infective endocarditis in the injection drug user-september 2002

Infective endocarditis in the injectiondrug user

Patricia D. Brown, MDa,*, Donald P. Levine, MDb

aDivision of Infectious Diseases, Wayne State University School of Medicine,

3990 John R, Detroit, MI 48201, USAbDivision of General Medicine, Department of Internal Medicine, Wayne State

University School of Medicine, 4201 St. Antoine, Detroit, MI 48201, USA

Infective endocarditis is responsible for 5% to 8% of hospital admissionsamong injection drug users, and the overall incidence of infective endocar-ditis in this population is estimated to be 1 to 20 cases per 10,000 injectiondrug users per year [1,2]. Among 210 episodes of infective endocarditis seenat a community teaching hospital from 1980 to 1990, 33 episodes (16%) wererelated to injected drug use [3]. In a large series from the Detroit MedicalCenter, 41% of injection drug users with bacteremia was found to haveinfective endocarditis [4]. A prospective study of febrile injection drug userspresenting to the emergency department found that the prevalence ofinfective endocarditis was 13% [5]. In the Detroit Medical Center study themale:female ratio among injection drug users with infective endocarditis was5.4:1. Men with infective endocarditis were somewhat older (mean age, 32.7years versus 31.4 years) and had significantly longer histories of addiction(10.2 years versus 7.1 years) than women [4]. In a more recent series of injec-tion drug users with infective endocarditis seen at Cook County Hospital inChicago, the male:female ratio was 2:1 [6]. Injection drug users are also atsignificantly increased risk of recurrent endocarditis [7]. Cocaine use has beenreported to be an independent risk factor for the development of infectiveendocarditis in injection drug users [8]. Whether this increased risk is causedby systemic or immunosuppressive effects of cocaine or by injection habits(more frequent injection or needle sharing) is currently unknown. Injectiondrug users with underlying HIV infection seem to be at an increased risk forinfective endocarditis [9,10].

Infect Dis Clin N Am 16 (2002) 645–665

* Corresponding author.

E-mail address: [email protected]

0891-5520/02/$ - see front matter � 2002, Elsevier Science (USA). All rights reserved.

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Pathophysiology

The pathophysiology of infective endocarditis involves damage to thevalvular endothelium, the formation of a platelet-fibrin thrombus, andadherence of bacteria to the platelet-thrombus plaque, followed by the pro-liferation of the infecting organism. In an autopsy series of injection drugusers with infective endocarditis, 81% of patients were found to have no evi-dence of underlying valvular pathology, and all right-side valves were foundto be normal except for the evidence of bacterial infection [11]. Mitral valveinfective endocarditis may be more common in women who inject drugs,perhaps as a result of the increased prevalence of mitral valve prolapse inwomen [12]. Factors unique to the pathogenesis of right-sided endocarditisin injection drug users include injury to the valvular endothelium as a resultof physical trauma caused by injected particulate matter or the physiologiceffects of the injected drugs and immunologic dysfunction related to injecteddrug use. Physiologic effects of injected drug use that have been postulatedto be important in the pathogenesis of infective endocarditis include drug-induced pulmonary hypertension leading to increased right-sided pressuresand tricuspid valve damage caused by increased turbulence, diluent-inducedvalvular damage with resultant thrombus formation, and valvular throm-bus formation secondary to cocaine use. Frontera and Gradon recently re-viewed the current understanding of the pathogenesis of right-sided infectiveendocarditis [13].

The organisms that cause infective endocarditis in injection drug users arethought to originate from the skin or from contamination of the injecteddrug, diluent, or injection paraphernalia. Nasal colonization with Staphylo-coccus aureus has been shown to provide a reservoir from which the skinmay be colonized [14]. Certain organisms including Streptococcus pyogenes,Serratia marcescens, and Enterococcus spp have been associated almostexclusively with left-sided involvement with infective endocarditis in injec-tion drug users [4,15,16].

Microbiology

In injection drug users with infective endocarditis, S. aureus is the mostcommonly implicated pathogen, accounting for 60.8% of cases in theDetroit Medical Center series [4]. Other Gram-positive organisms includingS. pyogenes, group G and group B streptococci, and Enterococci wereresponsible for 16.2% of cases. Outbreaks of methicillin-resistant S. aureusinfections among injection drug users, including infective endocarditis, havebeen described in Detroit [17], Boston [18], and most recently in Zurich,Switzerland, where the outbreak was caused by the epidemic spread of asingle clone of methicillin-resistant S. aureus [19]. Coagulase-negative staph-ylococci are rarely isolated from injection drug users with infective endo-carditis.

