Infect Dis Clin N Am 16 (2002) 645665

Infective endocarditis in the injection

drug user
Patricia D. Brown, MDa,*, Donald P. Levine, MDb
a

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

3990 John R, Detroit, MI 48201, USA
b
Division 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 admissions

among injection drug users, and the overall incidence of infective endocarditis in this population is estimated to be 1 to 20 cases per 10,000 injection
drug users per year [1,2]. Among 210 episodes of infective endocarditis seen
at a community teaching hospital from 1980 to 1990, 33 episodes (16%) were
related to injected drug use [3]. In a large series from the Detroit Medical
Center, 41% of injection drug users with bacteremia was found to have
infective endocarditis [4]. A prospective study of febrile injection drug users
presenting to the emergency department found that the prevalence of
infective endocarditis was 13% [5]. In the Detroit Medical Center study the
male:female ratio among injection drug users with infective endocarditis was
5.4:1. Men with infective endocarditis were somewhat older (mean age, 32.7
years versus 31.4 years) and had signicantly longer histories of addiction
(10.2 years versus 7.1 years) than women [4]. In a more recent series of injection drug users with infective endocarditis seen at Cook County Hospital in
Chicago, the male:female ratio was 2:1 [6]. Injection drug users are also at
signicantly increased risk of recurrent endocarditis [7]. Cocaine use has been
reported to be an independent risk factor for the development of infective
endocarditis in injection drug users [8]. Whether this increased risk is caused
by systemic or immunosuppressive eects of cocaine or by injection habits
(more frequent injection or needle sharing) is currently unknown. Injection
drug users with underlying HIV infection seem to be at an increased risk for
infective endocarditis [9,10].

* Corresponding author.
E-mail address: pbrown@intmed.wayne.edu
0891-5520/02/$ - see front matter
2002, Elsevier Science (USA). All rights reserved.
PII: S 0 8 9 1 - 5 5 2 0 ( 0 2 ) 0 0 0 1 9 - 3

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Pathophysiology
The pathophysiology of infective endocarditis involves damage to the
valvular endothelium, the formation of a platelet-brin thrombus, and
adherence of bacteria to the platelet-thrombus plaque, followed by the proliferation of the infecting organism. In an autopsy series of injection drug
users with infective endocarditis, 81% of patients were found to have no evidence of underlying valvular pathology, and all right-side valves were found
to be normal except for the evidence of bacterial infection [11]. Mitral valve
infective endocarditis may be more common in women who inject drugs,
perhaps as a result of the increased prevalence of mitral valve prolapse in
women [12]. Factors unique to the pathogenesis of right-sided endocarditis
in injection drug users include injury to the valvular endothelium as a result
of physical trauma caused by injected particulate matter or the physiologic
eects of the injected drugs and immunologic dysfunction related to injected
drug use. Physiologic eects of injected drug use that have been postulated
to be important in the pathogenesis of infective endocarditis include druginduced pulmonary hypertension leading to increased right-sided pressures
and tricuspid valve damage caused by increased turbulence, diluent-induced
valvular damage with resultant thrombus formation, and valvular thrombus formation secondary to cocaine use. Frontera and Gradon recently reviewed the current understanding of the pathogenesis of right-sided infective
endocarditis [13].
The organisms that cause infective endocarditis in injection drug users are
thought to originate from the skin or from contamination of the injected
drug, diluent, or injection paraphernalia. Nasal colonization with Staphylococcus aureus has been shown to provide a reservoir from which the skin
may be colonized [14]. Certain organisms including Streptococcus pyogenes,
Serratia marcescens, and Enterococcus spp have been associated almost
exclusively with left-sided involvement with infective endocarditis in injection drug users [4,15,16].
Microbiology
In injection drug users with infective endocarditis, S. aureus is the most
commonly implicated pathogen, accounting for 60.8% of cases in the
Detroit Medical Center series [4]. Other Gram-positive organisms including
S. pyogenes, group G and group B streptococci, and Enterococci were
responsible for 16.2% of cases. Outbreaks of methicillin-resistant S. aureus
infections among injection drug users, including infective endocarditis, have
been described in Detroit [17], Boston [18], and most recently in Zurich,
Switzerland, where the outbreak was caused by the epidemic spread of a
single clone of methicillin-resistant S. aureus [19]. Coagulase-negative staphylococci are rarely isolated from injection drug users with infective endocarditis.

