TAKE-HOME POINTS FROM EDUCATIONAL PRESENTATIONS BY CLEVELAND CLINIC FACULTY AND VISITING PROFESSORS

MEDICAL GRAND ROUNDS WILLIAM S. WILKE, MD, EDITOR

Antimicrobial resistance: An ecological approach to a growing threat

Vancomycin-resistant S aureus may be unstoppable

S T E V E N M . G O R D O N , M D Hospital Epidemiologist, Department of Infectious Diseases, Cleveland Clinic

B ABSTRACT Antibiotic resistance among pathogenic bacteria poses an increasing threat. To control it, we need a concerted effort from clinicians, patients, farmers, pharmaceutical companies, and public health officials.

"To regard any form of life merely as slave or foe will one day be considered poor philosophy, for all living things constitute an integral part of the cosmic order."1

— R E N E D U B O S , M I C R O B I O L O G I S T A N D E N V I R O N M E N T A L I S T

N COPING WITH the growing problem of antibiotic resistance, we physicians

need to make a radical change in the way we think and act. Instead of confidently await-ing the next generation of antibiotics to conquer antibiotic resistance, physicians must take a humbler view (TABLE 1 ) . We must:

• Prescribe fewer antibiotics. • Prescribe antibiotics that target as nar-

row a range of bacteria as possible. • Observe the oft-ignored basics of infec-

tion control, such as washing our hands care-fully between patient visits and working to make sure the same standards are observed by all health care workers coming in contact with patients.

In addition, the medical community must begin to examine the consequences of the overuse of antibiotics in agriculture.

As Dubos noted in the quote above, bac-teria are not simply foes to be vanquished, but a part of the natural world, capable of making deft adaptations to the drugs we use to fight them.

• HOW BACTERIA ACQUIRE RESISTANCE

Although bacteria cari acquire resistance through inherited mutations in their chro-mosomes, more often they do so through changes in their plasmids—circular, double-stranded DNA molecules outside the chro-mosomes (FIGURE 0.2.3 This is particularly important because bacteria exchange plasmid genes through conjugation, allowing entire populations to quickly become resistant. In another mechanism, viral vectors can even transfer genetic material between entirely different species of bacteria. Thus, antibiotic resistance does not rely exclusively on evolu-tion within a single clonal proliferation.

Bacteria can also lose resistance. In the absence of antibiotics, antibiotic-resistant bacteria are actually at a selective disadvan-tage, since they must expend energy and resources to manufacture the proteins that confer resistance. Over time, the prevalence of resistant bacteria declines after antibiotics are withdrawn. Indeed, several outbreaks of infections with resistant bacteria in hospital units were stopped only after all antibiotics were withdrawn.4

H WHAT ORGANISMS ARE BECOMING RESISTANT?

Staphylococcus aureus At least 30% of S aureus strains are now resistant to methicillin.5 Ominously, a few cases of S aureus infections that were resis-tant to vancomycin have recently been reported/1

Since many strains already exist that are resistant to all antibiotics except van-comycin, vancomycin-resistant S aureus may be unstoppable.

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• How antibiotic use leads to resistance

ANTIBIOTICS KILL BACTERIA BY:

D a m a g i n g or i n h i b i t i n g synthesis o f t h e cell m e m b r a n e (polymyxins) -

M e t a b o l i z i n g o r i n h i b i t i n g synthesis o f nuc le ic acids (rifampin, nitrofurantoins, nitromidazoles)

D a m a g i n g or i n h i b i t i n g synthesis o f t h e cel l w a l l (penicillins, cephalosporins, monobactams, carbapenems, bacitracin, vancomycin, -cycloserine, fosfomycin)

RESISTAMI BACTERIA FOIL ANTIBIOTIC THERAPY BY:

C r e a t i n g enzymes t h a t d e s t r o y a n t i b i o t i c mo lecu les

M a k i n g t h e cell w a l l less p e r m e a b l e

A l t e r i n g t h e b i n d i n g site o f t h e a n t i b i o t i c

C r e a t i n g a second, i nac t i ve s i te f o r t h e a n t i b i o t i c

Dead bacter ium

I n h i b i t i n g p r o t e i n b iosynthes is -(aminoglycosides, tetracyclines, chloramphenicol, erythromycin, clindamycin, spectinomycin, mupirocin, fusidic acid)

M o d i f y i n g e n e r g y m e t a b o l i s m (sulfonamides,— trimethoprim, dapsone, isoniazid)

Resistant bacter ium

BACTERIA ACQUIRE RESISTANCE BY: Receiv ing a p lasm id b e a r i n g a res is tance g e n e f r o m a n o t h e r b a c t e r i u m d i rec t l y

Receiv ing a resistance g e n e f r o m ano the r b a c t e r i u m by v i ra l de l i ve ry

M u t a t i n g a n d passing o n changes in c h r o m o s o m a l D N A

Scaveng ing D N A f r o m d e a d bacter ia

F I G U R E 1

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MEDICAL GRAND ROUNDS

T A B L E 1

W h a t p h y s i c i a n s a n d p a t i e n t s c a n d o t o s l o w t h e s p r e a d o f a n t i b i o t i c - r e s i s t a n t b a c t e r i a Advice to physicians

Wash hands thoroughly between patient visits

Do not give antibiotics when not needed, even if patients ask for them

When possible, prescribe antibiotics that target only a narrow range of bacteria; computerized systems may help16

Isolate hospital patients with multidrug-resistant infections

Familiarize yourself wi th local data on antibiotic resistance

Advice to patients

Do not demand antibiotics

When given antibiotics, take them exactly as prescribed and complete the full course of treatment; do not hoard pills for later use

Wash fruit and vegetables thoroughly; avoid raw eggs and undercooked meat, especially in ground form

Use soaps and other products with antibacterial chemicals only when protecting a sick person whose defenses are weakened

SOURCE: ADAPTED F R O M LEVY SB. THE CHALLENGE OF ANTIBIOTIC RESISTANCE. SCI A M M A R C H 1 9 9 8 ; 2 7 8 ( 3 ) : 4 6 - S 3 .

COPYRIGHT 1 9 9 8 BY SCIENTIFIC A M E R I C A N , INC. ALL RIGHTS RESERVED

Enterococcus faecalis, E faecium Enterococci, which are already largely resistant to penicillin and aminoglycoside antibiotics, are acquiring resistance to vancomycin as well. Ten percent of cases of E faecalis infection were vancomycin-resistant in 1995, compared with only 0.3% in 1989.7 Further, vancomycin-resistant enterococcal infections, formerly found only in intensive care units, are now seen in patients throughout the hospital.

No antimicrobial regimen is of established efficacy for vancomycin-resistant enterococcal infections. Chloramphenicol, fluoroquinolone, tetracycline, and rifampin may have some value for susceptible isolates, but these agents are not bactericidal. Experience is growing with using the streptogamin Synercid (quin-upristin-dalfopristin) to treat vancomycin-

resistant E faecium, but this agent is not active against E faecalis.

Examples of resistance in community-acquired organisms

Neisseria gonorrhoeae. Until 1992 almost all N gonorrhoeae strains were suscepti-ble to fluoroquinolone antibiotics, including ciprofloxacin. However, in a series of cases of gonorrhea in men in Cleveland from 1992 to March 1994, 7.4% of isolates were resistant to ciprofloxacin.8 Although quinolone-resistant N gonorrhoeae occur rarely in the United States, the prevalence could increase to the point that fluoroquinolones no longer reliably eradicate gonococcal infections.