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Gram-negative organisms that have been isolated from injection drugusers with infective endocarditis include Pseudomonas aeruginosa and Serra-tia marcescens. Pseudomonas aeruginosa infective endocarditis has beenassociated with the use of tripelenamine and pentazocine (‘‘Ts and blues’’)and was isolated from 13.5% of injection drug users with infective endocar-ditis at the Detroit Medical Center [4]. Pseudomonas aeruginosa has beenreported from other geographic regions as well [20–22]. Serratia marcescensinfective endocarditis in injection drug users was first reported from the SanFrancisco Bay area [16] but has since been described from other geographicregions. The reasons for the unusual geographic clustering of S. marcescensinfections among injection drug users in the San Francisco Bay area in the1970s remain unclear. Haemophilus spp have been reported to cause infec-tive endocarditis in injection drug users including a syndrome of occult poly-microbial endocarditis caused by H. parainfluenzae [23,24]. The practice oflicking the needle before injection or ‘‘cleaning’’ the injection site with salivahas been associated with infective endocarditis caused by Eikenella corro-dens [25], Neisseria sicca [26], and Rothia dentocariosa [27].

Polymicrobial infective endocarditis is well described in injection drugusers and was seen in 8.1% of patients in the series from the Detroit MedicalCenter [4]. Anaerobic bacteria other than Eikenella are rarely reported, butinfective endocarditis caused by Fusobacterium spp, Clostridia bifermentans,and Bacteroides spp has been described in injection drug users [28–30].Infective endocarditis associated with injected drug use and caused byCorynebacterium (Archanobacterium) hemoltyicum, C. jeikeium, andC. diptheriae has been reported [4,31,32].

Fungi are important pathogens in injection drug users with infectiveendocarditis. Non-albicans Candida spp including C. parapsilosis and C. tro-picalis predominate. Earlier series from the late 1970s and early 1980s re-ported fungal pathogens more frequently than domore recent reports [33,34].

Clinical presentation

Mathew, Addai, Anand, et al recently studied the clinical features ininjection drug users with infective endocarditis [6]. Fever is the most com-mon clinical finding at presentation and was seen in 77.6% of patients. Threeprospective studies of febrile injection drug users presenting to the emer-gency department showed that clinical findings at the time of presentationare frequently insufficient to exclude the diagnosis of infective endocarditisreliably. Hospitalization of febrile injection drug users awaiting the resultsof blood cultures is generally recommended [5,35,36]. Injection drug userswith infective endocarditis are more likely to present earlier than nonaddictsfor medical evaluation after the onset of symptoms. In one series of patientswith infective endocarditis, 94% of injection drug users reported symptomsof less than 1-week duration, whereas 86% of non–drug users reportedsymptoms of more than 2 weeks’ duration before hospitalization [37].

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A murmur was detected on presentation in 69.6% of patients in the seriesfrom Cook County Hospital. In the Detroit Medical Center series, however,a murmur was detected in only 35.1% of patients. In some series, left-sideddisease is more frequently associated with the presence of a murmur on pre-sentation than right-sided infection, but a murmur was detected in 72% ofpatients in a large series of injection drug users with right-sided infectiveendocarditis [38].

Chest pain is reported in approximately half of patients with infectiveendocarditis and is frequently associated with tricuspid valve involvementand septic pulmonary emboli. Splenomegaly is seen in 10% to 15% ofpatients. Findings classically associated with infective endocarditis such asRoth’s spots, Osler’s nodes, and splinter hemorrhages are rarely seen in injec-tion drug users. In a series of S. aureus infective endocarditis in injection drugusers and non–drug users, a presumed primary source of infection was iden-tified in 46% of the nonaddicts but in only 15% of injection drug users [39].

Radiographic abnormalities consistent with septic pulmonary emboli arereported in 28% to 47% of injection drug users with infective endocarditis[4,6]. Other abnormalities that may be visualized on chest radiographs in-clude pneumonia (23%) and evidence of congestive cardiac failure (13%) [6].

Right-sided (tricuspid valve) infective endocarditis has been associatedmore frequently with injected drug use; however, in several recent series,left-sided involvement has predominated [6,12]. In the 125 injection drugusers with infective endocarditis reported from Cook County Hospital,right-sided infection alone was seen in 34% of patients, left-sided infectionalone was seen in 46% of patients, and evidence of involvement of both sideswas seen in 13% of patients. Among those with left-sided infection, themitral valve was involved in 32% and the aortic valve in 19%. Pulmonicvalve infective endocarditis has been reported in injection drug users butis exceedingly rare.

Complications

Complications are reported in most injection drug users with infectiveendocarditis. The most frequently reported complication in many series isseptic pulmonary emboli, reflecting the greater prevalence of tricuspid valveinfection. Pneumothorax may result from septic pulmonary emboli [40].Pleural effusions (including empyema), pneumonia, and mycotic aneurysmsof the pulmonary vessels are also described. Cardiac complications mayoccur in those with left- or right-sided involvement and include congestivecardiac failure, valvular insufficiency, myocardial abscess, myocarditis, peri-carditis, and myocardial infarction caused by emboli to the coronary vessels.

