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Infect Dis Clin N Am 16 (2002) 413435

Staphylococcus aureus bacteremia

and endocarditis
Cathy A. Petti, MDa, Vance G. Fowler Jr, MD, MHSb,*

Departments of Pathology and Medicine, Box 3879, Duke University

Medical Center, Durham, NC, 27710, USA
Division of Infectious Diseases, Box 3281, Department of Medicine,
Duke University Medical Center, Durham, NC 27710, USA

Staphylococcus aureus is a leading cause of bacteremia and endocarditis.

Over the past several years, the frequency of S. aureus bacteremia (SAB) has
increased dramatically. This increasing frequency, coupled with rising rates
of antibiotic resistance, has renewed interest in this serious, common infection. S. aureus is a unique pathogen because of its virulent properties, its
protean manifestations, and its ability to cause endocarditis on architecturally normal cardiac valves. Although the possibility of underlying endocarditis arises in virtually every patient with SAB, only a minority of bacteremic
patients will actually have cardiac involvement. Distinguishing patients with
S. aureus infective endocarditis (IE) from those with uncomplicated SAB is
essential, but often dicult. In this review, the authors address the recent
changes in the epidemiology of SAB and IE, discuss the challenges in distinguishing SAB from IE, and discuss current trends in the management of
patients with SAB and IE.

Increasing rates of S. aureus bacteremia
The overall frequency of SAB is increasing. From 1980 to 1989, rates of
SAB reported to the National Nosocomial Infections Surveillance System
(NNIS) increased by 283% in non-teaching hospitals and 176% in large

This study was supported by National Institutes of Health grant AI-01647 and by a Glaxo
SmithKline Faculty Development Award (to V.G. Fowler).
* Corresponding author.
E-mail address: (V.G. Fowler).
0891-5520/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 8 9 1 - 5 5 2 0 ( 0 1 ) 0 0 0 0 3 - 4


C.A. Petti, V.G. Fowler Jr / Infect Dis Clin N Am 16 (2002) 413435

teaching hospitals [1]. By 1998, S. aureus had become the second most common bloodstream isolate, contributing to 16% of all hospital-acquired bacteremias [2]. A major contributing factor to the increasing frequency of SAB
has been progress in therapies and evolution of medical interventions. The
expanding use of invasive procedures, prosthetic devices, and intravascular
catheters has resulted in a large population of patients at risk for staphylococcal bloodstream infections. A recent investigation conducted by Emory
University documented that intravascular device-associated SAB accounted
for 70% of documented increases in hospital-acquired S. aureus bloodstream
infections over a 10-year study period [3]. Other investigators have conrmed the important role of intravascular catheters in developing SAB by
using logistic regression analysis of prospectively identied cohorts [4].
Because of the shift of acute medical care to outpatient settings and the
increased use of long-term intravascular devices in patients with chronic diseases (e.g., cancer and end stage renal disease), a new group of patients has
emerged: those who acquire catheter-associated SAB in the community [5].
For example, one recent prospective analysis found that intravascular
devices accounted for 22% of episodes of community-acquired SAB from
1990 to 1993 [3]. In another report, approximately one-third of patients with
catheter-associated SAB had community-acquired infections [6]. The full
impact of these healthcare-associated causes of community-acquired SAB
awaits clarication.
While healthcare-associated infections contribute to a growing portion
of the overall cases of SAB, traditional at-risk populations remain subject
to S. aureus bloodstream infection. In many large urban referral hospitals,
injection drug use (IDU) remains a primary source of SAB, while in other
sites traditional, community-acquired infections continue to cause a signicant number of SAB cases [7,8].
Increasing rates of S. aureus endocarditis
Rates of IE due to S. aureus have also increased [912]. Although
the majority of cases of S. aureus IE are still community-acquired [13], the
increasing prevalence of healthcare-associated S. aureus IE may reect in
part the growing use of interventional procedures and implantable devices.
For example, a recent evaluation of 329 consecutive patients with denite or
possible IE at the authors institution from 1993 to 1999 demonstrated that
the number of cases associated with hemodialysis dependence (P 0.04),
immune suppression (P 0.008), and S. aureus (P < 0.001) increased during the study period, while rates of infection due to viridans group streptococci decreased (P 0.007). Hemodialysis was independently associated
with IE caused by S. aureus (OR 3.1, 95% CI: 1.65.9) [9]. These ndings
indicate a relationship between changing medical practices and the epidemiology of S. aureus IE . The increased use of intravascular devices is likely
at least partially responsible for growing numbers of healthcare-associated