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Gram-negative organisms that have been isolated from injection drug

users with infective endocarditis include Pseudomonas aeruginosa and Serratia marcescens. Pseudomonas aeruginosa infective endocarditis has been
associated with the use of tripelenamine and pentazocine (Ts and blues)
and was isolated from 13.5% of injection drug users with infective endocarditis at the Detroit Medical Center [4]. Pseudomonas aeruginosa has been
reported from other geographic regions as well [2022]. Serratia marcescens
infective endocarditis in injection drug users was rst reported from the San
Francisco Bay area [16] but has since been described from other geographic
regions. The reasons for the unusual geographic clustering of S. marcescens
infections among injection drug users in the San Francisco Bay area in the
1970s remain unclear. Haemophilus spp have been reported to cause infective endocarditis in injection drug users including a syndrome of occult polymicrobial endocarditis caused by H. parainuenzae [23,24]. The practice of
licking the needle before injection or cleaning the injection site with saliva
has been associated with infective endocarditis caused by Eikenella corrodens [25], Neisseria sicca [26], and Rothia dentocariosa [27].
Polymicrobial infective endocarditis is well described in injection drug
users and was seen in 8.1% of patients in the series from the Detroit Medical
Center [4]. Anaerobic bacteria other than Eikenella are rarely reported, but
infective endocarditis caused by Fusobacterium spp, Clostridia bifermentans,
and Bacteroides spp has been described in injection drug users [2830].
Infective endocarditis associated with injected drug use and caused by
Corynebacterium (Archanobacterium) hemoltyicum, C. jeikeium, and
C. diptheriae has been reported [4,31,32].
Fungi are important pathogens in injection drug users with infective
endocarditis. Non-albicans Candida spp including C. parapsilosis and C. tropicalis predominate. Earlier series from the late 1970s and early 1980s reported fungal pathogens more frequently than do more recent reports [33,34].
Clinical presentation
Mathew, Addai, Anand, et al recently studied the clinical features in
injection drug users with infective endocarditis [6]. Fever is the most common clinical nding at presentation and was seen in 77.6% of patients. Three
prospective studies of febrile injection drug users presenting to the emergency department showed that clinical ndings at the time of presentation
are frequently insucient to exclude the diagnosis of infective endocarditis
reliably. Hospitalization of febrile injection drug users awaiting the results
of blood cultures is generally recommended [5,35,36]. Injection drug users
with infective endocarditis are more likely to present earlier than nonaddicts
for medical evaluation after the onset of symptoms. In one series of patients
with infective endocarditis, 94% of injection drug users reported symptoms
of less than 1-week duration, whereas 86% of nondrug users reported
symptoms 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 series

from Cook County Hospital. In the Detroit Medical Center series, however,
a murmur was detected in only 35.1% of patients. In some series, left-sided
disease is more frequently associated with the presence of a murmur on presentation than right-sided infection, but a murmur was detected in 72% of
patients in a large series of injection drug users with right-sided infective
endocarditis [38].
Chest pain is reported in approximately half of patients with infective
endocarditis and is frequently associated with tricuspid valve involvement
and septic pulmonary emboli. Splenomegaly is seen in 10% to 15% of
patients. Findings classically associated with infective endocarditis such as
Roths spots, Oslers nodes, and splinter hemorrhages are rarely seen in injection drug users. In a series of S. aureus infective endocarditis in injection drug
users and nondrug users, a presumed primary source of infection was identied in 46% of the nonaddicts but in only 15% of injection drug users [39].
Radiographic abnormalities consistent with septic pulmonary emboli are
reported in 28% to 47% of injection drug users with infective endocarditis
[4,6]. Other abnormalities that may be visualized on chest radiographs include pneumonia (23%) and evidence of congestive cardiac failure (13%) [6].
Right-sided (tricuspid valve) infective endocarditis has been associated
more frequently with injected drug use; however, in several recent series,
left-sided involvement has predominated [6,12]. In the 125 injection drug
users with infective endocarditis reported from Cook County Hospital,
right-sided infection alone was seen in 34% of patients, left-sided infection
alone was seen in 46% of patients, and evidence of involvement of both sides
was seen in 13% of patients. Among those with left-sided infection, the
mitral valve was involved in 32% and the aortic valve in 19%. Pulmonic
valve infective endocarditis has been reported in injection drug users but
is exceedingly rare.
Complications
Complications are reported in most injection drug users with infective
endocarditis. The most frequently reported complication in many series is
septic pulmonary emboli, reecting the greater prevalence of tricuspid valve
infection. Pneumothorax may result from septic pulmonary emboli [40].
Pleural eusions (including empyema), pneumonia, and mycotic aneurysms
of the pulmonary vessels are also described. Cardiac complications may
occur in those with left- or right-sided involvement and include congestive
cardiac failure, valvular insuciency, myocardial abscess, myocarditis, pericarditis, and myocardial infarction caused by emboli to the coronary vessels.
Central nervous system complications of infective endocarditis in injection drug users include stroke, mycotic aneurysm, brain abscess, meningitis,
and spinal epidural abscess. Stroke was reported in 11.4% of patients in the
series from Cook County [6]. Mycotic aneurysms may occur in virtually any