Central nervous system complications of infective endocarditis in injec-tion drug users include stroke, mycotic aneurysm, brain abscess, meningitis,and spinal epidural abscess. Stroke was reported in 11.4% of patients in theseries from Cook County [6]. Mycotic aneurysms may occur in virtually any


location. The pathogenesis may involve direct damage to the vessel wall bylarge septic emboli or ischemic injury to the vessel wall by smaller emboli tothe vasa vasorum [41,42]. Splenic abscesses complicate infective endocarditisin injection drug users and occur more commonly in those with S. aureusinfection. Endophthalmitis may also occur as a result of hematogenousdissemination of infection. Immune complex–mediated glomerulonephritismay complicate infective endocarditis in injection drug users; one series ofpatients with S. aureus endocarditis that compared addicts with nonaddictssuggested that, although evidence of renal involvement (hematuria, pyuria)was equal in the two groups, acute renal failure was more common in thenonaddicted group [39].

Bone and joint infection as a result of hematogenous seeding may com-plicate infective endocarditis. The risk of musculoskeletal infections in injec-tion drug users with infective endocarditis seems to be significantly higherthan among nonaddicts with infective endocarditis [43]. Because musculo-skeletal complaints are common in hospitalized injection drug users, clini-cians must maintain a high index of suspicion and pursue an aggressivediagnostic evaluation in injection drug users with infective endocarditis andmusculoskeletal complaints. In a recent study, vertebral osteomyelitis wasthe most common musculoskeletal infection seen in association with infec-tive endocarditis [43].

The risk of mortality in injection drug users with infective endocarditisvaries depending on the valve involved and the causative organism. In theDetroit Medical Center series, the overall mortality rate was 12% [4]. Themortality rate was highest (30%) for those with infective endocarditis causedby P. aeruginosa. In the more recent series from Cook County, the overallmortality rate was 9%; patients with left-sided involvement were at signifi-cantly higher risk of requiring surgery and of dying [6]. In a study of injec-tion drug users with right-sided infective endocarditis (in which 82% of caseswere caused by S. aureus), the overall mortality rate was 7% [38]. Althoughthe overall prognosis is more favorable for injection drug users with infectiveendocarditis than for nonaddicts, a recent autopsy series from the Baltimoremedical examiner’s office suggested that injection drug users with infectiveendocarditis are at markedly greater risk of sudden death than are non-addicts with infective endocarditis [44].

As discussed previously, injection drug users infected with HIV seem tobe at higher risk for infective endocarditis. In this group of patients mortal-ity is associated with the severity of underlying immunodeficiency, as evi-denced by CD4 cell count [45–47].

Diagnosis

It may be difficult, based solely on initial clinical findings, to distinguishinjection drug users who have infective endocarditis from those without[48]. Nevertheless, the diagnosis often becomes apparent after minimal


evaluation. Frequently the clinical pattern of pulmonary signs and symp-toms or evidence of left-sided cardiac involvement in a septic-appearinginjection drug user makes the diagnosis straightforward.

No single test establishes the diagnosis of infective endocarditis. In con-junction with blood cultures, the echocardiogram is often considered to bethe best tool for assessing the likelihood of a patient’s having infective endo-carditis. Many investigators have evaluated the sensitivity of echocardiogra-phy for confirming the diagnosis. In one study comparing transthoracic(TTE) and transesophageal (TEE) echocardiography, the authors concludedthat the likelihood of either test’s being positive increased as the pretestprobability increased. In patients with intermediate or high clinical prob-ability, the two approaches were equivalent. The authors recommended astepwise approach, starting with TTE and advancing to TEE if the first testis negative [49]. A TTE is at least equivalent, if not superior, to TEE fordetecting lesions involving the tricuspid valve [50–53]. Patients with nativevalve endocarditis and large aortic valve vegetations demonstrated by TTEare at high risk of developing major complications such as congestive heartfailure during treatment [54,55]. In another study the size of vegetationsdetermined by TTE was not significant, but the risk of periannular extensionof infection was twice as great in injection drug users with vegetations on theaortic valve than in those without aortic-valve vegetations and in non–drugusers [56]. The finding of large tricuspid valve vegetations in injection drugusers does not seem to be a marker for a poor outcome [57].

Transesophageal echocardiography may be reserved for patients with sus-pected left-sided involvement in whom TTE is inconclusive. Transesopha-geal echocardiography is preferred for assessment of perivalvular lesions,such as valve-ring abscess or valve perforation [58] and is also superior toTTE in patients with infective endocarditis involving a vestigial eustachianvalve [50,51,59]. Although TEE has excellent predictive ability, a negativeTEE does not rule out infective endocarditis [60].