C.A. Petti, V.G. Fowler Jr / Infect Dis Clin N Am 16 (2002) 413435


S. aureus IE [1316]. For example, in a report of 59 cases of S. aureus IE

prospectively identied from 1994 to 1998, the presumed source of infection
in over 50% of patients was an intravascular device [13]. In another recent
prospective cohort of 22 patients with hospital-acquired IE (17 of which were
due to S. aureus), an infected intravenous catheter was the most common
source of bacteremia, identied in 50% of cases [17]. Similar ndings have
been reported in other centers. Fernandez-Guerrero et al. reported a 10-fold
increase in the number of cases of hospital-acquired IE (most of which were
due to S. aureus) from 1978 to 1992 compared with the number of cases
occurring from 1960 to 1975 [10]. Collectively, these data suggest that evolving medical practices, in particular the use of intravascular catheters, have
contributed to the increased rate and changing characteristics of S. aureus IE.
The increasing frequency of S. aureus IE also may be due in part to better
recognition of the disease through increasing application of echocardiography in evaluating patients with SAB (see below).
Increasing rates of antibiotic resistance
The past decade has also seen a signicant rise in rates of methicillinresistant S. aureus (MRSA). Over 50% of S. aureus isolates from intensive
care units reported to the NNIS in 1999 were methicillin-resistant, a 43%
increase compared to 1994 through 1998 [18]. Approximately 30% of S. aureus bloodstream isolates in the United States are now methicillin-resistant
[2]. Widespread antibiotic use and poor adherence to infection control precautions have both contributed to the rise in MRSA infection rates [19]. Over
the past decade, the prevalence of community-acquired MRSA infection also
appears to be increasing. For example, Herold and colleagues recently
reported that the prevalence of community-acquired MRSA without identied risk increased from 10 per 100,000 admissions in 1988 to 1990 to 259 per
100,000 admissions in 1993 to 1995 [20]. While healthcare contact remains
the primary risk factor for the majority of patients with community-acquired
MRSA infection [21], sporadic reports of MRSA infection with no identiable healthcare contacts or risk factors have been documented from various
sites, including the midwestern United States [22] and Australia [23].
The past decade also witnessed the rst clinical isolates of S. aureus with
reduced susceptibility to vancomycin. The rst glycopeptide-intermediate
S. aureus isolate was reported from Japan in 1997 [24]. Several patients with
vancomycin-intermediate S. aureus (VISA) infections have been reported in
the United States [25,26]. Most of these patients were hemodialysis dependent and had deep tissue or prosthetic device MRSA infections treated with
prolonged courses of vancomycin [25].
Complications of SAB
Approximately one-third of patients with SAB develop one or more complications [7,2730]. Acute systemic complications typically occur within the


C.A. Petti, V.G. Fowler Jr / Infect Dis Clin N Am 16 (2002) 413435

rst 48 hours of an initial positive blood culture and include septic shock,
acute respiratory distress syndrome, and disseminated intravascular coagulation. Localized (metastatic) complications of SAB usually result from
hematogenous seeding of a deep tissue site (e.g., heart valves, prosthetic
material) or direct extension from an adjacent site of existing infection. Such
metastatic complications may be clinically obvious at the time of the initial
bacteremia or may only become evident several weeks later. Although endocarditis is one of the most important localized complications of SAB, virtually any organ system may be involved. For example, Lautenschlager
et al. identied metastatic foci in 27% of 281 retrospectively identied patients
with SAB. Common sites of metastatic disease were joints (36%), kidneys
(29%), central nervous system (28%), skin (16%), intervertebral disk (15%),
lungs (15%), hepatosplenic (13%), bone (11%), and heart valves (8%). Importantly, more than one metastatic site of infection was present in half of the
cases [7].
Because of the diverse and often occult manifestations of metastatic
S. aureus infections, the primary step in evaluating every patient with SAB
is to identify the extent of infection. Failure to identify a site of metastatic
infection (e.g., infected prosthetic device, occult endocarditis, epidural
abscess) can destine an otherwise appropriate management plan to failure.
Clinical evaluation is the cornerstone of managing every patient with SAB;
unfortunately, serious metastatic infections are not always clinically apparent. A variety of clinical characteristics have been identied that place a particular patient with SAB at particular risk for metastatic complications. In
this section, the authors discuss recent data regarding these risk factors.
Importantly, the absence of such predisposing conditions does not imply the
absence of risk for invasive localized disease.
Risk factors for metastatic disease
Cardiac valvular disease
Underlying cardiac disease remains one of the most important risk factors for IE among patients with SAB [31]. Although rheumatic heart disease
was historically the primary valvular risk factor for IE among patients with
SAB [32], it has been largely replaced by other cardiac structural abnormalities. Mitral valve prolapse, bicuspid aortic valve [33], senile/degenerative
aortic valve stenosis or sclerosis, congenital heart disease, and previous IE
are now more common predisposing cardiac conditions. The presence of a
prosthetic cardiac valve also places the patient who develops bacteremia
at particularly high risk for IE (see below).
Prosthetic implants
The presence of an indwelling prosthetic device is an important risk factor for metastatic complications following SAB. In a carefully conducted
prospective cohort investigation, Fang and colleagues demonstrated that