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location. The pathogenesis may involve direct damage to the vessel wall by
large septic emboli or ischemic injury to the vessel wall by smaller emboli to
the vasa vasorum [41,42]. Splenic abscesses complicate infective endocarditis
in injection drug users and occur more commonly in those with S. aureus
infection. Endophthalmitis may also occur as a result of hematogenous
dissemination of infection. Immune complexmediated glomerulonephritis
may complicate infective endocarditis in injection drug users; one series of
patients with S. aureus endocarditis that compared addicts with nonaddicts
suggested that, although evidence of renal involvement (hematuria, pyuria)
was equal in the two groups, acute renal failure was more common in the
nonaddicted group [39].
Bone and joint infection as a result of hematogenous seeding may complicate infective endocarditis. The risk of musculoskeletal infections in injection drug users with infective endocarditis seems to be signicantly higher
than among nonaddicts with infective endocarditis [43]. Because musculoskeletal complaints are common in hospitalized injection drug users, clinicians must maintain a high index of suspicion and pursue an aggressive
diagnostic evaluation in injection drug users with infective endocarditis and
musculoskeletal complaints. In a recent study, vertebral osteomyelitis was
the most common musculoskeletal infection seen in association with infective endocarditis [43].
The risk of mortality in injection drug users with infective endocarditis
varies depending on the valve involved and the causative organism. In the
Detroit Medical Center series, the overall mortality rate was 12% [4]. The
mortality rate was highest (30%) for those with infective endocarditis caused
by P. aeruginosa. In the more recent series from Cook County, the overall
mortality rate was 9%; patients with left-sided involvement were at signicantly higher risk of requiring surgery and of dying [6]. In a study of injection drug users with right-sided infective endocarditis (in which 82% of cases
were caused by S. aureus), the overall mortality rate was 7% [38]. Although
the overall prognosis is more favorable for injection drug users with infective
endocarditis than for nonaddicts, a recent autopsy series from the Baltimore
medical examiners oce suggested that injection drug users with infective
endocarditis are at markedly greater risk of sudden death than are nonaddicts with infective endocarditis [44].
As discussed previously, injection drug users infected with HIV seem to
be at higher risk for infective endocarditis. In this group of patients mortality is associated with the severity of underlying immunodeciency, as evidenced by CD4 cell count [4547].
Diagnosis
It may be dicult, based solely on initial clinical ndings, to distinguish
injection drug users who have infective endocarditis from those without
[48]. Nevertheless, the diagnosis often becomes apparent after minimal

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evaluation. Frequently the clinical pattern of pulmonary signs and symptoms or evidence of left-sided cardiac involvement in a septic-appearing
injection drug user makes the diagnosis straightforward.
No single test establishes the diagnosis of infective endocarditis. In conjunction with blood cultures, the echocardiogram is often considered to be
the best tool for assessing the likelihood of a patients having infective endocarditis. Many investigators have evaluated the sensitivity of echocardiography for conrming the diagnosis. In one study comparing transthoracic
(TTE) and transesophageal (TEE) echocardiography, the authors concluded
that the likelihood of either tests being positive increased as the pretest
probability increased. In patients with intermediate or high clinical probability, the two approaches were equivalent. The authors recommended a
stepwise approach, starting with TTE and advancing to TEE if the rst test
is negative [49]. A TTE is at least equivalent, if not superior, to TEE for
detecting lesions involving the tricuspid valve [5053]. Patients with native
valve endocarditis and large aortic valve vegetations demonstrated by TTE
are at high risk of developing major complications such as congestive heart
failure during treatment [54,55]. In another study the size of vegetations
determined by TTE was not signicant, but the risk of periannular extension
of infection was twice as great in injection drug users with vegetations on the
aortic valve than in those without aortic-valve vegetations and in nondrug
users [56]. The nding of large tricuspid valve vegetations in injection drug
users does not seem to be a marker for a poor outcome [57].
Transesophageal echocardiography may be reserved for patients with suspected left-sided involvement in whom TTE is inconclusive. Transesophageal echocardiography is preferred for assessment of perivalvular lesions,
such as valve-ring abscess or valve perforation [58] and is also superior to
TTE in patients with infective endocarditis involving a vestigial eustachian
valve [50,51,59]. Although TEE has excellent predictive ability, a negative
TEE does not rule out infective endocarditis [60].
For many clinicians, the results of the many studies comparing the two
echocardiographic techniques leads to diculty in deciding when to employ
which test. In a recent cost-eectiveness study, the authors determined that,
in patients for whom the pretest probability of endocarditis exceeds 60%, it
is more cost-eective to treat for infective endocarditis without performing
an echocardiogram. Transesophageal echocardiography rather than TTE is
recommended for patients with a pretest probability of 4% to 60%. If the
clinical assessment of infective endocarditis results in a clinical probability
of infective endocarditis of less than 4%, treatment for bacteremia rather
than infective endocarditis is most cost-eective [61].
Despite the impressive body of literature, nothing has done as much to
elevate the importance of the echocardiogram in infective endocarditis as
the diagnostic criteria developed by David Durack and colleagues at Duke
University. Over time clinicians struggled to dene a set of criteria that
could be widely applied to establish a diagnosis of endocarditis. Although

