylation, adenylation, orphosphorylation. The most prevalent AME geneamong enterococci with HLAR to gentamicin is
aac(6’)-Ie-aph(2”)-Ia, which has both acetyltrans- v
Mayo Clin Proc. �

ferase and phosphotransferase activity.59 This com-on AME confers resistance to all available amino-

lycosides, except streptomycin. Commonly, HLARo streptomycin is mediated by either ant(6’)-Ia ornt(3’’)-Ia; in such cases, streptomycin should not besed in combination with a �-lactam agent. Detec-ion of HLAR to both gentamicin and streptomycinrecludes the use of aminoglycosides for synergism

n any clinical situation.Enterococcus faecium possesses a naturally oc-

urring AME, resulting in moderate resistance to to-ramycin (MICs, 64-1000 �g/mL). The presence of

the aac(6’)-Ii gene precludes synergistic treatmentith tobramycin, kanamycin, netilmicin, or sisomi-

in. In addition, many enterococci possess theph(3’)-IIIa gene, which confers high-level resis-ance to kanamycin and abolishes any synergisticffect with amikacin. Thus, gentamicin and strepto-ycin are the only 2 aminoglycosides to test and

onsider for synergistic therapy. Novel genes carry-ng AMEs mediating resistance to gentamicin, suchs aph(2’’)-Ib, aph(2’’)-Ic, aph(2’’)-Id, and aph(2’’)-Ie,ave been discovered and may further complicateLAR testing because the susceptibilities to various

minoglycosides differ.60 Because of the large num-bers of AME-encoding genes, molecular HLARscreening in enterococci remains investigational andhas not yet been widely available in clinical micro-biology laboratories.61

Issues that continue to challenge HLAR screen-ng in enterococci include the isolation of multipleMEs within single enterococcal isolates, isolates

hat harbor infrequent AMEs but do not demon-trate the HLAR phenotype, and the increasing prev-lence of various HLAR enzymes in enterococci.

ETECTION OF VANCOMYCIN-RESISTANTNTEROCOCCIhe vancomycin-resistant enterococci (VRE) are im-ortant opportunistic pathogens in many healthare facilities and common colonizers of the gastro-ntestinal tract. The VRE are among the most com-

on causes of hospital-acquired infections in thenited States, and patients colonized with VRE in

he gastrointestinal tract may serve as reservoirs forosocomial transmission.62,63

Two common patterns of enterococcal resis-ance exist, both of which result in elevated vanco-ycin MICs. The first, and most clinically impor-

ant, is vancomycin resistance due to acquisition ofenetic information, usually on a plasmid or otherransmissible genetic element.64 This acquired traits most commonly observed in strains of E faeciumnd Enterococcus faecalis harboring the vanA or vanBenes that encode for high-level vancomycin resis-ance. Expression of the vanA gene results in ele-
ated vancomycin MICs (�128 �g/mL) and is the

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dominant resistance factor in enterococci. By com-parison, expression of the vanB gene results in lowervancomycin MICs, typically in the range of 16 to 64�g/mL. The second pattern of resistance, intrinsic(inherent) in nature, is characteristically seen in En-terococcus gallinarum and Enterococcus casseliflavus.Most frequently encoded by vanC, this pattern ofresistance may also be due to the expression of genesother than vanC (eg, vanE, vanG, and vanL) and re-sults in either low-level resistant or intermediateMICs, typically in the 2- to 16-�g/mL range.65 Con-tact precautions are generally only required for pa-tients harboring enterococci with acquired resis-tance, such as E faecium or E faecalis. Guidelines forsusceptibility testing of enterococcal pathogenswhen grown in culture from blood or other siteshave remained fairly standard over time. How-ever, there have been several recent advances inboth culture-based and molecular-based screen-ing of stool for VRE, facilitating identification ofpatients who are potential reservoirs for infectionand transmission.

The CLSI guidelines for vancomycin suscepti-bility testing of enterococci isolated from varioussites suggest the use of standard BMD or disk diffu-sion testing.5 If disk diffusion or Etest is performed,the susceptibility plates must be held for a total of 24hours to obtain accurate readings. Organisms forwhich vancomycin MICs are in the range of 8 to 16�g/mL should be further identified by biochemicaltesting because infection control precautions willdiffer based on identification of the organism as anEnterococcus sp other than E faecalis or E faecium.Accordingly, isolates with intermediate zones ondisk testing should be tested by an MIC methodand/or further identified by biochemical and otheridentification tests to guide appropriate infectioncontrol practices.

A variety of culture-based and molecularmethods have been studied to support active sur-veillance efforts to identify VRE from the gastroin-testinal tract.66,67 Although culture-based methods arenot as rapid as molecular-based screening methods,isolates obtained from culture can be stored for fur-ther study or identification. Molecular-based VREscreening methods decrease the time to identifica-tion but are costly. Culture remains the screeningmethod of choice for VRE stool screening, but mo-lecular methods are becoming increasingly recog-nized and used. Some investigators advocate theuse of a broth enrichment step before inoculationof a culture plate or a molecular assay to increasesensitivity.66

Traditional screening agars for VRE from stoolspecimens include Campylobacter medium with 5antibiotics, including 10 �g/mL of vancomycin, and
various types of bile esculin azide agar with vanco- o

mycin.68,69 The traditional VRE screening agars re-uire 24 to 48 hours to identify colonies preliminar-

ly, with additional time required for confirmatorydentification and susceptibility testing and up to 5ays to final identification. Various chromogenicRE media demonstrate adequate sensitivity andpecificity, with reduced turnaround time to resultshrough early visual colony identification. There areany selective and differential chromogenic VRE

gars that appear promising for use in VRE stoolcreening. However, performance data vary accord-ng to whether prior overnight broth enrichment ofhe specimen in liquid media was performed.67

Real-time PCR is a sensitive and rapid approacho the identification of VRE from gastrointestinalract specimens.66 Recently, the BD GeneOhm VanR

(BD Diagnostics, Spark, MD) and Xpert vanA/vanB(Cepheid, Sunnydale, CA) assays, which detect iso-lates carrying vanA and vanB genes within 2 to 4

ours, have been introduced.70 Most FDA-clearedssays have been marketed for direct detection ofRE from rectal or perianal swabs, although detec-

ion from stool specimens has shown comparableesults. Some studies have demonstrated improvederformance of molecular assays after overnight aer-bic or anaerobic preenrichment of stool in brothedia; however, the preenrichment step increases

he turnaround time to results.70 Occasionally,ower specificity has been shown with the use oferianal sampling due to the presence of anaerobeshat carry the vanB gene.69

In summary, there are a variety of VRE screen-ng methods available, the most promising of whichppear to be chromogenic media and molecular as-ays, due to rapid result reporting. However, somessays require an overnight preenrichment step toaximize sensitivity.

LINDAMYCIN RESISTANCE IN STREPTOCOCCIND STAPHYLOCOCCIlindamycin and erythromycin resistance in strep-

ococci may either be due to erm genes, which leado the production of macrolide ribosomal methyl-ses, or to expression of the mef gene, which encodesn efflux pump targeting only the macrolides. Byomparison, erm enzymes methylate the 23S ribo-omal RNA component of the 50S bacterial ribo-omal subunit, which causes decreased binding ofacrolides, lincosamides (clindamycin), and strep-

ogramin B antibiotics (designated the MLSB pheno-ype). In staphylococci, inducible clindamycin resis-ance is also due to the MLSB phenotype, but itsfflux pump is encoded by the msrA gene.