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15 of 44 patients (34%) with prosthetic cardiac valves who developed SAB

also had prosthetic valve IE [34]. Four of these 15 patients had SAB with
subsequent development of new IE. Patients with permanent pacemakers
or implantable cardioverter debrillators who develop SAB are also at
increased risk for IE or infection involving the cardiac device. Among 33
prospectively identied patients with a permanent pacemaker or implantable cardioverter debrillator that developed SAB, the overall rate of conrmed device infection was 45.4% [35]. Other prosthetic devices are also
at high risk for infection among patients with SAB. In a series of 80 prospectively identied patients with SAB and orthopedic devices, Murdoch et al.
observed that the rate of hematogeneous seeding of an arthroplasty was
34% [36]. In addition to device infection around the time of SAB, the presence of prosthetic material is an important risk factor for subsequent relapsing infection. For example, the presence of an indwelling foreign body was
the single greatest predictor (OR 18.2, 95% CI: 7.643.6) of subsequent
relapse (as conrmed by pulsed-eld gel electrophoresis) among 309 prospectively identied cases of SAB [37].
Community-acquired versus healthcare-associated SAB
Community-acquired SAB has repeatedly been shown to be an important
risk factor for metastatic complications and IE [7,38,39]. For example, Willcox et al. reported that 90% of 113 South African patients with communityacquired SAB and no history of injection drug use had one or more metastatic complications [39]. This high rate of metastatic infections among
patients with community-acquired SAB may be due in part to the typically
prolonged disease course and duration of bacteremia prior to detection.
Comorbid conditions
The impact of advanced age on the outcome of patients with SAB has
been evaluated recently [40,41]. Among 385 prospectively identied patients
with SAB, older patients (>65 years) experienced a higher total mortality of
29.7% versus 15% (OR 2.21; 95% CI: 1.323.70) and attributable mortality
of 14.5% versus 6.3% (OR 2.30; 95% CI: 1.134.69) when compared with
younger adult patients with SAB [40]. Older patients may also be more likely
to develop IE than younger patients [42]. The impact of diabetes mellitus
upon the outcome of SAB is unresolved. Although early investigations suggested that diabetic patients with SAB were more likely to develop metastatic complications than non-diabetic patients [43], to date no denitive
data have established diabetes as an independent risk factor for S. aureus
infection [44]. The relationship between human immunodeciency virus
(HIV) infection and SAB is also dened incompletely. While the rate of SAB
and metastatic infections may be higher among HIV-infected persons [45],
mortality attributable to SAB among bacteremic HIV infected patients did
not dier signicantly from HIV-negative patients with bacteremia [46].
Important risk factors in HIV-positive persons for developing S. aureus


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infection, with or without SAB, include nasal carriage, presence of an intravascular catheter, and low CD4 count [4]. Patients who develop SAB while
undergoing hemodialysis may have increased rates of metastatic complications. In a recent prospective cohort study of 65 episodes of SAB among
hemodialysis-dependent patients, 44% of patients developed metastatic
complications of SAB and 14% died of their infection [47]. Other patient
conditions such as neoplasm [48] and neutropenia [49] have also been associated with poor clinical outcomes. However, because of the complex interplay of clinical characteristics in patients with SAB, a large prospective
cohort investigation will be required to clarify the clinical signicance of
each of these individual risk factors.
SAB in the surgical patient
The development of SAB in the postoperative patient is an important
indicator of the presence of postoperative wound infection. For example,
the presence of SAB was associated with a surgical wound infection in most
(66%) of 73 prospectively evaluated patients who developed SAB in the
postoperative setting. This association between SAB and an infected surgical wound was particularly strong among patients who underwent median
sternotomy. Among the 23 patients that developed SAB after undergoing
a median sternotomy, the positive predictive value (PPV) for developing
postoperative mediastinitis was 91.3% [50]. This observation has major implications for post-operative evaluation and management of such patients.
Impact of pathogen-specic characteristics on clinical severity
and outcome of SAB
Although an increasing body of evidence suggests that a variety of virulence factors in S. aureus contribute to the pathogenesis of infection [51,52],
little is known about their impact on the clinical outcome of patients with
SAB or IE. Day et al. recently identied a number of S. aureus clones whose
virulence factors may promote ecological abundance and potentially invasive disease [53]. Further studies will be required to identify specic bacterial
characteristics contributing to a particular strains ecological tness and
ability to cause invasive infection.
Clinical impact of methicillin resistance
The impact of methicillin resistance on the outcome of patients with SAB
and IE is unresolved. Some investigators have reported that infections due to
MRSA have a worse outcome than similar infections caused by methicillinsensitive strains [5456]. However, these studies often did not account for
the impact of comorbid conditions on patient outcomes. When statistical
techniques are employed to adjust for comorbid conditions, the apparent
adverse inuence of methicillin resistance upon the outcome of S. aureus
infections is no longer demonstrable [41,5759]. Future large prospective
trials that carefully adjust for the comorbid conditions of individual patients

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will be necessary to establish the true clinical impact of methicillin resistance

on the outcome of patients with SAB. At present, the available data suggest
that poor patient outcomes associated with MRSA infection is more likely
to be due to the adverse inuence of comorbid conditions than to heightened
intrinsic virulence of MRSA strains.
S. aureus IE
IE is one of the most devastating complications of SAB. In the 1950s
Wilson and Hamburger reported that 64% of patients with SAB had IE [32].
More recently, 3% to 25% of patients with SAB have been found to have
IE [7,8,27,60,61]. This wide range in the reported frequency of IE in patients
with SAB is likely due to the population studied, selection bias, and dierences in the methods used to make the diagnosis. The overall mortality of
S. aureus IE ranges from 19% to 65% [7,12,13,16,30,6163]. Even when
S. aureus IE is diagnosed and treated correctly, the risk of associated complications is high. Heart failure occurs in 20% to 50% of patients with S. aureus IE [11,13,61,63] and is associated with a poor prognosis [16]. Neurologic
manifestations occur in approximately 30% of patients with S. aureus IE
[6466] and are also accompanied by high mortality rates. Paravalvular cardiac abscesses are devastating complications of S. aureus IE. Because paravalvular abscesses may be dicult to diagnose and generally require surgical
debridement, prompt evaluation with transesophageal echocardiography
is an important step in the evaluation of patients at risk for this lethal
complication [67].