Streptococcus pneumoniae. Of great con-cern is the emerging resistance to penicillin in S pneumoniae. Pneumococcal disease affects persons in all age groups, but particularly the elderly and very young, lr is an important cause of otitis media in children. In a stLidy at a day care center in Cleveland, 52 (21%) of 250 children were found to carry S pneumoni-ae strains that were resistant to multiple antibiotics.9 Similarly, in 1997, approximately 20% of cases of community-acquired S pneu-moniae pneumonia seen at the Cleveland Clinic were with strains that were resistant to penicillin.

• WHY DO CLINICIANS OVERPRESCRIBE ANTIMICROBIAL DRUGS?

Antibiotics provide little or no benefit in treating colds, upper respiratory tract infec-tions, or bronchitis.10 Yet, these conditions accounted for an estimated .31% of prescrip-tions for antibiotics written by ambulatory care physicians.11 According to a study by Gonzalves et al,12 more than 50% of all patients who went to a physician with one of these conditions walked out with a prescrip-tion for an antibiotic.

One reason for using antibiotics in this sit-uation is that patients ask for them, and over-worked physicians acquiesce even though they know better. Education is needed for physi-cians, patients, and the public.1^ A public edu-cation campaign in Iceland succeeded in bringing down the rate of antibiotic use—and the rate of antibiotic-resistant bacteria. H

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National recommendations led to a decrease in the use of erythromycin and of ery-thromycin resistance in group A streptococcal infections in Finland.15

In addition, physicians often prescribe antibiotics on incorrect assumptions that they are indicated:

• Prolonged cough occurs commonly in patients with viral respiratory infections, and does not necessarily indicate the need for antimicrobial therapy.

• A positive urine culture in a patient with a Foley catheter may be meaningless if the patient has no fever and feels well.

• Culturing skin in patients with decubi-tus ulcers and treating all organisms isolated is not necessary.

• Coagulase-negative staphylococcus isolated from one of two blood cultures proba-bly represents a contaminant, and does not require treatment.

• PREVENTING THE SPREAD OF ANTIBIOTIC-RESISTANT ORGANISMS

Increased use of antibiotics in the hospital is often associated with an increase of resistance among nosocomial pathogens, and efforts focused on reducing inappropriate use of antimicrobials are one important strategy. Recommendations for preventing the spread of vancomycin resistance published by the Hospital Infection Control Practices Advisory Committee (HICPAC) are one example of emphasis on prudent antimicrobial use and education.7 In another direction, the use of a computerized antibiotic-management pro-gram has recently been shown to improve use of antimicrobial agents and improve the qual-ity of care of hospitalized patients.16

It should not be forgotten, however, that handwashing remains the single most impor-tant prevention strategy that reduces the risk for health care workers transmitting potential pathogens from one patient to another.17

Hands should be washed between patient con-tacts and after any contact with blood, body fluids, secretions, and contaminated equip-ment or fomites. Hands should also be washed after removing gloves. Use of a plain (nonan-timicrobial) soap is adequate for routine hand-washing.

• AGRIBUSINESS: INAPPROPRIATE ANTIBIOTICS IN THE FEEDLOTS

Approximately 40% of antibiotic production goes into livestock feed as prophylaxis against infection. (A substantial portion also goes to spraying fruit trees.) Although effective in the short run, this practice is encouraging micro-bial resistance not only among the livestock, but among agricultural workers, persons living in the vicinity,18 and people who consume the agricultural products.19

Approximately 6 billion broiler chickens are raised in the United States each year, and most are given antibiotics to improve their health and rate of growth. With the FDA licensing of fluoroquinolones for use in chick-ens, the level of drug-resistant Campylobacter in chickens and humans may be increasing.20

Potential strategies to reduce the use of antibi-otics fed to farm animals include the use of irradiation (to eliminate potential harmful bacteria after packaging for human consump-tion) and spraying newborn chickens with a mixture of beneficial microbes to colonize their gastrointestinal tracts and reduce or eliminate disease-causing bacteria.