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in most clinical settings such criteria are not needed; such a tool would be
important to clinicians in dicult clinical situations and to scientists involved in clinical research. Until recently, the most widely accepted schema
was the Von Reyn or Beth Israel criteria, which were developed before the
use of echocardiography became common [62]. Although generally useful,
these criteria were dicult to apply to some populations, most notably to
injection drug users.
The initial Duke system classied a variety of well-recognized signs and
symptoms associated with infective endocarditis and combined them with
patient characteristics and echocardiographic ndings into a set of major
and minor criteria. Identifying the correct number of major or minor criteria
permitted the probability of disease to be categorized as denite or possible
endocarditis; the diagnosis was rejected in cases that did not meet the criteria for either category [63]. After the criteria were published, a number of
investigators applied the Duke criteria to dierent patient populations and
in dierent clinical settings. In each instance, excellent positive and negative

Denition of endocarditis
Definite endocarditis
Pathologic criteria
Microorganisms demonstrated by culture or histology
Vegetations or intracardiac abscess confirmed by histology
Clinical criteria
2 major criteria; or
1 major criterion and 3 minor criteria; or
5 minor criteria
Possible endocarditis
1 major criterion and 1 minor criterion; or
3 minor criteria
Rejected
Firm alternate diagnosis explaining findings; or
Resolution of infective endocarditis syndrome with antibiotic
therapy for 4 days or less; or
No pathologic evidence of infective endocarditis at surgery or
autopsy, with antibiotic therapy for 4 days or less; or
Does not meet criteria for possible endocarditis
Adapted from: Li JS, Sexton DJ, Mick N, et al. Proposed modifications to
the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis
2000;30:6338, with permission.

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predictive value was demonstrated [6475]. It was soon recognized, however,

that shortcomings remained despite the substantial improvement over
previous systems. Culture-negative cases, most notably cases caused by
Coxiella burnetii (Q fever), were misclassied as rejected. Also, in the
original schema, the increased risk of endocarditis from S. aureus was not
considered, 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 classication of some cases. To address these problems, a set of revised Duke criteria was recently published. The denition of
infective endocarditis and the criteria for diagnosis are presented in the
accompanying boxes [76].

Criteria for diagnosis of infective endocarditis

Major criteria
Blood culture positive for infective endocarditis
Typical microorganism consistent with infective
endocarditis from two separate blood cultures:
Viridans streptococci, Streptococcus bovis, HACEK group,
Staphylococcus aureus; or
Community-acquired enterococci, in the absence of a
primary focus; or
Microorganisms consistent with infective endocarditis from
persistently positive blood cultures, defined as follows:
At least two positive cultures of blood samples drawn
more than 12 hours apart; or
All of three or a majority of four or more separate cultures
of blood (with first and last sample drawn at least 1 hour apart)
Single positive blood culture for Coxiella burnetti or
antiphase I IgG antibody titer higher than1:800
Evidence of endocardial involvement
Echocardiogram positive for infective endocarditis (TEE
recommended in patients with prosthetic valves, rated at least
possible infective endocarditis by clinical criteria, or
complicated infective endocarditis (paravalvular abscess);
TTE as first test in other patients), defined as follows:
Oscillating intracardiac mass on valve or supporting
structures, in the path of regurgitant jets, or on implanted
material in the absence of an alternative anatomic
explanation; or

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Abscess; or
New partial dehiscence of prosthetic valve
New valvular regurgitation (worsening or changing of
pre-existing murmur not sucient for diagnosis)
Minor criteria
Predisposition, predisposing heart condition, or use of injected
drugs
Fever, temperature higher than 38C
Vascular phenomena, major arterial emboli, septic pulmonary
infarcts, mycotic aneurysm, intracardiac hemorrhage,
conjunctival hemorrhages, and Janeways lesion
Immunologic phenomena: glomerulonephritis, Oslers node,
Roths spots, and rheumatoid factor
Microbiologic evidence: positive blood culture but does not meet
a major criterion as noted above or serologic evidence of active
infection with organism consistent with infective endocarditis
TEE, transesophageal echocardiography; TTE, transthoracic echocardiography
Adapted from: Li JS, Sexton DJ, Mick N, et al. Proposed modifications
to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis
2000;30:633-8, with permission.