Identifying IE in patients with S. aureus bacteremia
The single most important aspect in the management of patients with
SAB is identifying the extent and localization of potential sites of infection,
in particular the presence or absence of endocarditis. Careful clinical evaluation remains the cornerstone of assessing the patient with SAB. Historically,
clinicians distinguished uncomplicated SAB from IE by relying upon the
presence of typical Oslerian manifestations (e.g., changing or new murmur,
splenomegaly, embolic lesions) or other bedside criteria. For example, in
their classic 1976 investigation, Nolan and Beaty attempted to dene clinically relevant predictive criteria for identifying IE among patients with SAB.
Among their 105 retrospectively identied cases of SAB, most of the 26
cases of IE possessed the following characteristics: community-acquired
SAB, absence of a primary focus of infection, and presence of metastatic
sites of infection [38].
Despite these clinical evaluation tools, the diagnosis of IE among patients
with SAB is often dicult. While the presence of Oslerian manifestations of
IE or the Nolan and Beaty risk prole triad remains helpful, they may be


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absent in patients with S. aureus IE. Unlike endocarditis caused by less

virulent pathogens, S. aureus endocarditis is often characterized by a rapid
onset, frequent involvement of normal cardiac valves, and the absence of
physical stigmata of the disease on initial presentation [13,16,68]. A number
of investigations have now demonstrated that reliance solely upon physical
examination ndings is likely to result in underdiagnosis of S. aureus IE. For
example, 13% of febrile intravenous drug users evaluated in an emergency
room had IE, but this subgroup of patients could not have been identied
on the basis of the immediately avalailable clinical or laboratory data
[69]. Investigators in Denmark also demonstrated that the diagnosis of
S. aureus IE was not clinically suspected and was only obtained at autopsy
in 55% of 119 patients with S. aureus IE identied from 1976 to 1981 [31],
and 32% of 260 patients with S. aureus IE identied from 1982 to 1991
[61]. Thus, the absence of classic physical ndings cannot exclude the diagnosis of S. aureus IE.
Role of echocardiography in patients with SAB:
determining when IE is present
Because of the diculty in clinically identifying S. aureus IE, echocardiography has become widely used to evaluate patients with SAB. Because
it allows for direct visualization of valvular vegetations and sometimes
valvular perforations and intracardiac abscesses, the importance of twodimensional transthoracic echocardiography (TTE) quickly became apparent to clinicians. As a result of this increased use, the number of SAB
patients found to have clinically occult IE has increased. For example, Friedland et al. found unsuspected IE in 11% of 36 hospitalized South African
children with SAB who underwent transthoracic examination [70]. Bayer
found echocardiographic evidence of IE in 18% of 33 consecutive adult
patients with SAB but without stigmata of IE [71]. Recently, comprehensive
monitoring with echocardiography and other diagnostic testing for septic
complications in 68 patients with SAB revealed IE in 26% of patients [30].
Based on these ndings, many clinicians now recommend that patients with
community-acquired SAB should undergo screening echocardiography
[61,71]. Despite the increased ability of TTE to identify patients with IE,
important limitations exist due to limitations in image resolution from
the transthoracic approach. For example, the sensitivity of TTE to detect
vegetations among patients with IE was only 64% [72]. Thus, because of the
modest sensitivity of TTE, a negative result cannot exclude the diagnosis
of IE.
The development of transesophageal echocardiogram (TEE) has allowed
for improved image resolution with higher frequency transducers and
improved visualization of cardiac structures without interference from the
overlying chest wall and lung [73]. Recent advances such as multiplane
transducers provide clearer three-dimensional reconstruction of cardiac

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structures that allow for improved detection of vegetations than with earlier
TEE modes [74]. As a result, the sensitivity of TEE is much higher than that
of TTE in the identication of IE (90% versus 60%) [75]. TEE is also
superior to TTE in the identication of IE among elderly patients [42], prosthetic valve IE [76], right sided IE [77], non-valvular IE (e.g., mural or eustachian valve IE) [7882], and pacemaker IE [8385].
TEE has also improved the identication of IE complications. For example, TEE is signicantly more sensitive than TTE in the detection of papillary muscle rupture [86], valvular perforation [87], or intracardiac abscesses
[88] caused by IE. For these reasons investigators evaluating the outcome of
25 patients with aortic paravalvular abscess concluded that the early detection of this devastating complication by TEE was critical to optimize patient
outcome, particularly in the setting of S. aureus IE [89].
A recent investigation also indicates that TEE is superior to TTE in the
evaluation of IE in patients with SAB. In this investigation, 103 selected
patients with SAB who underwent both TTE and TEE were prospectively
evaluated. Although 26 patients had denite IE by Duke criteria using TEE
ndings, only seven met clinical criteria for denite IE by TTE ndings.
Importantly, only seven had physical evidence of IE on examination [60].
Investigators in Australia recently reported a similar experience. Among
52 prospectively identied consecutive patients with SAB that underwent
TEE, the incidence of IE identied by TEE was 28.3%. Sixty percent of these
cases of IE were clinically occult [90]. Together, these reports suggest that
TEE provides signicant advantages over TTE or clinical evaluation in the
detection of IE among patients with SAB.
Role of echocardiography in patients with SAB: exclusion of IE
Because of the high sensitivity of TEE in detecting the valvular vegetations associated with IE, a negative TEE report in a patient with native
valves can virtually exclude the diagnosis of IE [91,92]. For example, among
93 consecutive patients undergoing TEE to evaluate for IE, the negative predictive value of TEE in native valves was 100% [91]. The ability to exclude
the diagnosis of native valve IE has many important clinical implications,
such as reducing the duration of parenteral antibiotics indicated to achieve
cure. In the cohort reported by Lowry and colleagues, a negative TEE led to
a 60% reduction in duration of antibiotic administration [91]. Other investigators have suggested that a negative TEE evaluation could help to identify
patients with intravascular catheter-associated SAB who might safely
receive abbreviated courses of intravenous antibiotics [27,93].
Echocardiography and prognosis in SAB
Echocardiography has also been used in attempts to determine prognosis.
For example, researchers have used echocardiography to dene the relationship