For many clinicians, the results of the many studies comparing the twoechocardiographic techniques leads to difficulty in deciding when to employwhich test. In a recent cost-effectiveness study, the authors determined that,in patients for whom the pretest probability of endocarditis exceeds 60%, itis more cost-effective to treat for infective endocarditis without performingan echocardiogram. Transesophageal echocardiography rather than TTE isrecommended for patients with a pretest probability of 4% to 60%. If theclinical assessment of infective endocarditis results in a clinical probabilityof infective endocarditis of less than 4%, treatment for bacteremia ratherthan infective endocarditis is most cost-effective [61].

Despite the impressive body of literature, nothing has done as much toelevate the importance of the echocardiogram in infective endocarditis asthe diagnostic criteria developed by David Durack and colleagues at DukeUniversity. Over time clinicians struggled to define a set of criteria thatcould be widely applied to establish a diagnosis of endocarditis. Although


in most clinical settings such criteria are not needed; such a tool would beimportant to clinicians in difficult clinical situations and to scientists in-volved in clinical research. Until recently, the most widely accepted schemawas the Von Reyn or Beth Israel criteria, which were developed before theuse of echocardiography became common [62]. Although generally useful,these criteria were difficult to apply to some populations, most notably toinjection drug users.

The initial Duke system classified a variety of well-recognized signs andsymptoms associated with infective endocarditis and combined them withpatient characteristics and echocardiographic findings into a set of majorand minor criteria. Identifying the correct number of major or minor criteriapermitted the probability of disease to be categorized as definite or possibleendocarditis; the diagnosis was rejected in cases that did not meet the crite-ria for either category [63]. After the criteria were published, a number ofinvestigators applied the Duke criteria to different patient populations andin different clinical settings. In each instance, excellent positive and negative

Definition of endocarditis

Definite endocarditis

Pathologic criteriaMicroorganisms demonstrated by culture or histologyVegetations or intracardiac abscess confirmed by histology

Clinical criteria2 major criteria; or1 major criterion and 3 minor criteria; or5 minor criteria

Possible endocarditis

1 major criterion and 1 minor criterion; or3 minor criteria

Rejected

Firm alternate diagnosis explaining findings; orResolution of infective endocarditis syndrome with antibiotic

therapy for 4 days or less; orNo pathologic evidence of infective endocarditis at surgery or

autopsy, with antibiotic therapy for 4 days or less; orDoes not meet criteria for possible endocarditis

Adapted from: Li JS, Sexton DJ, Mick N, et al. Proposed modifications tothe Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis2000;30:633–8, with permission.


predictive value was demonstrated [64–75]. It was soon recognized, however,that shortcomings remained despite the substantial improvement overprevious systems. Culture-negative cases, most notably cases caused byCoxiella burnetii (Q fever), were misclassified as ‘‘rejected.’’ Also, in theoriginal schema, the increased risk of endocarditis from S. aureus was notconsidered, nor was the increased use of TEE for diagnosis. Furthermore,it became clear that the category of ‘‘possible endocarditis’’ was too broad,leading to problems with classification of some cases. To address these prob-lems, a set of revised Duke criteria was recently published. The definition ofinfective endocarditis and the criteria for diagnosis are presented in theaccompanying boxes [76].

Criteria for diagnosis of infective endocarditis

Major criteria

Blood culture positive for infective endocarditis

Typical microorganism consistent with infectiveendocarditis from two separate blood cultures:

• Viridans streptococci, Streptococcus bovis, HACEK group,Staphylococcus aureus; or

• Community-acquired enterococci, in the absence of aprimary focus; or

Microorganisms consistent with infective endocarditis frompersistently positive blood cultures, defined as follows:

• At least two positive cultures of blood samples drawnmore than 12 hours apart; or

• All of three or a majority of four or more separate culturesof blood (with first and last sample drawn at least 1 hour apart)

Single positive blood culture for Coxiella burnetti orantiphase I IgG antibody titer higher than1:800

Evidence of endocardial involvement

Echocardiogram positive for infective endocarditis (TEErecommended in patients with prosthetic valves, rated at least‘‘possible infective endocarditis’’ by clinical criteria, orcomplicated infective endocarditis (paravalvular abscess);TTE as first test in other patients), defined as follows:

Oscillating intracardiac mass on valve or supportingstructures, in the path of regurgitant jets, or on implantedmaterial in the absence of an alternative anatomicexplanation; or