The MLS resistance phenotype can be either in-uced or constitutively expressed. Inducible clinda-ycin resistance cannot be detected by routine MIC

r disk testing of clindamycin.71 Therefore, the 14-

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and 15-member macrolides, which are better induc-ers of clindamycin resistance than is clindamycinitself, must be used for induction of clindamycin inthe clinical laboratory.72 Testing of streptococci andstaphylococci for inducible clindamycin resistanceis important because clindamycin is frequently usedto treat staphylococcal, group B streptococcal, andgroup A streptococcal infections. In addition, resis-tance to clindamycin is increasing in prevalence,with a recent estimate of 12.8% inducible clindamy-cin resistance among S aureus in the United States.73

Both inducible and constitutive clindamycin resis-tance has likewise become increasingly commonamong �-hemolytic streptococci, with less resis-tance reported for group A streptococcal than forgroup B streptococcal infections.74

The CLSI has recommended 2 different meth-ods for detection of inducible clindamycin resis-tance in staphylococci and �-hemolytic strepto-cocci.5 One method is the disk approximation test,also known as the D-zone test. With this approach,separate erythromycin and clindamycin disks areplaced specific distances apart on an agar plate, de-pending on whether staphylococci or streptococciare being tested. If there is flattening of the zone ofinhibition between the 2 disks and the zone resem-bles the letter “D,” the test result is interpreted aspositive for induction of clindamycin resistance.The second method suggested by the CLSI is the useof a single-well microdilution test containing botherythromycin and clindamycin. Whenever induc-ible MLSB resistance is detected, clindamycin treat-ment should be avoided, if possible. However, theCLSI states in their guidelines that clindamycin maystill be clinically effective in some patients, despite apositive induction test result.

Automated methods for identification of induc-ible clindamycin resistance have also recently beenintroduced.75 Molecular assays using primers forvarious erm genes have been used in various re-search settings for the purpose of following resis-tance trends or validating BMD assays.71 However,PCR assays for inducible clindamycin resistance arenot currently considered the standard of care in theclinical microbiology laboratory.

Constitutive or inducible resistance to clinda-mycin may also be seen in S pneumoniae due to ex-pression of a ribosomal methylase encoded by theermB gene. The methylase alters the binding site onthe ribosomes for the macrolides and clindamycin,similar to that seen for �-hemolytic streptococci andstaphylococci.76 Clindamycin is recommended as asecond- or third-line antibiotic choice for pediatricpatients receiving long-term antibiotic therapy forsome conditions, such as pneumococcal osteomy-elitis and/or joint infections.77 Because pneumo-
cocci are capable of expressing inducible clindamy-
Mayo Clin Proc. �

cin resistance, some authors suggest that isolatesof S pneumoniae be tested for erm-mediated resis-ance in certain clinical situations involving pedi-tric patients. Jorgensen et al77 recently assessederformance of the CLSI-suggested disk and BMDethods for detection of inducible clindamycin

esistance in pneumococci.

ETECTION OF EXTENDED-SPECTRUM�-LACTAMASE PRODUCTION AMONG

NTEROBACTERIACEAEembers of Enterobacteriaceae (and other organ-

sms, including P aeruginosa) can produce �-lacta-ases, referred to as extended-spectrum �-lactam-

ses (ESBLs), capable of hydrolyzing penicillins, theonobactam aztreonam, and cephalosporins (in-

luding expanded-spectrum cephalosporins, suchs cefotaxime, ceftriaxone, ceftizoxime, and ceftazi-ime).78 The CLSI guidelines specify screening cri-

teria and confirmatory testing approaches for detec-tion of ESBL production by Escherichia coli, Kpneumoniae, and Proteus mirabilis.5 For organismssuch as Enterobacter spp and Serratia spp, whichproduce AmpC-type enzymes, ESBL screeningshould not be performed because false-negative re-sults can occur. These screening and confirmatorytests were necessary because standard disk diffusionand MIC tests did not uniformly identify isolatesproducing ESBLs. Because ESBLs are usually inhib-ited by clavulanic acid, the CLSI made use of thisproperty in developing the tests recommended toclinical laboratories for their detection and recom-mending that isolates producing ESBLs be reportedas resistant to all penicillins, cephalosporins, andaztreonam. On establishment of new, lower inter-pretive criteria for many of these compounds,largely based on pharmacokinetic and pharmacody-namic principles and limited clinical data, the CLSIrevised their recommendations for reporting.5

When the new breakpoints are adopted by clinicallaboratories, the CLSI recommends that results forspecific cephalosporins and aztreonam be reportedand interpreted as they are tested and that the ESBLscreening and confirmatory tests need only be per-formed for epidemiological and infection controlpurposes. By comparison, although the EuropeanCommittee on Antimicrobial Susceptibility Testing(EUCAST) breakpoints for the cephalosporins aresimilar to those now recommended by the CLSI,EUCAST recommends that laboratories continue toscreen and confirm ESBL production due to the lim-ited supporting clinical data and that cephalosporinreports be changed from susceptible to intermediateor intermediate to resistant if an isolate tests positive
for ESBL production.79

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DETECTION OF CARBAPENEMASE ACTIVITYAMONG ENTEROBACTERIACEAECarbapenemases, enzymes that hydrolyze carba-penem class antibiotics (ertapenem, imipenem,meropenem, and doripenem), usually hydrolyzeall other currently available �-lactams, with theexception of aztreonam for some metallo-�-lactamases. The genome encoding for the produc-tion of these enzymes may be located on plasmids(eg, K pneumoniae carbapenemases), a feature thatmakes them of particular concern from an infec-tion control perspective. There are 3 classes ofcarbapenemases: serine class A (including KPC,SME, IMI, GES, and NMC), class B enzymesknown as the metallo-�-lactamases (such as VIM,IMP, and NDM), and the class D OXA enzymes.80

Carbapenemases have been identified in a widerange of gram-negative genera. The KPC enzyme,the most frequently identified class A carbapen-emase in the United States, is most often found inthe Enterobacteriaceae but has also been detectedin P aeruginosa.81 Metallo-�-lactamases are mostfrequently seen in Acinetobacter spp and P aerugi-nosa, but recently NDM has become widespreadin some regions of the world among species ofEnterobacteriaceae, particularly K pneumoniae.OXA carbapenemases are most frequently foundin Acinetobacter spp but have also been reportedamong isolates of Enterobacteriaceae.

In 2009 the CLSI Subcommittee on Antimi-crobial Susceptibility Testing (SAST) recom-mended the modified Hodge test for the detectionof carbapenemase activity in Enterobactericeae.82

Advantages of this assay include its ease of perfor-mance, the ability to test several isolates on a sin-gle plate, and the detection of different classes ofcarbapenemases with one test.83,84 The primarydisadvantages are subjectivity in reading the re-sults, its inability to differentiate the various car-bapenemases (potentially useful from an epidemi-ological perspective), and the false-positiveresults that can occur with some organisms pro-ducing AmpC or ESBL enzymes.

The modified Hodge test was originally rec-ommended for the detection of carbapenemasesin bacteria for which carbapenem MICs were ele-vated but still fell within the susceptible range.When isolates tested positive, the SAST recom-mended that they be designated carbapenemase-producing strains in the patient report with awarning indicating that the therapeutic outcomesof patients infected with such organisms andtreated with the relevant carbapenem were un-known, particularly when alternative dosing reg-imens were used (eg, continuous or prolongedinfusion). In 2010, though, the SAST lowered the
carbapenem breakpoints to capture most carba- r

enemase-producing strains, which would nowest either as resistant or intermediate to theseompounds.5 Implementation of the revised break-

points eliminates the need for laboratories to rou-tinely perform the modified Hodge test, althoughsuch testing may in some cases still be of value froman epidemiological or infection control perspective.A number of phenotypic tests allow detection anddifferentiation of class A (eg, inhibition by boronicacid) and class C (eg, inhibition by chelating agentssuch as ethylenediaminetetraacetic acid) carbapen-emases, but these tests fail to detect class D (OXA)and are primarily used for strain characterizationrather than for clinical purposes.

DETECTION OF PLASMID-MEDIATEDAMPC-TYPE �-LACTAMASES

hromosomally mediated, inducible, AmpC-type�-lactamases are produced by several gram-negativepecies. Often referred to as the ASPACE or ASPICErganisms, these include, but are not restricted to,eromonas spp, Serratia spp, P aeruginosa, Acineto-acter spp indole-positive Proteae (Providencia spp,organella morganii, and Proteus vulgaris), Citrobac-

er spp, and Enterobacter spp.85 Resistant to the cur-rently available �-lactamase inhibitors, such astazobactam, sulbactam, and clavulanic acid, these en-zymes result in resistance to a wide range of �-lactamantibiotics. The combination of a porin deletion withan AmpC-type enzyme can result in resistance to car-bapenems. The genome encoding AmpC-type �-lacta-

ases may also be harbored on transmissible plasmidsnd has been reported among a number of species thato not naturally produce inducible chromosomallyediated AmpC-type enzymes, including K pneu-oniae, E coli, P mirabilis, and Salmonella spp.86 Similar

to the plasmids carrying the genes encoding ESBLs,those with AmpC-type genes often harbor resistancedeterminants for multiple classes of drugs.