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between vegetation size and clinical outcome among patients with IE.
A recent meta-analysis by Tischler evaluated 738 patients in 10 studies to
determine the clinical impact of vegetation size among patients with IE. This
analysis revealed that patients with small vegetations (<10 mm) were less
likely than patients with large valvular vegetations (>10 mm) to sustain systemic emboli (19% versus 37%; P < 0.01) or require valve replacement (21%
versus 36%, P < 0.01) [94]. These results suggest that patients with large
vegetations (>10 mm) are at higher risk for adverse clinical outcome and
may benet from prompt valve replacement. An increase in vegetation size
as seen by echocardiography during therapy of IE may also identify patients
at high risk for complications of IE [95].
The identication of vegetations by TTE may also have prognostic signicance for patients with SAB. In a recent prospective evaluation of patients
with S. aureus IE, patients in whom valvular vegetations were identied by
TTE were signicantly more likely to die or sustain a major embolic event
than patients with S. aureus IE in whom vegetations were only visible by
TEE [13]. These ndings are consistent with the previous ndings that injection drug users (IDUs) with S. aureus IE with tricuspid vegetations detectable by TTE were signicantly more likely to experience prolonged fevers
[96,97], early evidence of subclinical right heart failure [96], and eventual
need for tricuspid valve replacement [96] than those in whom vegetations
were not visualized by TTE.
Echocardiography in SAB: TTE or TEE?
The question of which form of echocardiography to employ when evaluating the patient with SAB is unresolved, and is likely to depend in part
upon the prior probability for IE (e.g., prevalence of IDU, presence of prosthetic valves, and so forth), as well as the availability of the technology at a
particular institution. Heidenreich and colleagues sought to answer this
important question with decision tree and Markov modeling, using published data to simulate the outcomes and costs of care for patients with suspected IE. They found that TEE was the optimal imaging modality for the
range of prior probability of IE most commonly observed in clinical practice
(4%60%), while TTE was optimal for only a narrow range of low prior
probability (23%) of IE [98]. Other authorities have suggested that TTE
should be the diagnostic procedure of choice for patients with intermediate
or high clinical suspicion of IE, while TEE should be reserved only for
patients with prosthetic valves and in whom TTE is either technically inadequate or indicates an intermediate probability of IE [99]. Finally, the signicance of cardiac vegetations demonstrated solely by TEE in patients with an
otherwise uncomplicated clinical course is unknown [100]. An adequately
powered trial evaluating the clinical outcomes of patients with SAB randomized to receive either TTE or TEE will likely be required to answer these
important clinical questions.

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TEE is currently highly favored at our institution and others [15] for the
evaluation of most patients with SAB. The authors believe that TEE is likely
to be cost-eective in this application, particularly for patients at higher risk
for IE or associated complications. Such patients would include those with
prosthetic cardiac valves or other permanent cardiac devices (e.g., pacemaker
devices, implantable cardioverter debrillators), patients with prolonged
bacteremia or persistent symptoms of bacteremia (fever, sepsis, and so forth),
new cardiac conduction abnormalities, or patients with community-acquired
SAB. In addition, the authors believe that TEE should be considered for patients with SAB in whom TTE is nondiagnostic, or patients with SAB for
whom abbreviated courses of intravenous antibiotics are being considered.
Echocardiography in patients with SAB: the Duke criteria
In 1994 Durack et al. [101] developed new criteria for IE that improved
the clinical indicators identied by von Reyn [102] and others, and incorporated echocardiographic ndings. Many studies have now demonstrated the
superiority of the Duke criteria when compared to previous diagnostic
schema [103105], as well as in elderly patients [42], pediatric patients [106],
patients with prosthetic cardiac valves [76], and injection drug users [63].
Despite early questions regarding the clinical signicance of some echocardiographic ndings [107], the specicity of the Duke criteria is excellent. For
example, Hoen et al. found that the specicity of the Duke criteria was 0.99
(95% CI: 0.971) among 100 retrospectively identied patients at low risk
for IE who presented with acute fever or fever of unknown origin [108].
Thus, based on the data summarized above, a recent Scientic Statement
of the American Heart Association concluded that the Duke criteria should
be used as the primary diagnostic schema in the clinical evaluation of
patients suspected of having IE [67].
Recently, two sets of investigators have proposed modications to the
Duke criteria in an eort to more accurately categorize patients with possible IE [109,110]. Lamas and Eykyn suggested modications to the Duke
criteria to include newly diagnosed splenomegaly, new clubbing, elevated
erythrocyte sedimentation rate, high C-reactive protein level, hematuria,
central nonfeeding venous lines, and peripheral venous lines. When compared to the Duke criteria in 100 histopathologically conrmed cases of
native valve endocarditis, these modications were more sensitive in the
identication of IE than the Duke criteria (94% versus 83%) [109]. However,
it must be recognized that this modest increase in sensitivity will be at the
cost of decreased specicity. Li and colleagues suggested the following modications to the Duke criteria: (1) the category possible IE should be
dened as having at least one major and one minor criterion or 3 minor criteria, (2) the minor criterion echocardiogram consistent with IE but not
meeting major criterion should be eliminated given the widespread use of
TEE, (3) bacteremia due to S. aureus should be considered a major criterion,