Laboratory ndings
The hallmark of endocarditis has always been, and remains, persistent
bacteremia [62,63,76]. Usually the bacteremia is high grade, and most blood
cultures are positive [4,39]. Ideally, the cultures are obtained over a period of
hours to demonstrate true persistence. Even in injection drug users with
apparent infective endocarditis, the signs and symptoms of disease have usually been present for days; unless the patient is critically ill, delaying a few
hours before starting empiric therapy is unlikely to result in harm to the
patient. In emergency situations when therapy must be initiated quickly,
blood cultures should be obtained from dierent sites if at all possible. In
most cases blood cultures remain positive even after a few days of antibiotic
therapy, frequently allowing recovery of the etiologic agent even when the
patient has taken antibiotics before coming to medical attention or has
received empiric therapy before blood cultures were obtained [4,39,77]. In
such cases, blood cultures are more likely to be positive if the isolate is resistant to the antibiotic that was used. In other cases, prior antibiotic use
may suppress bacteremia. The duration of suppression is both variable and
unpredictable, but repeating blood cultures after a period of time before initiating therapy will probably allow recovery of the causative pathogen [78].

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True culture-negative endocarditis is rare in injection drug users, and negative blood cultures should raise a question about the diagnosis. The bacteremia in endocarditis may result in secondary infection. Therefore, when
there is evidence that other structures are involved, cultures of uid or other
material from those sites may lead to isolation of the oending pathogen.
The specimens most likely to yield a positive culture result are synovial uid
or urine, but care is necessary to distinguish infection caused by the continuous bacteremia of endocarditis from primary infection leading to bacteremia that can be mistakenly diagnosed as infective endocarditis.
Other laboratory studies reveal a variety of abnormalities in injection
drug users with infective endocarditis, but none are specic for endocarditis.
Indeed, even among injection drug users, standard laboratory studies reveal
nothing to dierentiate addicts with infective endocarditis from those with
other diseases [4,5]. There are few dierences between injection drug users
with infective endocarditis and nonaddicts with infective endocarditis. Perhaps the only signicant dierence is the bacteriology of the disease in injection drug user. As noted previously, S. aureus is isolated far more often in
injection drug users than in any other population. Unusual organisms and
multiple pathogens are also more likely to be found in injection drug users
than in other groups; special techniques may be needed to ensure that
dicult-to-isolate organisms are not missed [79,80]. Anemia is common in
addicts because of frequent blood loss that occurs with self-administration
of illicit drugs. Hence, anemia is common in injection drug users with endocarditis [4], but it is no more common in addicts than in any other population with infective endocarditis. As expected, injection drug users with
infective endocarditis have elevated white blood cell counts with a left shift.
The mean white blood cell counts are signicantly higher in injection drug
users with infective endocarditis than in bacteremic injection drug users
without infective endocarditis, but this dierence is not useful in distinguishing one group from the other [4]. Neutropenia and thrombocytopenia are
occasionally seen. Platelet counts below 100,000 are associated with a poor
prognosis [81].
Another nding, nonspecic but striking in injection drug users with
infective endocarditis, is mild hyponatremia (125133 mEq/L) that is
observed in almost 40% of these patients immediately after admission and
before uid supplementation. Hyponatremia is also seen, but signicantly
less often, in bacteremic injection drug users who do not have endocarditis
(28%, P 0.002). The reason for this nding is unknown, but it is an important prognostic indicator because it identies patients who are more likely to
have prolonged fever and greater associated morbidity [4]. The electrolyte
abnormalities almost always correct immediately after initiation of uid
resuscitation.
Because the bacteremia of endocarditis is typically high grade and persistent, virtually every organ is aected. A number of nonspecic abnormal
blood test results reect this involvement. Indeed, virtually every laboratory

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test may reveal an abnormality. Abnormal hepatic enzymes and serum proteins are routinely seen in the early stages of disease. Also, because of the
frequency of renal complications, elevated serum urea nitrogen (BUN) and
creatinine levels are typical. These elevations may represent pre-renal azotemia, drug toxicity, immune-complex nephritis, or direct involvement of the
kidney by the infecting organism. An active urinary sediment, including
pyuria, hematuria, and albuminuria, is also observed. Patients with septic
pulmonary emboli are likely to have abnormal pleural uid. Abnormal
cerebrospinal is common in patients with infective endocarditis [82].
Although CNS complications occur less frequently in addicts than in nonaddicts, they are often the presenting symptom, particularly if a mycotic
aneurysm has ruptured. The cerebrospinal uid is abnormal in such cases,
but increased white blood cell counts and protein are also found in patients
with no overt CNS signs or symptoms. Because abnormal laboratory results
are so common, the authors recommend waiting for the condition to stabilize after the patient has received several days of therapy before beginning
a work up to evaluate the numerous abnormal laboratory results. Usually
these results become normal, and there is no reason to perform additional
studies.