Laboratory findings

The hallmark of endocarditis has always been, and remains, persistentbacteremia [62,63,76]. Usually the bacteremia is high grade, and most bloodcultures are positive [4,39]. Ideally, the cultures are obtained over a period ofhours to demonstrate true persistence. Even in injection drug users withapparent infective endocarditis, the signs and symptoms of disease have usu-ally been present for days; unless the patient is critically ill, delaying a fewhours before starting empiric therapy is unlikely to result in harm to thepatient. In emergency situations when therapy must be initiated quickly,blood cultures should be obtained from different sites if at all possible. Inmost cases blood cultures remain positive even after a few days of antibiotictherapy, frequently allowing recovery of the etiologic agent even when thepatient has taken antibiotics before coming to medical attention or hasreceived empiric therapy before blood cultures were obtained [4,39,77]. Insuch cases, blood cultures are more likely to be positive if the isolate is resis-tant to the antibiotic that was used. In other cases, prior antibiotic usemay suppress bacteremia. The duration of suppression is both variable andunpredictable, but repeating blood cultures after a period of time before ini-tiating therapy will probably allow recovery of the causative pathogen [78].

Abscess; or

New partial dehiscence of prosthetic valve

New valvular regurgitation (worsening or changing ofpre-existing murmur not sucient for diagnosis)

Minor criteria

Predisposition, predisposing heart condition, or use of injecteddrugs

Fever, temperature higher than 38�CVascular phenomena, major arterial emboli, septic pulmonaryinfarcts, mycotic aneurysm, intracardiac hemorrhage,conjunctival hemorrhages, and Janeway’s lesionImmunologic phenomena: glomerulonephritis, Osler’s node,Roth’s spots, and rheumatoid factorMicrobiologic evidence: positive blood culture but does not meeta major criterion as noted above or serologic evidence of activeinfection with organism consistent with infective endocarditis

TEE, transesophageal echocardiography; TTE, transthoracic echocardiography

Adapted from: Li JS, Sexton DJ, Mick N, et al. Proposed modificationsto the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis2000;30:633-8, with permission.


True culture-negative endocarditis is rare in injection drug users, and nega-tive blood cultures should raise a question about the diagnosis. The bacter-emia in endocarditis may result in secondary infection. Therefore, whenthere is evidence that other structures are involved, cultures of fluid or othermaterial from those sites may lead to isolation of the offending pathogen.The specimens most likely to yield a positive culture result are synovial fluidor urine, but care is necessary to distinguish infection caused by the contin-uous bacteremia of endocarditis from primary infection leading to bacter-emia that can be mistakenly diagnosed as infective endocarditis.

Other laboratory studies reveal a variety of abnormalities in injectiondrug users with infective endocarditis, but none are specific for endocarditis.Indeed, even among injection drug users, standard laboratory studies revealnothing to differentiate addicts with infective endocarditis from those withother diseases [4,5]. There are few differences between injection drug userswith infective endocarditis and nonaddicts with infective endocarditis. Per-haps the only significant difference is the bacteriology of the disease in injec-tion drug user. As noted previously, S. aureus is isolated far more often ininjection drug users than in any other population. Unusual organisms andmultiple pathogens are also more likely to be found in injection drug usersthan in other groups; special techniques may be needed to ensure thatdifficult-to-isolate organisms are not missed [79,80]. Anemia is common inaddicts because of frequent blood loss that occurs with self-administrationof illicit drugs. Hence, anemia is common in injection drug users with endo-carditis [4], but it is no more common in addicts than in any other popula-tion with infective endocarditis. As expected, injection drug users withinfective endocarditis have elevated white blood cell counts with a left shift.The mean white blood cell counts are significantly higher in injection drugusers with infective endocarditis than in bacteremic injection drug userswithout infective endocarditis, but this difference is not useful in distinguish-ing one group from the other [4]. Neutropenia and thrombocytopenia areoccasionally seen. Platelet counts below 100,000 are associated with a poorprognosis [81].

Another finding, nonspecific but striking in injection drug users withinfective endocarditis, is mild hyponatremia (125–133 mEq/L) that isobserved in almost 40% of these patients immediately after admission andbefore fluid supplementation. Hyponatremia is also seen, but significantlyless often, in bacteremic injection drug users who do not have endocarditis(28%, P¼ 0.002). The reason for this finding is unknown, but it is an impor-tant prognostic indicator because it identifies patients who are more likely tohave prolonged fever and greater associated morbidity [4]. The electrolyteabnormalities almost always correct immediately after initiation of fluidresuscitation.