Because detection of plasmid-mediated AmpC-producing pathogens may have epidemiological andinfection control importance, several assays havebeen developed in an attempt to accurately detectthis resistance type.87-94 None, however, has beenufficiently standardized or tested against an ade-uate number of organisms producing plasmid-me-iated AmpC-type enzymes to be considered supe-ior in performance to the other assays.

ESTING TO DETECT BACTERICIDAL ACTIVITYhe AST methods used in the clinical microbiology

aboratory typically assess only the inhibitory activ-ties of antimicrobial agents. This is generally suffi-ient for patient management for most bacterial in-ections encountered by clinicians. In some, albeit
are, situations it may also be of value to determine
p.2012.01.007 301

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the bactericidal activity of an antibiotic against aspecific patient bacterial pathogen. Serious infec-tions in which a bactericidal effect is generally con-sidered necessary for optimal treatment include bac-teremia in neutropenic patients, patients withchronic osteomyelitis, and patients with bacterialendocarditis.95-97

Minimum Bactericidal Concentration TestingAfter determination of MICs in a broth system understandard conditions, measured aliquots of growthmedia may be subcultured quantitatively to solidmedia to assess bactericidal activity. To calculate theextent of killing at each antibiotic concentration,plates are incubated under appropriate conditions,colony counts are performed, and results are com-pared to that of the growth control tube or well. Theaccepted definition of the minimum bactericidalconcentration (MBC) is the lowest concentration ofantibiotic at which a 99.9% (3 log) or greater reduc-tion in growth compared with the initial inoculum isobserved.98 As with the MIC, the antibiotic MBC isreported in micrograms per milliliter or in some re-gions of the world in milligrams per liter. Determi-nation of the MBC allows one to detect potentialtolerance by the patient’s specific isolate to an anti-biotic usually considered bactericidal, a phenome-non reportedly leading to clinical failure amongsome patients.99-101 Tolerance occurs when the an-tibiotic MIC for an organism is low (within the sus-ceptible range) but the MBC is elevated, frequentlyat a concentration beyond that generally consideredclinically achievable from a pharmacokinetic per-spective. Tolerance is specifically defined as an MBC32-fold or more higher than the MIC for the antibi-otic under consideration.98,100 Failure to demon-strate at least a 3-log10 decrease in colony-formingunits per milliliter in the time-kill assay is also con-sidered to represent tolerance.98

Time-Kill Kinetic AssaysTime-kill assays allow one to assess the rate of bac-tericidal activity at varying antibiotic concentrationsover time. Although these assays are time-consum-ing and laborious to perform because they requiresubculture of media at specific times during a 24-hour period, results of combinations of antimicro-bial agents can also be assessed. In 1999, standardmethods for performance of the assay were pub-lished by the CLSI (previously the National Com-mittee for Clinical Laboratory Standards).98 Resultsof time-kill assays are typically presented graphi-cally, plotting colony counts for each antimicrobialagent and concentration tested at each time point atwhich subcultures were performed (usually at 0, 4,
8, 12, and 24 hours). As with the MBC, bactericidal
Mayo Clin Proc. �

ctivity is defined as a 99.9% or greater killing at apecified time. When antibiotics are tested in com-ination using the time-kill approach, synergy isypically defined as a 2-log decrease or more in theumber of colony-forming units achieved with theombination of antibiotics when compared withhat achieved by the most active agent tested alone.

ESTS FOR ASSESSMENT OF INTERACTIONSMONG ANTIMICROBIAL AGENTShe value of in vitro testing to assess antibiotic in-

eractions (ie, synergy testing) remains highly con-roversial. With a few bacterial species and antibi-tic combinations, synergistic bactericidal activity isctually predictable and need not be routinely de-ermined (eg, ampicillin, penicillin, or a glycopep-ide plus gentamicin or streptomycin against sus-eptible strains of enterococci). When synergyesting is performed, the results should be inter-reted with caution because they do not take intoccount drug interactions from a pharmacokineticr a patient safety (adverse effect) perspective.

The checkerboard BMD test, wherein 2 antimi-robial agents are serially diluted in a 2-dimensionalashion to include all combinations during a speci-ed clinically relevant range, is a somewhat less la-or-intensive approach to assessing antibiotic inter-ctions in vitro than the time-kill assay. This samepproach to drug interaction testing can be takensing an agar dilution approach, although theethod is even more laborious. Using these meth-

ds, one is able to recognize synergistic, additive,ndifferent, or antagonistic interactions occurringith the agents being tested. By this method, a frac-

ional inhibitory concentration (�FIC) is calculatedy comparing the MIC of each drug alone to the MICf that drug in combination with the second agent.ynergy is usually defined as a 4-fold decrease in theIC of the agents in combination when comparedith the antibiotics tested alone.102 The FIC is cal-

culated and interpreted as follows:

�FIC � FIC of agent A � FIC of agent B

FIC of agent A �MIC of agent A in combination

MIC of agent A alone

FIC of agent B �MIC of agent B in combination

MIC of agent B alone

Synergy is defined as �FIC � 0.5

Indifference is defined as 0.5 � �FIC � 4

Antagonism is defined as �FIC � 4

Some investigators consider compounds additive
when �0.5 �FIC �1.

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The time-kill approach appears to correlate moreclosely with in vivo studies of combined antibiotic ef-fects than does the checkerboard method.103,104 Asimpler approach, albeit less standardized, is the use ofEtest strips. Using this method, synergy is again de-fined by the FIC as described earlier.105

SERUM BACTERICIDAL TESTING (SCHLICHTERASSAYS)Another approach to assessing bactericidal activityand determining the effects of antibiotic combina-tions is serum bactericidal testing. Determinationsof serum inhibitory titers and serum bactericidal ti-ters (SBTs) are performed in a manner analogous tothat for MIC and MBC testing, except that thepatient’s serum, rather than serially diluted concen-trations of antibiotic, is used. A guideline outliningthe specifics for performance of SBT testing has beenpublished by the CLSI.106 To perform the testing, 1or more blood samples are collected from the pa-tient (usually attempting to draw the specimenswhen antibiotic peak and trough levels areachieved). Serial 2-fold dilutions of the patient se-rum in pooled, pretested human serum are then pre-pared in tubes or wells of microtiter plates. Eachtube or well is then inoculated with a standardizedsuspension of the patient’s infecting pathogen in anapplicable growth medium. The serum inhibitorytiter is defined as the highest dilution of the patient’sserum preventing visible growth after an appropri-ate incubation period. Similar to MBC testing, quan-titative subcultures are then performed from eachdilution of the patient’s serum that prevented visiblegrowth. The SBT is defined as that dilution resultingin a 99.9% or greater decrease in the original inoc-ulum based on standardized rejection value tables.Results are then reported as titers (dilutions) of thepatient’s serum. The purpose of this assay is to de-termine whether the dosage regimen chosen fortreatment of the infection results in sufficient bacte-ricidal activity in the patient’s blood.96,107 Higherserum titers suggest that adequate patient dosinghas been achieved, unexpected antibiotic elimina-tion has not occurred, and the bacterial pathogen isnot tolerant. A peak SBT of 1:64 or higher and atrough SBT of 1:32 or higher have been shown tocorrelate with rapid bacterial eradication from theblood and optimal time to cardiac vegetation steril-ization in cases of endocarditis.96,108 Lower bacteri-cidal titers, however, do not necessarily predict apoor clinical response. Limited data have indicatedthat in cases of acute and chronic osteomyelitis apeak SBT of 1:16 or higher and a trough SBT of 1:4or higher are predictive of therapeutic efficacy.96,109

Major disadvantages of this assay include its labor-
intensive nature and the requirement to obtain, pre- p

pare, and pretest pooled human serum for use in theprocedure.