Treatment
The fundamentals of treatment of infective endocarditis are the same in
injection drug users as in the general population. Unlike nonaddicts, however, injection drug users often have dicult or nonexistent venous access,
making it a challenge to administer the parenteral agents typically required.
It is also dicult, if not potentially risky, to administer the therapy on an
outpatient basis, whereas such an approach is becoming routine in the nonaddicted population.
Because the organisms in a vegetation are shielded from the host immune
system, eective management depends on antibiotics alone. The selection of
bactericidal agents must be guided by carefully performed susceptibility testing. These antibiotics must be capable of penetrating to the core of the
lesion, and the regimen must be of sucient duration to assure eradication
of all organisms. In some cases, depending on the particular organism and
the site of infection, synergistic activity between two or more antibiotics may
permit a shorter duration of therapy than is usually possible in infective
endocarditis. In other cases a synergistic regimen is necessary to achieve
an acceptable cure rate. In some situations, most notably infections caused
by Gram-negative or fungal pathogens, studies have yet to indicate the best
therapeutic regimen, and recommendations are based on small series or individual case reports.
The decision to initiate antibiotic therapy in a febrile injection drug
user requires careful consideration. Every eort must be made to identify the

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oending pathogen. At least two or three blood cultures should be obtained

before starting empiric therapy. It is preferable to withhold treatment while
awaiting culture results. In some cases blood cultures are only transiently
positive, and all signs of sepsis disappear after only a few hours of observation [4,83]. In other cases cultures are negative, and there is no obvious focus
of infection. In these cases, if the patient receives therapy prematurely, the
clinician may feel committed to a prolonged course of therapy based on
an incorrect diagnostic assumption. With negative cultures and disappearance of signs and symptoms, the patient can be managed like any other
patient who had a transient febrile episode.
In most cases the decision to begin therapy immediately after obtaining
cultures is appropriate. The only question is which regimen to begin. Knowledge of the usual pathogens isolated in a given community is helpful, particularly if there is a high likelihood the causative agent is resistant to the
antibiotics most often prescribed in empiric regimens. In every case, given the
usual bacteriology of infective endocarditis in addicts, the regimen should be
designed to cover S. aureus. The decision to begin with a beta-lactam antibiotic or vancomycin (to assure activity against methicillin-resistant staphylococci) is based on the prevalence of methicillin-resistant S. aureus in the
community. The authors do not routinely cover for Gram-negative organisms
in the empiric regimen. The Gram-negative organism most commonly seen
at the Wayne State University School of Medicine is P. aeruginosa, which
produces an indolent infection and which requires serum concentrations
of aminoglycosides much higher than would be used in an empiric regimen
[15,84,85]. Routine aminoglycoside doses contribute very little to the outcome but increase the risk of toxicity. In other locations, where Gram-negative organisms other than P. aeruginosa cause infective endocarditis, an
aminoglycoside-containing empiric regimen may be appropriate.
Once the causative agent has been identied, the initial empiric regimen
should be changed to a denitive regimen. In 1995 the American Heart
Association published guidelines for the treatment of endocarditis caused
by the usual pathogens [86]. Although not specically designed to treat
endocarditis in injection drug users, the guidelines are useful for the management of most cases. Some circumstances, however, deserve special mention. As noted, S. aureus is the most common cause of infective endocarditis
in injection drug users, and the tricuspid valve is often involved. Numerous
investigators have observed that S. aureus endocarditis in drug users is associated with a favorable prognosis and responds well to therapy. Even
patients who leave the hospital against medical advice after clearing the
bloodstream but before completing a standard course of therapy are rarely
readmitted because of relapse or worsening of their condition. Consequently
Chambers, Miller, Newman, and colleagues performed studies to determine
if an abbreviated course of therapy could be used in patients with uncomplicated S. aureus tricuspid valve infective endocarditis [87]. Patients with evidence of left-sided infection, renal failure, extrapulmonary metastatic