Because the bacteremia of endocarditis is typically high grade and persis-tent, virtually every organ is affected. A number of nonspecific abnormalblood test results reflect this involvement. Indeed, virtually every laboratory


test may reveal an abnormality. Abnormal hepatic enzymes and serum pro-teins are routinely seen in the early stages of disease. Also, because of thefrequency of renal complications, elevated serum urea nitrogen (BUN) andcreatinine levels are typical. These elevations may represent pre-renal azote-mia, drug toxicity, immune-complex nephritis, or direct involvement of thekidney by the infecting organism. An active urinary sediment, includingpyuria, hematuria, and albuminuria, is also observed. Patients with septicpulmonary emboli are likely to have abnormal pleural fluid. Abnormalcerebrospinal is common in patients with infective endocarditis [82].Although CNS complications occur less frequently in addicts than in non-addicts, they are often the presenting symptom, particularly if a mycoticaneurysm has ruptured. The cerebrospinal fluid is abnormal in such cases,but increased white blood cell counts and protein are also found in patientswith no overt CNS signs or symptoms. Because abnormal laboratory resultsare so common, the authors recommend waiting for the condition to stab-ilize after the patient has received several days of therapy before beginninga work up to evaluate the numerous abnormal laboratory results. Usuallythese results become normal, and there is no reason to perform additionalstudies.

Treatment

The fundamentals of treatment of infective endocarditis are the same ininjection drug users as in the general population. Unlike nonaddicts, how-ever, injection drug users often have difficult or nonexistent venous access,making it a challenge to administer the parenteral agents typically required.It is also difficult, if not potentially risky, to administer the therapy on anoutpatient basis, whereas such an approach is becoming routine in the non-addicted population.

Because the organisms in a vegetation are shielded from the host immunesystem, effective management depends on antibiotics alone. The selection ofbactericidal agents must be guided by carefully performed susceptibility test-ing. These antibiotics must be capable of penetrating to the core of thelesion, and the regimen must be of sufficient duration to assure eradicationof all organisms. In some cases, depending on the particular organism andthe site of infection, synergistic activity between two or more antibiotics maypermit a shorter duration of therapy than is usually possible in infectiveendocarditis. In other cases a synergistic regimen is necessary to achievean acceptable cure rate. In some situations, most notably infections causedby Gram-negative or fungal pathogens, studies have yet to indicate the besttherapeutic regimen, and recommendations are based on small series or indi-vidual case reports.

The decision to initiate antibiotic therapy in a febrile injection druguser requires careful consideration. Every effort must be made to identify the


offending pathogen. At least two or three blood cultures should be obtainedbefore starting empiric therapy. It is preferable to withhold treatment whileawaiting culture results. In some cases blood cultures are only transientlypositive, and all signs of sepsis disappear after only a few hours of observa-tion [4,83]. In other cases cultures are negative, and there is no obvious focusof infection. In these cases, if the patient receives therapy prematurely, theclinician may feel committed to a prolonged course of therapy based onan incorrect diagnostic assumption. With negative cultures and disappear-ance of signs and symptoms, the patient can be managed like any otherpatient who had a transient febrile episode.

In most cases the decision to begin therapy immediately after obtainingcultures is appropriate. The only question is which regimen to begin. Knowl-edge of the usual pathogens isolated in a given community is helpful, partic-ularly if there is a high likelihood the causative agent is resistant to theantibiotics most often prescribed in empiric regimens. In every case, given theusual bacteriology of infective endocarditis in addicts, the regimen should bedesigned to cover S. aureus. The decision to begin with a beta-lactam anti-biotic or vancomycin (to assure activity against methicillin-resistant staphy-lococci) is based on the prevalence of methicillin-resistant S. aureus in thecommunity. The authors do not routinely cover forGram-negative organismsin the empiric regimen. The Gram-negative organism most commonly seenat the Wayne State University School of Medicine is P. aeruginosa, whichproduces an indolent infection and which requires serum concentrationsof aminoglycosides much higher than would be used in an empiric regimen[15,84,85]. Routine aminoglycoside doses contribute very little to the out-come but increase the risk of toxicity. In other locations, where Gram-neg-ative organisms other than P. aeruginosa cause infective endocarditis, anaminoglycoside-containing empiric regimen may be appropriate.

Once the causative agent has been identified, the initial empiric regimenshould be changed to a definitive regimen. In 1995 the American HeartAssociation published guidelines for the treatment of endocarditis causedby the usual pathogens [86]. Although not specifically designed to treatendocarditis in injection drug users, the guidelines are useful for the man-agement of most cases. Some circumstances, however, deserve special men-tion. As noted, S. aureus is the most common cause of infective endocarditisin injection drug users, and the tricuspid valve is often involved. Numerousinvestigators have observed that S. aureus endocarditis in drug users is asso-ciated with a favorable prognosis and responds well to therapy. Evenpatients who leave the hospital against medical advice after clearing thebloodstream but before completing a standard course of therapy are rarelyreadmitted because of relapse or worsening of their condition. ConsequentlyChambers, Miller, Newman, and colleagues performed studies to determineif an abbreviated course of therapy could be used in patients with uncompli-cated S. aureus tricuspid valve infective endocarditis [87]. Patients with evi-dence of left-sided infection, renal failure, extrapulmonary metastatic


infection, infection caused by methicillin-resistant S. aureus, or who werepregnant were excluded. The investigators initially compared a 2-week regi-men of nafcillin plus aminoglycoside with a 2-week regimen of vancomycinplus aminoglycoside. The vancomycin arm was stopped early because onlyone of three patients in this arm was cured. The success rate for patients inthe nafcillin aminoglycoside arm was 94%.