ANTIFUNGAL SUSCEPTIBILITY TESTINGThere have been major advances in the standardiza-tion and clinical interpretation of antifungal suscep-tibility testing in recent years. The number of anti-fungal agents is increasing as the incidence ofsystemic and other infections due to Candida spp,Aspergillus spp, Zygomycetes, and other filamentousfungi is increasing.110 Susceptibility testing of clin-ically significant isolates, especially those from usu-ally sterile sites, is important both epidemiologicallyand clinically for guiding treatment. Antifungal sus-ceptibility testing standards for yeasts and moldshave been developed by both the CLSI and Euro-pean Committee on Antimicrobial SusceptibilityTesting (EUCAST) for a variety of antifungalagents.111-115

The standard antifungal reference testing methodgainst which many other susceptibility testing meth-ds are measured is the BMD method.112 The BMDethods proposed by different organizations vary

y the media used, supplements and inoculumdded, incubation conditions, and end point inter-retations. The CLSI provides MIC breakpoint and

nterpretive data for Candida spp for several antifun-gal agents, including fluconazole, itraconazole, vori-conazole, anidulafungin, caspofungin, micafungin,and flucytosine.111 The CLSI breakpoints for flu-onazole, voriconazole, and the echinocandins haveecently been revised for Candida species.116-118

The susceptible dose-dependent category for theazoles infers that susceptibility to these antifungalsby Candida spp is dependent on achieving the max-imal possible blood level. In addition, the flucona-zole data for the CLSI breakpoints were gatheredfrom studies involving patients with oropharyngealcandidiasis and invasive candidal infections in non-neutropenic patients. Therefore, the clinical rele-vance of fluconazole breakpoints in clinical situa-tions other than those mentioned has not beenestablished. Interpretive data for the echinocandinclass of drugs are based primarily on experiencewith nonneutropenic patients with candidemia, andclinical relevance of these data in other patient pop-ulations is uncertain. Finally, itraconazole data arebased on experience with mucosal infections only,and data supporting the CLSI breakpoints for inva-sive infections are not available. Although there areno CLSI breakpoints currently approved for ampho-tericin B when testing Candida spp, isolates forwhich the MICs are greater than 1.0 �g/mL are gen-rally considered resistant.111 Although the CLSI

documents only provide guidelines for Candida spp,ome investigators have applied the CLSI break-
oints to Cryptococcus spp, and correlations have
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been demonstrated between higher MICs and treat-ment failures.119

Because the BMD testing method is difficult toperform in daily practice in clinical microbiologylaboratories, other testing approaches have been in-vestigated. Disk diffusion antifungal susceptibilitytesting is a simple and cost-effective method for bothyeasts and molds. Fluconazole disk diffusion testingof Candida spp has been available for several years.The CLSI has also established guidelines for diskdiffusion testing of filamentous fungi, which is arelatively simple, rapid, and cost-effective alterna-tive to BMD testing.115 Etests are likewise less laborintensive than BMD and are relatively simple andreproducible for the testing of antifungal agents, es-pecially against molds.120 Sensititre YeastOne (TrekDiagnostic Systems) is a colorimetric antifungal sus-ceptibility testing MIC plate that exhibits high agree-ment with the CLSI BMD method.121 A new diskagar diffusion method, the Neo-Sensitabs tablet dif-fusion assay (Rosco, Taastrump, Denmark) has alsobeen developed and tested for antifungal testing ofmolds and yeasts.122 Finally, commercial auto-mated systems for MIC determination of yeasts aresimple alternative methods and are comparable toother established antifungal susceptibility testingmethods.123

Antifungal susceptibility testing of Candida albi-cans and other Candida spp is fairly simple to per-form, with determination of fluconazole susceptibil-ity as the most important first step. If the C albicansisolate is fluconazole resistant or if the isolate isnon–C albicans, further susceptibility testing will of-ten be required. In contrast, antifungal susceptibilitytesting of molds is not currently as useful clinicallybecause of both the long turnaround time of suchtesting and the difficulties in developing accuratebreakpoints for molds.124

CONCLUSIONThe goal of this article was to provide a review ofcurrent concepts in laboratory methods and ap-proaches that serve to assist clinicians in makingoptimal antibiotic decisions for treatment of infec-tions in this era of ever-evolving antimicrobial resis-tance. By its nature, the review could not be all-inclusive. For example, a standard has beendeveloped for the susceptibility testing of Myco-plasma spp and Ureaplasma urealyticum.125 Until re-cently, M pneumoniae, an important cause of com-munity-acquired pneumonia, was thought to beuniversally susceptible to the macrolide class of an-tibiotics. Not only has macrolide resistance nowbeen reported, but it is in fact widespread in somecountries, including China and Israel, renderingavailability of standardized methods for testing,
heretofore of limited value but now of clinical im-
Mayo Clin Proc. �

ortance.126,127 A topic that warrants considerations the influence and effect of standards-setting orga-izations (eg, CLSI, EUCAST, and FDA) on AST andeporting. This is, however, beyond the scope of thisrticle but has been addressed in another recentublication.128 Many of the testing approaches re-iewed in these discussions have been used, essen-ially unchanged, for decades. As molecular tech-iques increasingly become a part of the dailyoutine in clinical laboratories, the day may comehen such highly sensitive and specific methods

eplace many of the assays currently being used toredict antimicrobial susceptibility and resistance.s bacterial pathogens continue to exhibit increas-

ng antibiotic resistance and appropriate empiricalntibiotic decisions become more and more diffi-ult, AST will take on an even more important rolen managing patient infections.

Correspondence: Address to Stephen G. Jenkins, PhD,Department of Pathology, Weill Cornell Medical College,East 68th Street, Starr 737A, New York, NY 10065([email protected]). Individual reprints of this articleand a bound reprint of the entire Symposium on Antimi-crobial Therapy will be available for purchase from ourWeb site www.mayoclinicproceedings.org.

The Symposium on Antimicrobial Therapy will continuein an upcoming issue.

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HIV Screening in the Health Care Setting:Status, Barriers, and Potential SolutionsStacey A. Rizza, MD; Robin J. MacGowan, MPH; David W. Purcell, JD, PhD;Bernard M. Branson, MD; and Zelalem Temesgen, MD

Abstract

Thirty years into the human immunodeficiency virus (HIV) epidemic in the United States, an estimated 50,000 personsbecome infected each year: highest rates are in black and Hispanic populations and in men who have sex with men.Testing for HIV has become more widespread over time, with the highest rates of HIV testing in populations mostaffected by HIV. However, approximately 55% of adults in the United States have never received an HIV test. Becauseof the individual and community benefits of treatment for HIV, in 2006 the Centers for Disease Control and Preventionrecommended routine screening for HIV infection in clinical settings. The adoption of this recommendation has beengradual owing to a variety of issues: lack of awareness and misconceptions related to HIV screening by physicians andpatients, barriers at the facility and legislative levels, costs associated with testing, and conflicting recommendationsconcerning the value of routine screening. Reducing or eliminating these barriers is needed to increase the implemen-tation of routine screening in clinical settings so that more people with unrecognized infection can be identified, linkedto care, and provided treatment to improve their health and prevent new cases of HIV infection in the United States.