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657

infection, infection caused by methicillin-resistant S. aureus, or who were

pregnant were excluded. The investigators initially compared a 2-week regimen of nafcillin plus aminoglycoside with a 2-week regimen of vancomycin
plus aminoglycoside. The vancomycin arm was stopped early because only
one of three patients in this arm was cured. The success rate for patients in
the nafcillin aminoglycoside arm was 94%.
Similar good results were found in a European trial, although in this
study 4 of 72 patients required prolongation of therapy to achieve a cure
[88]. In another study to determine if an aminoglycoside is a necessary
component of a 2-week regimen, Ribera, Gomez-Jimenez, Cortes, and colleagues compared a 2-week regimen of cloxacillin alone with 2 weeks of
cloxacillin plus gentamicin [89]. The results were comparable for both arms
(89% for the single agent versus 92% for the combination). In this trial, the
aminoglycoside was administered only for the rst 7 days of therapy. If the
aminoglycoside had been given for the full 2 weeks, the results in the combination arm might have been even better than those obtained, although the
outcome for patients receiving the single-drug regimen are so good that it
would be dicult to demonstrate any signicant dierence. Pending additional information, most clinicians are more comfortable using the combination regimen. Whether drugs other than beta-lactam antibiotics can also be
used in abbreviated regimens has not been established. It is clear that glycopeptides are inferior and should not be used.
Fortun, Perez-Molina, Anon, et al [90] conducted a trial of short-course
therapy in which the combination of cloxacillin and gentamicin was compared with either vancomycin or teicoplanin, both given in conjunction with
gentamicin for 2 weeks. There were no failures in the cloxacillin arm, but the
rate of either clinical or microbiologic failure was 40% in the vancomycin
arm and 30% in the teicoplanin arm. The study was stopped prematurely
because of the lack of success in the glycopeptide arms. The substantial
number of HIVpositive patients in this study might have aected the outcome, but they were evenly distributed, and the median CD4 cell counts
exceeded 200 cells/mm3. Regimens containing glycopeptides were also found
to be ineective in a number of other studies.
The importance of adequate dosing and serum concentrations was demonstrated in the initial trials of teicoplanin in the United States. Despite
apparent satisfactory outcomes in other studies, the failure rate was unacceptably high when injection drug users with infective endocarditis were
treated with teicoplanin. Rybak, Lerner, Levine, et al determined that the
excretion rate of the drug in addicts is approximately double that in nonaddicts, leading to inadequate serum concentrations in injection drug users
[91]. In another clinical trial, teicoplanin was inferior to the combination
of oxacillin plus gentamicin because serum levels were insucient during the
second week of therapy [90].
Vancomycin has also been shown to be less eective than beta-lactam
antibiotics. In a study by Small and Chambers, bacteremia recurred in 2

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P.D. Brown and D.P. Levine / Infect Dis Clin N Am 16 (2002) 645665

of 13 patients treated with vancomycin for 4 weeks; an additional 2 patients

required a change in therapy. In vitro time-kill studies showed vancomycin
to be less rapidly bactericidal than nafcillin. Levine et al compared vancomycin with and without rifampin in patients with methicillin-resistant
S. aureus endocarditis [92]. The vancomycin-treated patients remained
bacteremic for a median period of 9 days [92], whereas patients treated with
nafcillin for methicillin-susceptible S. aureus endocarditis were bacteremic
for 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 oer an alternative to both beta-lactam
antibiotics and vancomycin for the treatment of S. aureus and a variety of
other pathogens. Quinolones are bactericidal, diuse rapidly into the core
of vegetations, and have excellent bioavailability when given orally. Oral
administration is especially useful for the treatment of injection drug users,
in whom venous access is often dicult. In a small trial in patients with
S. aureus infective endocarditis, ciprooxacin (administered intravenously
and then switched to oral administration) was eective in all 10 patients who
completed therapy [94]. In another study, injection drug users with S. aureus
endocarditis received intravenous oxacillin or vancomycin (plus gentamicin
for the rst 5 days) or oral ciprooxacin plus rifampin for 28 days. The
results for the oral regimen were equivalent to those in the parenterally
treated group [95]. Unfortunately, staphylococcal resistance to ciprooxacin
is a major concern, and the use of quinolones for endocarditis has not
gained wide acceptance.
Clinaoxacin is an investigational quinolone with broad activity against
Gram-positive and gram-negative bacteria as well as against anaerobes. Thus
far, development of resistance to clinaoxacin has not been observed in in
vitro or in clinical trials. The authors therefore evaluated clinaoxacin in the
treatment of infective endocarditis caused by any susceptible organism in
patients with native or prosthetic valve infection. Therapy was initiated with
intravenous clinaoxacin and was switched to oral therapy when the patient
was deemed clinically stable. Patients were followed for up to 6 months.
Fifty-four patients with native valve infection and 13 with prosthetic valve
infection were treated. Sixteen of 17 patients treated for S. aureus infection
were cured. The success rate for streptococcal infection was 83% (15 of 18
patients were cured); for enterococcal infection the success rate was 75%
(three of four patients were cured); and for Gram-negative infection the success rate was 100% (three of three patients were cured). Among patients with
prosthetic valve infection, 9 of 13 were cured. The 4 patients who failed to
improve were admitted after suering what proved to be fatal complications
of infective endocarditis. These results, although encouraging, must be corroborated in future studies. If the results are reproduced, quinolone therapy
of endocarditis, some or all of which may be administered orally, may
represent a true advance for all patients, and especially for dicult-to-treat
injection drug users.

