Staphylococcus Aureus Bacteremia and Endocarditis

8/9/2019 Staphylococcus Aureus Bacteremia and Endocarditis

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Staphylococcus aureus bacteremiaand endocarditis

Cathy A. Petti, MDa, Vance G. Fowler Jr, MD, MHSb,*aDepartments of Pathology and Medicine, Box 3879, Duke University

Medical Center, Durham, NC, 27710, USAbDivision 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 ofS. aureusbacteremia (SAB) has

increased dramatically. This increasing frequency, coupled with rising rates

of antibiotic resistance, has renewed interest in this serious, common infec-

tion. S. aureus is a unique pathogen because of its virulent properties, its

protean manifestations, and its ability to cause endocarditis on architectur-

ally normal cardiac valves. Although the possibility of underlying endocar-

ditis 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 difficult. In this review, the authors address the recent

changes in the epidemiology of SAB and IE, discuss the challenges in distin-

guishing SAB from IE, and discuss current trends in the management of

patients with SAB and IE.

Epidemiology

Increasing rates ofS. 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

Infect Dis Clin N Am 16 (2002) 413435

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: [email protected] (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


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teaching hospitals [1]. By 1998,S. aureus had become the second most com-

mon bloodstream isolate, contributing to 16% of all hospital-acquired bac-

teremias [2]. A major contributing factor to the increasing frequency of SABhas 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 staphylo-

coccal bloodstream infections. A recent investigation conducted by Emory

University documented that intravascular device-associated SAB accounted

for 70% of documented increases in hospital-acquiredS. aureusbloodstream

infections over a 10-year study period [3]. Other investigators have con-

firmed the important role of intravascular catheters in developing SAB by

using logistic regression analysis of prospectively identified 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 dis-

eases (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 SABawaits clarification.

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 signifi-

cant number of SAB cases [7,8].

Increasing rates ofS. aureus endocarditis

Rates of IE due to S. aureus have also increased [912]. Although

the majority of cases ofS. aureus IE are still community-acquired [13], the

increasing prevalence of healthcare-associated S. aureus IE may reflect in

part the growing use of interventional procedures and implantable devices.

For example, a recent evaluation of 329 consecutive patients with definite 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 dur-ing the study period, while rates of infection due to viridans group strepto-

cocci decreased (P 0.007). Hemodialysis was independently associated

with IE caused byS. aureus(OR 3.1, 95% CI: 1.65.9) [9]. These findings

indicate a relationship between changing medical practices and the epide-

miology ofS. aureusIE . The increased use of intravascular devices is likely

at least partially responsible for growing numbers of healthcare-associated

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


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

prospectively identified from 1994 to 1998, the presumed source of infection

in over 50% of patients was an intravascular device [13]. In another recentprospective 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, identified in 50% of cases [17]. Similar findings 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 evolv-

ing medical practices, in particular the use of intravascular catheters, have

contributed to the increased rate and changing characteristics ofS. aureus IE.The increasing frequency ofS. aureusIE also may be due in part to better

recognition of the disease through increasing application of echocardiogra-

phy in evaluating patients with SAB (see below).

Increasing rates of antibiotic resistance

The past decade has also seen a significant rise in rates of methicillin-

resistant S. aureus (MRSA). Over 50% ofS. 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% ofS. aur-eus bloodstream isolates in the United States are now methicillin-resistant

[2]. Widespread antibiotic use and poor adherence to infection control pre-

cautions 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 identi-

fied 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-acquiredMRSA infection [21], sporadic reports of MRSA infection with no identifi-

able 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 first clinical isolates ofS. aureus with

reduced susceptibility to vancomycin. The first glycopeptide-intermediate

S. aureusisolate was reported from Japan in 1997 [24]. Several patients with

vancomycin-intermediateS. aureus (VISA) infections have been reported in

the United States [25,26]. Most of these patients were hemodialysis depen-

dent and had deep tissue or prosthetic device MRSA infections treated withprolonged courses of vancomycin [25].