CME Activity

Target Audience: The target audience for Mayo Clinic Proceedings is pri-marily internal medicine physicians and other clinicians who wish to advancetheir current knowledge of clinical medicine and who wish to stay abreastof advances in medical research.Statement of Need: General internists and primary care providers mustmaintain an extensive knowledge base on a wide variety of topics coveringall body systems as well as common and uncommon disorders. Mayo ClinicProceedings aims to leverage the expertise of its authors to help physiciansunderstand best practices in diagnosis and management of conditions en-countered in the clinical setting.Accreditation: College of Medicine, Mayo Clinic is accredited by the Ac-creditation Council for Continuing Medical Education to provide continuingmedical education for physicians.Credit Statement: College of Medicine, Mayo Clinic designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s).TM

Physicians should claim only the credit commensurate with the extent of theirparticipation in the activity.Learning Objectives: Educational objectives. On completion of this article,you should be able to (1) describe briefly the current epidemiology ofhuman immunodeficiency virus (HIV) in the United States, (2) summarizecurrent status of testing for HIV in the United States, (3) explain the Centersfor Disease Control and Prevention’s revised recommendations for HIVtesting in health care settings, (4) discuss potential barriers and solutions tothe implementation of the Centers for Disease Control and Prevention’srevised recommendations for HIV testing in health care settings, and (5)articulate the potential benefits of antiretroviral therapy.Disclosures: As a provider accredited by ACCME, College of Medicine,Mayo Clinic (Mayo School of Continuous Professional Development) mustensure balance, independence, objectivity, and scientific rigor in its educa-tional activities. Course Director(s), Planning Committee members, Faculty,and all others who are in a position to control the content of this educa-

tional activity are required to disclose all relevant financial relationships withany commercial interest related to the subject matter of the educationalactivity. Safeguards against commercial bias have been put in place. Facultyalso will disclose any off-label and/or investigational use of pharmaceuticalsor instruments discussed in their presentation. Disclosure of this informationwill be published in course materials so that those participants in the activitymay formulate their own judgments regarding the presentation.In their editorial and administrative roles, William L. Lanier, MD, Scott C.Litin, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA,have control of the content of this program but have no relevant financialrelationship(s) with industry.Drs Rizza, MacGowan, Purcell, and Branson have no potential competinginterests to declare. Dr. Temesgen has educational grants from Merck, GileadSciences, Inc, and Janssen Pharmaceuticals, Inc, and a research grant from Pfizer.Method of Participation: In order to claim credit, participants must com-plete the following:1. Read the activity.2. Complete the online CME Test and Evaluation. Participants must achieve

a score of 80% on the CME Test. One retake is allowed.Participants should locate the link to the activity desired at http://bit.ly/MiTZ8G. Upon successful completion of the online test and evaluation, youcan instantly download and print your certificate of credit.Estimated Time: The estimated time to complete each article is approxi-mately 1 hour.Hardware/Software: PC or MAC with Internet access.Date of Release: 9/1/2012Expiration date: 8/31/2014 (Credit can no longer be offered after it haspassed the expiration date.)Privacy Policy: http://www.mayoclinic.org/global/privacy.htmlQuestions? Contact [email protected].


FtR

T he Centers for Disease Control and Preven-tion (CDC) recently estimated that each yearapproximately 50,000 Americans are in-

fected with human immunodeficiency virus (HIV)and that 18,000 people with AIDS die.1 The numberof people living with HIV in the United States is
estimated to be almost 1.2 million, and it continues to 2
Mayo Clin Proc. � September 2012;87(9):915-924 � http://dx.doi.orwww.mayoclinicproceedings.org � © 2012 Mayo Foundation for Me

grow annually, thereby providing more opportunitiesfor transmission.2 From 2007 through 2010, thenumber of diagnoses of HIV infection in adultsand adolescents remained stable in the 46 statesand 5 US-dependent areas with long-term confi-dential name-based HIV infection reporting.3 In

010 specifically, an estimated 48,079 adults and

g/10.1016/j.mayocp.2012.06.021dical Education and Research

rom the Division of Infec-ious Diseases, Mayo Clinic,ochester, MN (S.A.R., Z.T.);

Affiliations continued at
the end of the article.
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adolescents were diagnosed as having HIV infec-tion; of these, 79% of diagnoses were in males and21% were in females, a ratio that was stable from2007 through 2010.3

Some populations are particularly burdened byHIV and account for a disproportionate number ofcases owing to social, economic, and demographicfactors, such as stigma, discrimination, income, ed-ucation, and geographic region.4 The percentage ofHIV infection diagnoses in adults and adolescentsexposed through male-to-male sexual contact in-creased from 55% in 2007 to 61% in 2010, and thiswas the only group to experience an increase duringthose years. The percentages of diagnosed HIV in-fections attributed to injection drug use (IDU) (8%),male-to-male sexual contact and IDU (3%), and het-erosexual contact (28%) remained relatively stablefrom 2007 through 2010. Gay and bisexual menand other men who have sex with men (MSM) arethe most severely and disproportionately affected byHIV. Although composing only an estimated 4% ofmen,5 MSM accounted for 77% of new HIV diagno-ses in men in 2010.3

Black individuals are the most affected racial/ethnic group, comprising 14% of the populationand 44% of estimated reported cases in 2010 in the46 states and 5 US-dependent areas with long-termconfidential name-based HIV infection reporting.3

Hispanic adults and adolescents are also dispropor-tionately affected by HIV. Hispanics/Latinos repre-sent approximately 16% of the population but ac-counted for 22% of new HIV diagnoses in 2010.3 In2010, the estimated rate (per 100,000 population)of HIV infection diagnosis for black males (116.0)was more than 7.5 times higher than the rate forwhite males (15.3) and more than 2.5 timeshigher than the rate for Hispanic/Latino males(44.7). For female adults and adolescents, the es-timated rate of HIV infection diagnosis for blacks(41.7) was approximately 20 times higher thanthe rate for white females (2.1) and approximately4.5 times higher than the rate for Hispanic/Latinofemales (9.2).3

HIV TESTING IN THE UNITED STATESIn 1985, when the US Food and Drug Administrationapproved the first tests for the detection of antibodiesto HIV, the primary purpose was to screen blood do-nations to prevent HIV transmission from blood trans-fusion.6 To dissuade persons from using blood dona-tion centers to obtain an HIV test, HIV counselingand testing programs based at “alternative testingsites” were established to provide these services.During the past 25 years, HIV testing has becomemore widely available and acceptable.

Since 1987, numerous national surveys have
been conducted to estimate the proportion of US l
Mayo Clin Proc. � September 2012;8

adults who have ever received an HIV test. Althoughthe sample populations and methods have varied,the results for various periods have been consistentacross surveys. By the late 1980s, 1 in 6 adults in theUnited States had been tested for HIV.7,8 As accessto HIV testing services increased, by the mid-1990sestimates of the percentage of adults in the UnitedStates who had been tested for HIV, excluding viablood donations, ranged from 31% to 40%.9 Be-ween 2000 and 2006, the percentage of adults whoad been tested for HIV remained at approximately0%, and since then, there has been a gradual in-rease to approximately 45%, leaving 55% of adultsn the United States who have never been tested forIV (with considerable variation by demographicroups).10

Although most HIV/AIDS cases in the Unitedtates continue to be in males, a higher percentagef women report HIV testing. In 1985, 92% of AIDSases were in men,11 and HIV/AIDS was viewed as a

disease affecting primarily MSM and IDUs; by 1988,HIV testing was higher in men than in women.8 As

IV infection became more prevalent in the hetero-exual population, HIV testing significantly in-reased in women. A variety of factors may haveontributed to this increase, including women ac-essing medical services more frequently than men,linicians being more comfortable offering an HIVest to women, and the CDC recommending HIVcreening for all pregnant women in 1995.12,13 In

the 2002 National Survey of Family Growth, ahigher percentage of females (57%) reported HIVtesting than males (47%),7 and in the 2008 NationalHealth Interview Survey (NHIS), 48% of womenand 41% of men reported ever being tested forHIV.10

Testing for HIV also has differed significantly byace and ethnicity during the epidemic. In 1988, areater proportion of white adults (17%) reportedaving been tested for HIV compared with black14%) and Hispanic (14%) adults.8 By 1999, per-entages of HIV testing were higher in black (46%)nd Hispanic (33%) individuals than in white indi-iduals (29%), and these patterns have persisted.14

In 2008, 62% of black individuals, 48% of Hispanicindividuals, and 41% of white individuals reportedever being tested for HIV,10 with comparable per-entages reported in other surveys.15,16

A key driver of testing during the past 25 yearsas been recommendation by the CDC regardingho should be tested for HIV. Early in the epidemic,IV testing in the United States was predominantly

ecommended for persons considered at risk forIV infection, and HIV testing programs primarily

argeted persons who regarded themselves to be atisk. In 1988, 1 in 3 adults who acknowledged at
east one risk behavior (from a list of behaviors) for
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HIV SCREENING IN THE HEALTH CARE SETTING