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regardless of whether the infection is nosocomially acquired or whether a

removable source of infection is present, and (4) positive Q-fever serology
should be changed to a major criterion [110]. Further studies conducted
by independent investigators will be necessary to validate these ndings and
to establish the clinical utility of these proposed modications.
General therapeutic principles
Decisions regarding treatment are always patient-specic, relying upon
the judgment of the treating team, and must be made in light of each individual patients characteristics and the clinical setting. Occasionally, patients
with a low risk of complications or relapse may be reasonably treated for
longer periods of time if the consequences of a relapse or recurrence would
be catastrophic. Alternately, individual patients with a high risk of relapse
may be treated for shorter courses of therapy if other clinical considerations
(such as malignant disease or co-existing social or medical issues) are dominant. Thus, the treatment recommendations that follow are designed to be
guidelines for therapy, not absolute rules.
SAB: uncomplicated versus complicated
Decisions regarding the duration and type of therapy for SAB depend
upon the extent of infection. Because of the wide spectrum of disease caused
by S. aureus, specic management depends upon the sites of involvement as
well as patient-specic risk factors for complications. A convenient practice
is to group patients with SAB as having either uncomplicated or complicated
infection. Although the most common type of uncomplicated SAB is intravascular catheter-associated SAB, its optimal management is unresolved.
Because of high treatment failure rates among patients with intravascular
catheter-associated SAB in whom catheter salvage is attempted [111,112],
prompt removal of the catheter should occur whenever possible [113].
The appropriate duration of therapy for uncomplicated intravascularcatheter associated SAB is unknown [114,115]. Duration of less than 10 days
of intravenous antibiotics has generally been regarded as insucient because
of a higher rate of complications among patients receiving such therapy
[6,114,115]. Although some investigators have concluded that 14 days of
intravenous antibiotic therapy and prompt removal of the oending intravascular catheter is sucient [115,116], others have suggested that such
short course therapy is inadequate to eliminate any occult metastatic sites
of infection, leading to subsequent complications and relapses [29]. A meta
analysis of 11 studies containing 132 patients treated with short course (2
week) therapy for intravascular catheter associated SAB found an average
late complication rate among these patients to be 6.1%. The most common

C.A. Petti, V.G. Fowler Jr / Infect Dis Clin N Am 16 (2002) 413435


type of complication was IE. Based upon these ndings, Jernigan and Farr
concluded that patients with intravascular catheter-associated SAB should
receive more than 2 weeks of intravenous antibiotics pending more denitive
data [114].
Other investigators have sought a clinically meaningful way to distinguish patients with uncomplicated intravascular catheter-associated SAB
from those with intravascular catheter-associated SAB and metastatic complications. Among 55 retrospectively identied patients with catheter-related
SAB, Raad and Sabbagh found that an early complicated course was characterized by fever or bacteremia persisting for >3 days after catheter
removal [115]. More recently TEE data combined with favorable clinical
features (prompt defervescence, no indwelling prosthetic material or clinical
evidence of metastatic infection) and favorable microbiological ndings
(negative blood cultures drawn 24 days after removal of the intravascular
catheter) have been proposed as indicators to identify patients with uncomplicated intravascular catheter-associated SAB [27]. A recent analysis evaluated an antibiotic treatment strategy based upon TEE results: Two weeks
therapy if TEE is negative for IE, or 4 weeks therapy if TEE revealed
evidence of IE was compared with 2- or 4-week empirical therapy for the
management of patients with intravascular catheter-associated SAB. Importantly, patients with prosthetic valves or other prosthetic devices, clinically
apparent metastatic infection, immunosuppression, or a history of intravenous drug use were excluded from the analysis. Compared with empirical
short-course therapy, the TEE strategy cost $4938 per quality-adjusted life
year (QALY) gained. The eectiveness of the TEE strategy and the eectiveness of the long-course strategy were suciently similar that the additional
cost of empirical long-course therapy ($1,667,971 per QALY) was higher
than that which society usually considers to be cost-eective. These investigators concluded that for patients with clinically uncomplicated intravascular catheter-associated SAB, the use of TEE to determine therapy duration is
a cost-eective alternative to either 2- or 4-week therapy [93]. While these
ndings are promising, denitive recommendations regarding the management of intravascular catheter-associated SAB await the performance of
appropriate randomized, controlled trials. Until such denitive data are
available, management should follow the recommendations of recently published guidelines [113] and should not be based solely upon the presence of a
removable focus of infection.
Complicated SAB
Patients with complicated SAB include all patients with deep tissue involvement (e.g., IE, septic arthritis, deep tissue abscess, infection involving prosthetic material, and so forth). Therapy for patients with complicated SAB
typically involves at least 46 weeks of intravenous antibiotic therapy and
surgical drainage or debridement of the infected tissues as clinically indicated.