Similar good results were found in a European trial, although in thisstudy 4 of 72 patients required prolongation of therapy to achieve a cure[88]. In another study to determine if an aminoglycoside is a necessarycomponent of a 2-week regimen, Ribera, Gomez-Jimenez, Cortes, and col-leagues compared a 2-week regimen of cloxacillin alone with 2 weeks ofcloxacillin plus gentamicin [89]. The results were comparable for both arms(89% for the single agent versus 92% for the combination). In this trial, theaminoglycoside was administered only for the first 7 days of therapy. If theaminoglycoside had been given for the full 2 weeks, the results in the com-bination arm might have been even better than those obtained, although theoutcome for patients receiving the single-drug regimen are so good that itwould be difficult to demonstrate any significant difference. Pending addi-tional information, most clinicians are more comfortable using the combina-tion regimen. Whether drugs other than beta-lactam antibiotics can also beused in abbreviated regimens has not been established. It is clear that glyco-peptides are inferior and should not be used.

Fortun, Perez-Molina, Anon, et al [90] conducted a trial of short-coursetherapy in which the combination of cloxacillin and gentamicin was com-pared with either vancomycin or teicoplanin, both given in conjunction withgentamicin for 2 weeks. There were no failures in the cloxacillin arm, but therate of either clinical or microbiologic failure was 40% in the vancomycinarm and 30% in the teicoplanin arm. The study was stopped prematurelybecause of the lack of success in the glycopeptide arms. The substantialnumber of HIV–positive patients in this study might have affected the out-come, but they were evenly distributed, and the median CD4 cell countsexceeded 200 cells/mm3. Regimens containing glycopeptides were also foundto be ineffective in a number of other studies.

The importance of adequate dosing and serum concentrations was dem-onstrated in the initial trials of teicoplanin in the United States. Despiteapparent satisfactory outcomes in other studies, the failure rate was unac-ceptably high when injection drug users with infective endocarditis weretreated with teicoplanin. Rybak, Lerner, Levine, et al determined that theexcretion rate of the drug in addicts is approximately double that in nonad-dicts, leading to inadequate serum concentrations in injection drug users[91]. In another clinical trial, teicoplanin was inferior to the combinationof oxacillin plus gentamicin because serum levels were insufficient during thesecond week of therapy [90].

Vancomycin has also been shown to be less effective than beta-lactamantibiotics. In a study by Small and Chambers, bacteremia recurred in 2


of 13 patients treated with vancomycin for 4 weeks; an additional 2 patientsrequired a change in therapy. In vitro time-kill studies showed vancomycinto be less rapidly bactericidal than nafcillin. Levine et al compared vanco-mycin with and without rifampin in patients with methicillin-resistantS. aureus endocarditis [92]. The vancomycin-treated patients remainedbacteremic for a median period of 9 days [92], whereas patients treated withnafcillin for methicillin-susceptible S. aureus endocarditis were bacteremicfor a median period of 3.4 days [93]. In patients with infective endocarditis,vancomycin should be reserved for patients with high-grade penicillin allergy.

In the future quinolones may offer an alternative to both beta-lactamantibiotics and vancomycin for the treatment of S. aureus and a variety ofother pathogens. Quinolones are bactericidal, diffuse rapidly into the coreof vegetations, and have excellent bioavailability when given orally. Oraladministration is especially useful for the treatment of injection drug users,in whom venous access is often difficult. In a small trial in patients withS. aureus infective endocarditis, ciprofloxacin (administered intravenouslyand then switched to oral administration) was effective in all 10 patients whocompleted therapy [94]. In another study, injection drug users with S. aureusendocarditis received intravenous oxacillin or vancomycin (plus gentamicinfor the first 5 days) or oral ciprofloxacin plus rifampin for 28 days. Theresults for the oral regimen were equivalent to those in the parenterallytreated group [95]. Unfortunately, staphylococcal resistance to ciprofloxacinis a major concern, and the use of quinolones for endocarditis has notgained wide acceptance.