HIV infection had received an HIV test,8 a percent-age twice that in adults overall. In the 1995 NHISand the 1996 National Household Survey on DrugAbuse, 70% of adults at increased risk (eg, thosewho have sex with an at-risk partner, IDUs, andMSM) reported that they had ever been tested forHIV.9 In 1995, 48% of females aged 15 to 44 years atincreased risk for infection reported being tested forHIV, and by 2002, this percentage had increased to68%.7 The NHISs conducted in 1999 and 2008showed little change in the percentage of personsaged 18 to 64 years who reported an HIV risk factorand had been tested for HIV, approximately 72% inboth surveys.10,14 A high percentage of the popula-tions at greatest risk for HIV infection, MSM andIDUs, report that they have been tested for HIV.Recent data from the CDC’s National HIV Behav-ioral Surveillance surveys indicate that 90% of eachof these populations report ever being tested forHIV.17,18 Given the continued transmission of HIVin these populations, particularly MSM, testingmore frequently than once a year may be needed toidentify undiagnosed cases earlier in the course ofinfection and to link infected persons to treatmentservices.19 Rates of HIV testing are higher in regionswhere disproportionately affected populations aregreatest. Data from the Behavioral Risk Factor Sur-veillance System in 2001 and 2008 have docu-mented that the percentages ever tested and recentlytested (within the past 12 months) were typicallyhigher in states with high AIDS case rates.10,20

THE CRITICAL ROLE OF HIV TESTING INCURBING THE HIV EPIDEMICTesting for HIV plays a prominent role in the Na-tional HIV/AIDS Strategy released by the WhiteHouse in July 2010.21 As shown in the Figure, of theestimated 1.2 million persons living with HIV in theUnited States, 80% are aware of their infection, 62%have been linked to HIV care, 41% stay in HIV care,36% are receiving antiretroviral therapy, and only28% have a suppressed viral load.19 Transmissionrate modeling estimates that the 20% of persons liv-ing with HIV who are unaware of their infectionaccount for 49% of HIV transmissions.22

To prevent further HIV transmission, improvethe quality of life of persons with HIV, and reducedisparities associated with HIV infection, intensifiedeffort is needed to increase the percentage of personsat each stage of this continuum of care. IncreasingHIV diagnoses is the first step in this critical process.

After testing, it is important to immediately linknewly identified HIV-positive persons to care so thattheir disease status and need for treatment can beevaluated. Between 2005 and 2007, 41.4% of per-sons with a new HIV diagnosis from the 37 states
with name-based reporting systems had no CD4 cell
Mayo Clin Proc. � September 2012;87(9):915-924 � http://dx.doi.orwww.mayoclinicproceedings.org

count reported within 12 months, indicating thatthey were likely not receiving care for their HIV in-fection.23 In addition, 33.8% of those with a new

iagnosis had a CD4 cell count of less than 200/�L,hich since 1993 has indicated an immunologic di-

gnosis of AIDS.24 Such a low CD4 cell count at theime of HIV diagnosis indicates that HIV was firstdentified late in the course of infection.23

Despite the increase in HIV testing during therst 30 years of the epidemic in the United States, anstimated 236,000 persons with HIV are unaware ofheir infection.2,25 The CDC has continued to pro-ote HIV testing in the US populations and specif-

cally in persons disproportionately affected by HIV.n 2003, the CDC launched an initiative to increaseccess to early diagnosis and to services for personsith HIV.26 In 2006, the CDC revised the recom-

mendations for HIV testing for adults, adolescents,and pregnant women in health care settings to re-duce barriers to providing HIV testing. The majormodifications included the following recommenda-

1001,178,350

941,950

725,302

480,395

80

60

40

20

0

HIV-infected*

HIV-diagnosed*

Linked toHIV care†

Engagement in HIV care

Retained inHIV care‡

Perc

enta

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FIGURE. The figure shows the number and percepersons engaged in selected stages of the continuUnited States. CDC synthesized these findings toof persons in selected categories of the continuestimated that 328,475 (35%) of 941,950 persons d28% of all 1,178,350 persons with HIV) in the Usuppressed.19 *Source: Centers for Disease Con†Calculated as estimated number diagnosed timeslinked to care (77%). ‡Calculated as estimated nuestimated percentage retained in care (51%). §Cnumber retained in HIV care times percentage ptherapy (ART) in the Medical Monitoring Project (estimated number receiving ART times percentageload in the Medical Monitoring Project (77.0%). Testimated 1,178,350 persons in the United StatesHIV.

426,590328,475

On ART§ Suppressed viralload (≤200copies/mL)¶

ntage of HIV-infectedum of HIV care in thedetermine the numberum of HIV care, andiagnosed with HIV (or

nited States are virallytrol and Prevention.2

estimated percentagember diagnosed timesalculated as estimatedrescribed antiretroviral88.8%). ¶Calculated as

with suppressed viralhis value is 28% of thewho are infected with

tions: (1) opt-out testing should be provided unless

g/10.1016/j.mayocp.2012.06.021 917


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the patient declined, (2) persons at high risk for HIVinfection should be screened at least annually, (3)informed consent for medical care should cover HIVtesting on the same basis as other diagnostic orscreening tests, (4) prevention counseling shouldnot be required in conjunction with HIV testing fordiagnostic or screening purposes, and (5) HIVscreening should be a routine component of prena-tal screening.27 These guidelines encourage physi-cians to incorporate HIV screening into clinicalpractice for all adults, regardless of risk, when theprevalence of undiagnosed HIV infection is 0.1% orgreater and to offer HIV screening to high-risk per-sons more frequently. The recommendations alsoseek to reduce barriers associated with determiningrisk status and the requirement for preventioncounseling to the extent that this was a barrier totesting. In 2007, the CDC funded the ExpandedHIV Testing Initiative, under which 25 health de-partments were funded to facilitate HIV testingand increase diagnosis of infection in dispropor-tionately affected populations, especially non-Hispanic black individuals.28

The increase since 2006 in the percentage ofadults tested has coincided with CDC efforts to pro-mote HIV screening and earlier diagnosis of infec-tion. The use of point-of-care rapid HIV tests andreduced barriers to HIV testing have enhanced theability of providers to conduct testing in settings inwhich time can be a limiting factor, such as jails29

and clinical and acute care settings.30-32 Throughthe Expanded HIV Testing Initiative, nearly 2.8 mil-lion tests were performed, many of them in clinicalsettings, and more than 18,000 people were newlydiagnosed as having HIV infection.28

BARRIERS TO ROUTINE HIV TESTING IN THEHEALTH CARE SETTING AND POTENTIALSOLUTIONSHealth care professionals in the United States havebeen slow to implement the 2006 CDC recommen-dations for HIV screening of individuals aged 13 to64 years. For example, only 33% of communityhealth care personnel from Massachusetts incorpo-rated HIV screening into their practices.33 In an-other study, only one-quarter of eligible patients inan emergency department were offered HIV screen-ing,34 and less than 5% of adults seen in an emer-gency or urgent care setting were tested for HIV.35

These studies demonstrate that significant barriersto implementation of universal HIV testing in healthcare settings in the United States still exist. Thesebarriers are multifactorial and complex and require
a multipronged approach and strategy to overcome. t

Physician Awareness and PerceptionInconsistent levels of awareness of the 2006 CDCrecommendations for universal HIV screeningamong health care professionals in the United Stateshave created perceived barriers to implementing therecommendations. Among medical directors andadministrators from non–Ryan White–supportedcommunity health centers in Massachusetts, only27% were aware of the CDC recommendationscompared with 60% in Ryan White–supported cen-ters.36 Most health care professionals surveyed alsobelieved that they needed to obtain written consentand provide counseling before obtaining an HIVtest. Physicians also expressed concerns that pa-tients would not have time to reflect on the signifi-cance of an HIV test and make an informed decisionabout whether to accept the testing.37

Health care professionals also report feeling in-ecure about broaching the topic of HIV testing withheir patients, particularly those from low-risk back-rounds, citing that discussing HIV testing would bencomfortable for the patient and might damage theatient-physician bond.36 Physician were also con-erned that they would not receive support from thedministration at their health care facility to initiateIV screening, believing that it would be regarded

s more of a burden than a help. Moreover, manyhysicians did not feel equipped to answer all theatient’s questions regarding HIV testing and didot feel that they were capable of convincing theatient that the test should be performed.38