C.A. Petti, V.G. Fowler Jr / Infect Dis Clin N Am 16 (2002) 413435

Infected foreign bodies should almost always be removed. Although successful retention of infected orthopedic prostheses has been reported in a limited
number of highly selected patients with S. aureus infections [117], this practice
should generally be discouraged because of its high associated failure rate
observed in patients with prosthetic joints [118], prosthetic cardiac valves
[119,120], tunneled intravascular catheters [111], permanent pacemakers
[121], and other types of prosthetic devices. When surgical resection of
infected prosthetic material is contraindicated, an extended course of parenteral antibiotics followed by long-term or lifelong oral antibiotic therapy may
sometimes suppress active infection.
Right-sided native valve endocarditis
Because right-sided valve S. aureus IE has a low mortality and cure rates
of 90% to 100%, valve replacement is rarely indicated and the duration of
antibiotic therapy is often abbreviated. Several studies have demonstrated
that uncomplicated cases of right-sided IE without extrapulmonary metastatic disease may be treated successfully with as little as 2 weeks of a variety
of intravenous antistaphylococcal therapies [122125]. The incremental benet of adding an aminoglycoside to an antistaphylococcal penicillin when
treating right-sided IE appears to be small. Although one investigation suggested that the addition of an aminoglycoside to nafcillin was associated
with a one day reduction in average duration of bacteremia [124], a subsequent investigation of 90 consecutive injection drug users with isolated
methicillin-susceptible S. aureus IE found no dierence in mortality, relapse
rates, duration of bacteremia, or incidence of complications between
patients randomized to receive cloxacillin or cloxacillin plus gentamicin
[125]. Four weeks of oral ciprooxacin plus rifampin has also been shown
to be eective in a selected population of injection drug users with uncomplicated right-sided S. aureus IE [128].
Left-sided native valve endocarditis
The treatment of choice for left-sided native valve IE due to MSSA
includes 4 to 6 weeks of a parenteral semisynthetic penicillin (nafcillin or
oxacillin, 1.52 g IV q 4 h) [126,127]. When the infecting pathogen remains
susceptible to penicillin, benzyl penicillin (2024 million units IV daily) is the
preferred agent. A rst generation cephalosporin (e.g., cefazolin, 12 g IV q
8 h) is also an acceptable alternative in patients with non-life-threatening
penicillin allergy. Clindamycin [129] is associated with unacceptable relapse
rates and should not be used for the treatment of S. aureus IE. Early experience with continuous infusion b-lactam therapy for complicated S. aureus
infections, including IE, has been favorable [130].
Vancomycin remains the treatment of choice for IE among patients with
anaphylactic or anaphylactoid (e.g., giant urticaria) penicillin allergies or for

C.A. Petti, V.G. Fowler Jr / Infect Dis Clin N Am 16 (2002) 413435


IE due to MRSA. However, its use has been associated with treatment failure rates ranging from 14% to 40% [131,132]. For this reason, investigators
recently performed a decision analysis to calculate maximum expected utility for skin testing patients with MSSA IE who have a questionable history
of immediate-type hypersensitivity to penicillin. Whether utility, cost, or
average cost-utility was the outcome of interest, skin testing was preferred
to no skin testing in most situations. These investigators concluded that
patients with MSSA IE and questionable history of immediate type hypersensitivity to penicillin should be skin tested, and only those patients with a
reactive skin test should be treated with vancomycin [133].
The benets of combination therapy with an aminoglycoside have not
been established. Nonaddicts with primarily left-sided disease receiving
combination therapy with nafcillin and an aminoglycoside experienced a
more rapid clearance of bacteremia and a higher rate of nephrotoxicity,
but no reduction in mortality compared to patients treated with nafcillin
alone [124]. The most recent guidelines conclude that aminoglycoside therapy is optional for the treatment of native valve S. aureus IE, and, if used,
should only be administered in the rst 3 to 5 days to minimize nephrotoxicity [127].
The benet of adding rifampin to either b-lactam or vancomycin therapy
is also unclear. Despite potent activity against S. aureus in vitro, patients
with MRSA IE randomized to receive vancomycin plus rifampin had no
improvement in outcome compared to patients treated with vancomycin
alone [131].
Prosthetic valve endocarditis
S. aureus prosthetic valve IE has a poor prognosis, necessitating aggressive medical and surgical management. Combination therapy with a penicillinase-resistant penicillin (vancomycin if infection is due to MRSA) and
rifampin for 6 to 8 weeks plus an aminoglycoside for 2 weeks remains the
recommended treatment strategy for prosthetic valve IE [127]. Surgery is
usually required, and performing valve replacement surgery early in the
course of antimicrobial therapy may be associated with improved outcome
[119]. Even with aggressive management, the mortality rate associated with
S. aureus prosthetic valve IE is high (40%). Anticoagulant therapy may contribute to this mortality by increasing the chances of cerebral hemorrhage.
In one retrospective analysis of 56 patients with left-sided S. aureus IE, none
of 35 patients with native valve IE died due to central nervous system complications. By contrast, 52% of 21 patients with prosthetic valve IE (most of
whom were taking oral anticoagulation therapy at the time of diagnosis)
died due to a central nervous system event (P < 0.007) [134]. Prospective
validation of this important observation using a multinational registry of
consecutive cases of IE will assist in optimizing care of patients with prosthetic valve IE.