• CONCLUSIONS

Antimicrobial resistance is an emerging glob-al problem, and prevention and control of the spread of antibiotic resistance among bacterial pathogens will require a coordinated, concert-ed effort from clinicians, patients, farmers, pharmaceutical companies, and public health officials. Appropriate antibiotic use in humans and animals is an essential component in pro-grams to control resistance. In addition, in order to improve prescribing practices, more data is needed to determine appropriate dura-tion of antimicrobial therapy for many types of infections where antimicrobial agents are indicated. E3

• REFERENCES

1. Moberg CL. Rene Dubos: A harbinger of microbial resis-tance to antibiotics. Microbial Drug Resistance 1996; 2:287-297.

2. Neu HC. The crisis in antibiotic resistance. Science 1992; 257:1064-1073.

3. Gold HS, Moellering RC Jr. Antimicrobial-drug resistance. N Engl J Med 1996; 335:1445-1453.

50% of patients with colds receive antibiotics

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Price DJ, Sleigh JD. Control of infection due to Klebsiella aeruginosa in a neurosurgical unit by withdrawal of all antibiotics. Lancet 1970; 1213-1215. Mulligan ME, Murray-Leisure KA, Ribner BS, et al. Methicillin-resistant Staphylococcus aureus: A consensus review of microbiology, pathogenesis, and epidemiology with implications for prevention and management. Am J Med 1993; 94:313-328. Flores P, Gordon S. Vancomycin-resistant S aureus: An emerging public health threat. Cleve Clin J Med 1997; 64:527-531. Hospital Infection Control Practices Advisory Committee (HICPAC). Recommendations for preventing the spread of vancomycin resistance (published erra-tum appears in Infect Control Hosp Epidemiol 1995; 16:498). Infect Control Hosp Epidemiol 1995; 16:105-113. Gordon SM, Carlyn CJ, Doyle LJ, et al. The emer-gence of Neisseria gonorrhoeae with decreased sus-ceptibility to ciprofloxacin in Cleveland, Ohio: Epidemiology and risk factors. Ann Intern Med 1996; 125:465-470. Reichler MR, Allphin AA, Breiman RF, et al. The spread of multiply resistant Streptococcus pneumoniae at a day care center in Ohio. J Infect Dis 1992; 166:1346-1353. Verjeij TJM, Hermans J, Mulder JD. Effects of doxycycline in patients with acute cough and purulent sputum: a double-blind, placebo-controlled trial Br J Gen Pract 1994; 44:400-404. McCaig LF, Hughes JM. Trends in antimicrobial drug pre-scribing among office-based physicians in the United States. JAMA 1995; 273:214-219. Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997; 278:901-904. Avorn J, Harvey K, Soumerai SB, Herxheimer A, Plumridge R, Bardelay G. Information and education as determinants of antibiotic use: report of Task Force 5. Rev Infect Dis 1987; 9(Suppl 3):S286-S296. Stephenson J. Icelandic researchers are showing the way to bring down rates of antibiotic-resistant bacteria. JAMA 1996; 275:175. Seppala H, Klaukka T, Vuopio-Varkila J, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. N Engl J Med 1997; 337:441-446. Evans RS, Pestotnik SL, Classen DC, et al. A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med 1998; 338:232-238. Larson E. Association for Professionals In Infection Control and Epidemiology Guidelines Committee 1992-1994. APIC guideline for handwashing and hand antisepsis in health care settings. Am J Infect Control 1995; 23:251-269. Levy SB, FitzGerald GB, Macone AB. Changes in intestinal flora of farm personnel after introduction of a tetracy-dine-supplemented feed on a farm. N Engl J Med 1976; 295:583-588. Spika JS, Waterman SH, Hoo GW, et al. Chloramphenicol-resistant Salmonella newport traced through hamburger to dairy farms. A major persisting source of human salmonellosis in California. N Engl J Med 1987; 316:565-570. Burros M. Health concerns mounting over bacteria in chickens. New York Times Oct 20 1997; sect A pg

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