The primary solution to overcome this particu-ar barrier to HIV testing is education. Physicianshould be familiar with the CDC’s revised recom-endations for HIV Testing of Adults, Adolescents,

nd Pregnant Women in Health-Care Settings andhe rationale behind them. Providers should under-tand that despite the availability of effective treat-ent, HIV infection remains a leading cause ofeath and illness in the United States and that sub-tantial numbers of previously unrecognized infec-ions are diagnosed each year. Also, people who areware of their infection can not only receive treat-ent that is effective for improving their health and

educing transmission but also adopt behaviors tovoid transmitting their infection to others. Physi-ians should be informed that the processes androcedures that have previously impeded HIV test-

ng, such as pretest and posttest counseling and sep-rate written consent, are no longer required andhat the currently recommended screening for HIVses an opt-out strategy. This information should beccompanied by an explanation of what an opt-outtrategy is together with simulation of how to use itor HIV screening in various clinical settings. TheDC has developed free materials for physicians on

hese topics.39



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An important component of physician educa-tion is correcting misperceptions regarding HIVscreening in the clinical setting. Physicians may be-lieve that their patients are at low risk for HIV basedon patients’ own lack of reported risky behavior butnot uncommonly also because of inherent biases re-lated to race, ethnicity, age, sex, and socioeconomicstatus and their associations with risk of HIV. Phy-sicians may not realize that some patients may sim-ply choose not to disclose high-risk behaviors andthat as many as 10% to 25% of people testing posi-tive for HIV had reported no high-risk behaviorsbefore their diagnosis.40

Public Awareness and PerceptionThe HIV epidemic is now more than 30 years old.Although perceptions regarding HIV have improvedduring the past 3 decades, HIV still carries a stigma thatconcerns many patients. In a poll conducted by theKaiser Family Foundation in 2003, more than one-third of people stated that they feared people wouldthink less of them if they were infected with HIV. Theyexpressed additional worry that they would be dis-criminated against or be seen as morally inferior if oth-ers knew they were HIV positive.41 In a more recentstudy, patients presenting to an emergency depart-ment without a life-threatening illness or psychiatricdiagnosis cited fear and denial as the most significantbarrier to HIV screening. However, this was reportedin less than 5% of those surveyed, with participantsexpressing overwhelming (�85%) support for theCDC recommendations to perform HIV screening.42

Another contributing factor for suboptimal HIVtesting in the United States is that many individualsfeel that they do not require HIV testing becausethey have no HIV risks. In fact, when HIV-infectedpatients were asked why they had not been testedearlier for HIV, the most common answer (69%) wasthat they did not feel that they were at risk for HIVinfection.43 Patients also expressed concerns aboutthe confidentiality, access, and anonymity of HIVtesting in a health care setting. Furthermore, a re-cent survey of patients in a health care setting dem-onstrated that most were unaware that 20% of peo-ple infected with HIV in the United States areunaware of their diagnosis and that the CDC recom-mends HIV screening without regard to risk, andthey assumed that consent for HIV testing would beoverwhelming or intimidating.44

Education plays a primary role in raising aware-ness and removing negative perceptions regardingHIV testing among the public. This education can beprovided in various forms and at various levels ofsociety. The CDC leads the national effort to pro-mote HIV awareness and prevention in collabora-tion with other public health organizations and or-
ganizations that represent the populations hardest

hit by the HIV epidemic. On a regional and local level,community-based agencies, hospitals, clinics, physi-cian groups, and managed care organizations shouldparticipate in this national effort and educate their pa-tients and clients about HIV. Schools also have theresponsibility of teaching their students about HIV andsexually transmitted infections. Finally, physiciansshould have the appropriate knowledge and educationto be able to discuss behavioral risk factors for HIV andmotivate their patients to be tested for HIV.

The public should be made aware of the magni-tude of the HIV epidemic in the United States, thepersistent substantial numbers of new infections,and the contribution of those who are not aware oftheir infection to new transmissions. In addition, thepublic should be made to realize that effective treat-ment, although not curative, exists for HIV infectionand that this treatment is associated with substantialimprovement in survival and quality of life. It is nowclear that treatment has an additional public healthrole as it provides protection for sex partners of HIV-infected persons who themselves are not HIV in-fected.45 Education should also involve making the

ublic aware of how HIV is diagnosed and reportedo state health departments, the confidentiality ofesting, and the implications of a positive result onealth insurance coverage and employment.

ystemic Barriersvariety of systemic issues at the facility, state, and

ational levels have been identified as barriers toniversal HIV screening in health care settings.

ystemic Barriers at the Facility Level. The CDCecommendations to perform HIV screening asksost health care providers to change their tradi-

ional way of thinking. Conventionally, a patient’sresenting illness has always been the focus of the

imited time and resources available. Asking thehysician to consider, offer, and order what may becompletely unrelated laboratory test can be seen as

ntrusive and unwelcome. In fact, physicians citehat lack of time is the leading reason they have beeneticent to implement HIV screening in their prac-ices.33,36 Health care professionals’ concerns about

adequate time relates to obtaining written consentbefore testing each patient for HIV and time to coun-sel and discuss the implications of a positive orequivocal HIV test result with their patients. Thiswas a particularly important issue to physicians inemergency departments and urgent care settings,where many physicians averaged 10 minutes perpatient visit.46 Further concerns arose that time and re-sources would be needed to train staff and develop pro-
tocols in each health care setting to initiate HIV testing.47
g/10.1016/j.mayocp.2012.06.021 919


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Conventional HIV testing requires a blood testthat may take 24 to 48 hours for results to return inclinical settings. Therefore, after an HIV screeningtest is performed in a health care setting, a patientmust return or be called for results of the test. Arapid test might alleviate this barrier; however, es-pecially in high-volume settings, rapid tests can belabor intensive and disrupt patient flow. Even if arapid HIV test is used, a preliminary positive resultrequires a confirmatory test, typically Western blotanalysis, which takes several days for results to bereturned. To overcome these barriers, some high-volume emergency departments have used opt-outscreening and conventional (nonrapid) testing tech-nology to screen all patients who have blood col-lected by batching the blood hourly.48

Linkage-to-care concerns are enhanced in thescenario in which a patient is diagnosed as havingHIV after being screened in a health care setting butdoes not seek HIV care.49 In one study, only 48% ofpatients sought HIV care within 3 months of theirHIV diagnosis, with 22% not seeking HIV care at 12months.50 Possible reasons an HIV-infected individ-ual would not seek follow-up HIV care are complexand may include lack of health care insurance, men-tal illness, substance abuse, lack of sophisticationmaneuvering through the health care system, anddenial of HIV status.51 This dichotomy between pre-vention and care remains a significant hurdle forhealth care workers who do not have the infrastruc-ture needed to follow up on HIV test results andensure that all HIV-positive patients are referred forHIV care.47,52

The current CDC recommendation for HIVscreening in the health care setting does away withmany of the facility- and physician-level systemicbarriers, such as the need for counseling and sepa-rate written informed consent. However, it does notremove all the barriers, perceived or otherwise, as-sociated with the mechanics of ordering tests, aswell as interpreting and reporting test results, orinforming patients of their test results. Solutions toovercome these barriers include full integration andincorporation of HIV testing into standards of careand standard clinic operating procedures. All rele-vant staff in the facility must be engaged and partic-ipate in this practice. Clinical informatics solutionshave been found to be useful in enabling and accel-erating integration of HIV testing into the clinicwork flow by identifying eligible patients andprompting clinicians to order the test. These infor-matics solutions can also be used to facilitate linkagefor those found to be HIV infected and increaseoverall program efficiency.34

Legislative and Legal Barriers. The legal implica-
tions of HIV screening continue to make health care a

providers anxious.33,36,52 Although national recom-mendations influence state law, HIV testing laws re-main under state jurisdiction. Given that mosthealth care professionals are not directly involved inproviding HIV care, many would not be familiarwith state laws pertaining to HIV testing. Physicianshave expressed concerns about their legal obligationto document consent for HIV testing, to adequatelycounsel patients before testing, and to ensure thatpatients receive the test result and, if positive, arelinked to HIV care. There is also a general sense ofinsecurity regarding partner notification and thephysician’s legal roles and obligations.52