C.A. Petti, V.G. Fowler Jr / Infect Dis Clin N Am 16 (2002) 413435

Valve replacement therapy for S. aureus IE

Valve replacement surgery has become an important adjunctive therapy
in the management of both native and prosthetic valve S. aureus IE. The
decision to perform valve replacement surgery is a highly individualized one
that requires careful consideration of numerous patient-specic characteristics, including the presence of other metastatic or embolic complications, the
patients comorbid illnesses, and availability and experience of the cardiothoracic surgical team. Nonetheless, a number of generally accepted indications for surgical intervention for IE have emerged [135]. Such indications
include congestive heart failure, uncontrolled infection, hemodynamically
signicant valvular dysfunction, or local suppurative complications such
as paravalvular abscess. Because of the high mortality associated with
S. aureus prosthetic valve IE treated medically [120,136,137], early surgical
intervention for this condition [120,136,137] during simultaneous antibiotic
therapy [119] is also usually recommended. The role of echocardiography in
the decision to perform valve replacement surgery is dened incompletely.
The American Heart Association Committee on IE identied the following
echocardiographic features of endocarditis as associated with a potential
need for surgical intervention: (1) persistent vegetation after systemic embolization, (2) large (>1 cm) anterior mitral valve vegetations, (3) increase
in vegetation size after 4 weeks of antimicrobial therapy, (4) acute aortic
or mitral insuciency with signs of ventricular failure, (5) valve perforation or rupture, and (6) perivalvular extension (e.g., valvular dehiscence,
rupture or stula, or large abscess) [67].

Future directions
The increasing prevalence of resistant S. aureus has kindled intense interest in new treatments for this common pathogen. Two new antibiotics, quinupristin/dalfopristin (Synercid, Aventis) and linezolid (Zyvox, Pharmacia),
have been approved recently by the Food and Drug Agency (FDA) for the
treatment of several infections caused by resistant gram positive organisms.
Data from uncontrolled compassionate-use programs suggest that both quinupristin/dalfopristin [138] and linezolid [139] have clinical ecacy against
S. aureus. Studies are ongoing, but neither agent currently has an FDA indication for either S. aureus bacteremia or IE. Until the ndings of these retrospective investigations are conrmed by well designed, prospective trials,
these agents should only be considered for the treatment of S. aureus bacteremia or IE when no other therapeutic alternatives are available.
New antimicrobial products are also being explored for the treatment
of S. aureus infections. Since microbial adherence is central to the initiation and metastatic spread of S. aureus, the Microbial Surface Components
Recognizing Adhesive Matrix Molecules (MSCRAMM) family of bacterial

C.A. Petti, V.G. Fowler Jr / Infect Dis Clin N Am 16 (2002) 413435


surface adhesin proteins represents an excellent target for the development

of novel immunotherapies. Staphylococcus aureus Human Immune Globulin
(SA-IGIV, Inhibitex, Inc.) is a puried immunoglobulin G (IgG) product
derived from pooled human plasma selected for high titers of antibody to
MSCRAMMs. The MSCRAMM-specic IgG in SA-IGIV interferes with
S. aureus adherence to extracellular matrix proteins in vitro, and may
enhance opsonophagocytosis of S. aureus by polymorphonuclear leukocytes
[140]. In an animal model of S. aureus IE, addition of SA-IVIG to vancomycin signicantly increased bacterial clearance from the bloodstream when
compared to vancomycin alone (P < 0.008) [141]. An open-label, multicenter Phase 1/Phase 2 Pharmacokinetic Study of SA-IGIV in patients with IE
caused by MRSA is currently underway.
Vaccines may provide an important contribution to future eorts to
reduce rates of S. aureus infections. StaphVax (Nabi, Inc.) is the rst vaccine
with demonstrated clinical ecacy in reducing rates of staphylococcal infections. It consists of type 5 and type 8 capsular polysaccharides, the strains
accounting for more than 80% of S. aureus infections. In a recent doubleblinded, placebo-controlled Phase III clinical ecacy trial involving 1804
hemodialysis-dependent patients, StaphVax recipients had a 57% reduction
in SAB at 10 months compared to placebo recipients (P 0.015) [142]. Such
a vaccine could have important clinical applications among many patients at
risk for invasive S. aureus infections (e.g., persons with indwelling intravascular catheters, persons undergoing elective surgery, and so forth).

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