Clinafloxacin is an investigational quinolone with broad activity againstGram-positive and gram-negative bacteria as well as against anaerobes. Thusfar, development of resistance to clinafloxacin has not been observed in invitro or in clinical trials. The authors therefore evaluated clinafloxacin in thetreatment of infective endocarditis caused by any susceptible organism inpatients with native or prosthetic valve infection. Therapy was initiated withintravenous clinafloxacin and was switched to oral therapy when the patientwas deemed clinically stable. Patients were followed for up to 6 months.Fifty-four patients with native valve infection and 13 with prosthetic valveinfection were treated. Sixteen of 17 patients treated for S. aureus infectionwere cured. The success rate for streptococcal infection was 83% (15 of 18patients were cured); for enterococcal infection the success rate was 75%(three of four patients were cured); and for Gram-negative infection the suc-cess rate was 100% (three of three patients were cured). Among patients withprosthetic valve infection, 9 of 13 were cured. The 4 patients who failed toimprove were admitted after suffering what proved to be fatal complicationsof infective endocarditis. These results, although encouraging, must be cor-roborated in future studies. If the results are reproduced, quinolone therapyof endocarditis, some or all of which may be administered orally, mayrepresent a true advance for all patients, and especially for difficult-to-treatinjection drug users.


There are insufficient data to support any recommendation for treatmentof Gram-negative infective endocarditis. In studies by Reyes et al, the bestresults for patients with P. aeruginosa infection were achieved with extraor-dinary doses of aminoglycosides in combination with an antipseudomonalbeta-lactam antibiotic [85,96,97]. Patients with left-sided infection routinelyrequired surgical intervention. Cabinian and Kaatz treated a pregnantinjection drug user with P. aeruginosa endocarditis on both the aortic andtricuspid valves complicated by a brain abscess, presumably the result ofa septic embolus. Surgery was deemed too risky, so she was treated withhigh-dose tobramycin and ceftazadime. She made a complete recovery andwas well at 2-years’ follow up [98]. It is possible that with newer antipseudo-monal antibiotics, the previously noted dismal prognosis will be reversed.Similar combinations of high-dose aminoglycosides plus active cell-walldrugs are probably most likely to result in cure of other Gram-negativeorganisms. The role of quinolones in the treatment of Gram-negative endo-carditis is yet to be defined. Most Gram-negative organisms are susceptibleto quinolones, and this activity plus their favorable kinetics make thesedrugs potentially attractive in this setting. Firm recommendations mustawait clinical trials.

Fungal endocarditis has a generally poor prognosis. Ellis, Al-Abdely,Sandridge, et al recently reviewed the outcome of 269 published cases [99]. Thefatality rate was 72% (195 of 269 cases), and the cause of death was directlyrelated to endocarditis in 77% of the 195 patients who died. Patients treatedwith combined surgical and medical therapy had the best outcome. At 1 year,55% of those treated with combined therapy were still alive, compared withonly 36% of those who received only antifungal therapy. Among the antifun-gal agents, amphotericin B was used most commonly (93%). Flucytosine wasused in 22% of cases, rarely as monotherapy. The rest were treated with oneof the newer azoles. The dismal results prevent a recommendation of anyagent as the drug of choice. In view of these results, it seems prudent to com-bine antifungal therapy with an aggressive surgical approach.

As with fungal endocarditis, no recommendations can be made for infec-tive endocarditis caused by the variety of unusual pathogens that occasion-ally are found in injection drug users. Several authors report successfulregimens used to treat Stenotrophomonas maltophilia. A combination ofciprofloxacin plus chloramphenicol was used successfully in one publishedreport [100]; others used a combination of trimethoprim and sulfamethoxa-zole plus ticarcillin and clavulanate to treat a nonaddict [101]. Stenotropho-monas maltophilia rapidly develops resistance to a number of antibiotics,and continued diligence is required to detect relapse. Penicillin, with or with-out an aminoglycoside, was used to treat Eikenella corrodens [25], Neisseriamucosa [102], and group B streptococcus [103] but was inadequate whengiven orally in a patient with infective endocarditis caused by Clostridiumbifermentans. After relapse the patient responded to a 4-week course ofintravenous penicillin plus gentamicin [104].


The role of surgery for endocarditis has been well defined. The usual indi-cations are congestive heart failure caused by valve rupture or perforation,intracardiac abscess, multiple systemic septic emboli, or failure of medicalmanagement. Surgery can be performed safely even in a patient with activeinfection, and delaying a surgical procedure in hopes that the patient mayimprove often leads to a fatal outcome [96,105]. The type of surgery is leftto the discretion of the surgeon. Some favor vegetectomy with repair of thevalve when possible [106–108]. Arbulu and colleagues were first to removethe tricuspid valve completely without inserting a prosthetic valve in injec-tion drug users with right-sided endocarditis. Some argue that this proce-dure results in an unacceptable rate of long-term cardiac failure. Giventhese patients’ rate of return to drug use, however, the risk of acquiringprosthetic valve endocarditis is also high and results in a high fatality rate.Arbulu has followed a series of patients for more than 20 years and reportscontinued success for complete valvulectomy [109–113]. Regardless of thesurgical approach, early, aggressive surgical management optimizes the out-come [62,114].

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infective endocarditis in the injection drug user-september 2002

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