Because HIV screening programs must complyith state laws about HIV testing, physicians shouldave a clear and easily accessible source of informa-ion about state laws relevant to their practice. Theompendium of State HIV Testing Laws from theational HIV/AIDS Clinicians’ Consultation Centerrovides state profiles of key HIV testing laws andolicies and is updated periodically.53 However, re-isions depend on input from individuals or knowl-dge about newly passed legislation, and, as a result,he information may not always be up-to-date. Itould facilitate testing substantially if such informa-

ion were provided by each individual state depart-ent of health with clear and unambiguous lan-

uage and were posted prominently in all relevantlinical facilities. Note that many states have madehanges in their laws to make them compatible withhe CDC recommendations, and, at present, HIVesting laws no longer present a barrier to routinecreening for HIV in the clinical setting in nearly alltates.

ost and Cost-effectiveness of HIV Testing. Theost of HIV testing is another perceived barrier toIV screening. There is a considerable amount ofncertainty about insurance coverage for HIVcreening. Many health care professionals are con-erned that HIV testing will not be reimbursed bynsurance or that funding is not available to supportach patient’s test.54 In fact, lack of funding or re-mbursement for HIV testing was listed as a majoreason by community health care professionals forot performing HIV screening on their patients.33,36,52

There was also a worry that the health care systemin the United States would not be able to bear theburden and cost of caring for increased numbersof people being diagnosed as having HIV infec-tion.55 What these physicians may not fully ap-

reciate is the substantially increased cost of careor patients diagnosed late in the course of theirIV disease and the increased societal costs of

dditional cases of HIV when people with undi-
gnosed infection spread HIV to their partners.


ppvdrbTogbtHiiipsoHmdps(rmHitoupTebmlss


Medicaid currently allows coverage for routineHIV screening in the clinical setting as recommendedby the CDC. However, it is considered an optionalservice, and each state chooses whether to cover it intheir Medicaid program. The US Department of Healthand Human Services accepted the recommendation ofa recent Institute of Medicine report that private insur-ers be required to cover annual HIV counseling andscreening for sexually active women at no cost.

Some health insurance plans do not cover routineHIV screening. Instead, these plans cover HIV tests forpatients with known or perceived risk factors (eg,MSM and IDUs) and for patients who show symptomsof AIDS. In 2008, California became the first state tomandate that private insurers pay for HIV testing evenwhen it’s not related to a patient’s primary diagnosisduring a medical visit. Cost-effective is not the same asinexpensive or cost saving. Cost-effectiveness analysisattempts to provide information on the relationshipbetween resources expended on 2 or more alternativehealth interventions and health outcomes resultingfrom these interventions. This relationship or ratio (thedifference in costs over the difference in effectiveness)is commonly expressed as cost per quality-adjustedlife-year (QALY) saved. Several studies on the cost-effectiveness of HIV screening have been published.These studies have found that the cost-effectiveness ofHIV screening compares favorably with that of otherhealth interventions that are accepted as good uses ofresources.56 Annual mammography screening of allwomen in the United States aged 40 to 80 years wasassociated with a cost of $40,000 per additionalQALY,57 whereas the cost-effectiveness of HIV screen-ing was estimated to be $41,736 per QALY.58

Furthermore, HIV screening has been demon-strated to be cost-effective across a variety of riskgroups and age ranges, whether conventional or rapidtesting was used, and in populations with low HIVprevalence.58-64

Part of the solution to overcoming the percep-tion of cost or cost-effectiveness as a barrier to HIVscreening is education. In addition to emphasizingthe benefit of testing to the individual and the pub-lic, physicians, policy makers, and the public shouldbe made aware that screening for HIV has beenshown to be cost-effective, even with a prevalence aslow as 0.05% to 0.1%.47,54,63 The issue of insurancecoverage for HIV testing needs to be addressed at anational level legislatively, through revision of theUS Preventive Services Task Force (USPSTF) recom-mendations, or both.

Conflicting Recommendation From the USPSTFAlthough the revised CDC recommendations wereendorsed by many professional societies and orga-nizations, such as the American College of Physi-
cians, the American Academy of HIV Medicine, and

the HIV Medicine Association, endorsement has notbeen universal. Critically, the USPSTF reiterated in2007 its 2005 recommendation on HIV testing de-claring that the USPSTF did not find enough evi-dence to recommend for or against routine HIVscreening in the general population (a “C” recom-mendation).65 This USPSTF recommendation is im-

ortant because coverage and reimbursement forreventive services under Medicare, and most pri-ate insurance depends on the level of USPSTF en-orsement. Currently, an “A-” or “B-” level USPSTFecommendation is required for coverage and reim-ursement for preventive services under Medicare.he discrepancy between the CDC and USPSTF rec-mmendations has also confused physicians and theeneral public. What many do not realize is thatoth agencies, despite the differing recommenda-ions, actually agree on most issues that pertain toIV testing; both acknowledge that targeted screen-

ng would miss many infected persons and thatdentification and treatment of asymptomatic HIVnfection can result in marked reduction in clinicalrogression and mortality. The primary differenceeems to be differing conclusions about the strengthf the data regarding the effect of routine testing onIV transmission. In recent years, evidence docu-enting the impact of antiretroviral therapy on re-ucing HIV transmission, so-called treatment asrevention, has been accumulating. A landmarktudy, the HIV Prevention Trials Network 052HPTN 052) clinical trial, reported that antiretrovi-al therapy reduced the risk of heterosexual trans-ission by 96%.30 However, the results of thePTN 052 cannot be applied unless HIV-infected

ndividuals are identified and linked to care andreatment.66 Evidence supporting earlier initiationf antiretroviral therapy has also emerged, leading topdated treatment recommendations from the De-artment of Health and Human Services and others.his potentially invalidates one assumption in thevidence model used by the USPSTF in 2005 as aasis for their recommendation: antiretroviral treat-ent would be initiated only at CD4 T-cell counts of

ess than 200/�L. The USPSTF is currently recon-idering its recommendation on routine HIVcreening.67

CONCLUSIONThe benefits of antiretroviral therapy are undisput-ed; it substantially reduces illness and death attrib-uted to HIV infection. In addition, the HPTN 052clinical trial showed that antiretroviral therapy pre-vents the transmission of HIV to uninfected sexualpartners from HIV-infected persons receiving treat-ment. There is also emerging data supporting thatearlier initiation of antiretroviral therapy results in
improved outcomes for the individual and commu-
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nities. These benefits of antiretroviral therapy arenot available for HIV-infected individuals who havenot yet been diagnosed as having HIV infection. Afifth of the 1.2 million people estimated to be livingwith HIV in the United States remain unaware oftheir infection and contribute disproportionately tothe overall transmission of HIV. The CDC’s revisedrecommendations for HIV testing for adults, adoles-cents, and pregnant women in health care settingsare intended to facilitate the reduction of HIV trans-mission in the United States by removing barriers toproviding HIV testing. Although implementation ofthese revised recommendations has been limited bya variety of real and perceived barriers, these barriersare not insurmountable. With appropriate educa-tion of the public and physicians, and with the in-volvement of all stakeholders at national, regional,state, and community levels, it is hoped that one ofthe primary goals of the National HIV/AIDS Strat-egy, reducing the number of people who becomeinfected with HIV, will soon be achieved.

ACKNOWLEDGMENTSThe findings and conclusions in this report are thoseof the authors and do not necessarily represent theviews of the CDC.

Abbreviations and Acronyms: CDC � Centers for Dis-ease Control and Prevention; HIV � human immunodefi-ciency virus; HPTN 052 � HIV Prevention Trials Network052; IDU � injection drug use; MSM � men who have sexwith men; NHIS � National Health Interview Survey;QALY � quality-adjusted life-year; USPSTF � US Preven-tive Services Task Force

Affiliations (Continued from the first page of this ar-ticle.): and Division of HIV/AIDS Prevention, Centers forDisease Control and Prevention, Atlanta, GA (R.J.M.,D.W.P., B.M.B.).

Correspondence: Address to Zelalem Temesgen, MD, Di-vision of Infectious Diseases, Mayo Clinic, 200 First St SW,Rochester, MN 55905 ([email protected]). In-dividual reprints of this article and a bound reprint of theentire Symposium on Antimicrobial Therapy will be avail-able for purchase from our website www.mayoclinicproceed-ings.org.

The End of the Symposium on Antimicrobial Therapy.

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