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659

There are insucient data to support any recommendation for treatment

of Gram-negative infective endocarditis. In studies by Reyes et al, the best
results for patients with P. aeruginosa infection were achieved with extraordinary doses of aminoglycosides in combination with an antipseudomonal
beta-lactam antibiotic [85,96,97]. Patients with left-sided infection routinely
required surgical intervention. Cabinian and Kaatz treated a pregnant
injection drug user with P. aeruginosa endocarditis on both the aortic and
tricuspid valves complicated by a brain abscess, presumably the result of
a septic embolus. Surgery was deemed too risky, so she was treated with
high-dose tobramycin and ceftazadime. She made a complete recovery and
was well at 2-years follow up [98]. It is possible that with newer antipseudomonal antibiotics, the previously noted dismal prognosis will be reversed.
Similar combinations of high-dose aminoglycosides plus active cell-wall
drugs are probably most likely to result in cure of other Gram-negative
organisms. The role of quinolones in the treatment of Gram-negative endocarditis is yet to be dened. Most Gram-negative organisms are susceptible
to quinolones, and this activity plus their favorable kinetics make these
drugs potentially attractive in this setting. Firm recommendations must
await clinical trials.
Fungal endocarditis has a generally poor prognosis. Ellis, Al-Abdely,
Sandridge, et al recently reviewed the outcome of 269 published cases [99]. The
fatality rate was 72% (195 of 269 cases), and the cause of death was directly
related to endocarditis in 77% of the 195 patients who died. Patients treated
with combined surgical and medical therapy had the best outcome. At 1 year,
55% of those treated with combined therapy were still alive, compared with
only 36% of those who received only antifungal therapy. Among the antifungal agents, amphotericin B was used most commonly (93%). Flucytosine was
used in 22% of cases, rarely as monotherapy. The rest were treated with one
of the newer azoles. The dismal results prevent a recommendation of any
agent as the drug of choice. In view of these results, it seems prudent to combine antifungal therapy with an aggressive surgical approach.
As with fungal endocarditis, no recommendations can be made for infective endocarditis caused by the variety of unusual pathogens that occasionally are found in injection drug users. Several authors report successful
regimens used to treat Stenotrophomonas maltophilia. A combination of
ciprooxacin plus chloramphenicol was used successfully in one published
report [100]; others used a combination of trimethoprim and sulfamethoxazole plus ticarcillin and clavulanate to treat a nonaddict [101]. Stenotrophomonas maltophilia rapidly develops resistance to a number of antibiotics,
and continued diligence is required to detect relapse. Penicillin, with or without an aminoglycoside, was used to treat Eikenella corrodens [25], Neisseria
mucosa [102], and group B streptococcus [103] but was inadequate when
given orally in a patient with infective endocarditis caused by Clostridium
bifermentans. After relapse the patient responded to a 4-week course of
intravenous penicillin plus gentamicin [104].

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The role of surgery for endocarditis has been well dened. The usual indications are congestive heart failure caused by valve rupture or perforation,
intracardiac abscess, multiple systemic septic emboli, or failure of medical
management. Surgery can be performed safely even in a patient with active
infection, and delaying a surgical procedure in hopes that the patient may
improve often leads to a fatal outcome [96,105]. The type of surgery is left
to the discretion of the surgeon. Some favor vegetectomy with repair of the
valve when possible [106108]. Arbulu and colleagues were rst to remove
the tricuspid valve completely without inserting a prosthetic valve in injection drug users with right-sided endocarditis. Some argue that this procedure results in an unacceptable rate of long-term cardiac failure. Given
these patients rate of return to drug use, however, the risk of acquiring
prosthetic 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 reports
continued success for complete valvulectomy [109113]. Regardless of the
surgical approach, early, aggressive surgical management optimizes the outcome [62,114].

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