Complications of SAB

Approximately one-third of patients with SAB develop one or more com-

plications [7,2730]. Acute systemic complications typically occur within the

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first 48 hours of an initial positive blood culture and include septic shock,

acute respiratory distress syndrome, and disseminated intravascular coagu-

lation. Localized (metastatic) complications of SAB usually result fromhematogenous 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 endo-

carditis is one of the most important localized complications of SAB, vir-

tually any organ system may be involved. For example, Lautenschlager

et al. identified metastatic foci in 27% of 281 retrospectively identified 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%). Impor-

tantly, 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 appar-

ent. A variety of clinical characteristics have been identified that place a par-

ticular 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 fac-

tors 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 abnormal-

ities. 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 bacteremiaat particularly high risk for IE (see below).

Prosthetic implants

The presence of an indwelling prosthetic device is an important risk fac-

tor 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 pacemakersor implantable cardioverter defibrillators who develop SAB are also at

increased risk for IE or infection involving the cardiac device. Among 33

prospectively identified patients with a permanent pacemaker or implanta-

ble cardioverter defibrillator that developed SAB, the overall rate of con-

firmed 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 prospec-

tively identified 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 pres-ence of prosthetic material is an important risk factor for subsequent relap-

sing 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 confirmed by pulsed-field gel electrophoresis) among 309 pro-

spectively identified 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, Will-cox et al. reported that 90% of 113 South African patients with community-

acquired SAB and no history of injection drug use had one or more meta-

static 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 identified patientswith 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 sug-

gested that diabetic patients with SAB were more likely to develop meta-

static complications than non-diabetic patients [43], to date no definitive

data have established diabetes as an independent risk factor for S. aureusinfection [44]. The relationship between human immunodeficiency virus

(HIV) infection and SAB is also defined 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 differ significantly 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 intra-

vascular catheter, and low CD4 count [4]. Patients who develop SAB while

undergoing hemodialysis may have increased rates of metastatic complica-tions. 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 asso-

ciated with poor clinical outcomes. However, because of the complex inter-

play of clinical characteristics in patients with SAB, a large prospective

cohort investigation will be required to clarify the clinical significance 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 surgi-

cal 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 developingpostoperative mediastinitis was 91.3% [50]. This observation has major im-

plications for post-operative evaluation and management of such patients.

Impact of pathogen-specific characteristics on clinical severity

and outcome of SAB

Although an increasing body of evidence suggests that a variety of viru-

lence factors inS. aureuscontribute 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 identified a number ofS. aureusclones whosevirulence factors may promote ecological abundance and potentially inva-

sive disease [53]. Further studies will be required to identify specific bacterial

characteristics contributing to a particular strains ecological fitness 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 methicillin-sensitive 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 influence 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 likelyto be due to the adverse influence 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 differ-ences 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 com-

plications is high. Heart failure occurs in 20% to 50% of patients with S. aur-

eusIE [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 car-

diac abscesses are devastating complications ofS. aureus IE. Because para-

valvular abscesses may be difficult to diagnose and generally require surgicaldebridement, prompt evaluation with transesophageal echocardiography

is an important step in the evaluation of patients at risk for this lethal

complication [67].

Diagnosis

Identifying IE in patients with S. aureus bacteremia

The single most important aspect in the management of patients withSAB is identifying the extent and localization of potential sites of infection,

in particular the presence or absence of endocarditis. Careful clinical evalua-

tion 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 define clini-

cally relevant predictive criteria for identifying IE among patients with SAB.

Among their 105 retrospectively identified cases of SAB, most of the 26cases 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 difficult. While the presence of Oslerian manifestations of

IE or the Nolan and Beaty risk profile triad remains helpful, they may be



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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 identification of IE (90% versus 60%) [75]. TEE is alsosuperior to TTE in the identification of IE among elderly patients [42], pros-

thetic valve IE [76], right sided IE [77], non-valvular IE (e.g., mural or eusta-

chian valve IE) [7882], and pacemaker IE [8385].

TEE has also improved the identification of IE complications. For exam-

ple, TEE is significantly more sensitive than TTE in the detection of papil-

lary 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 detec-

tion of this devastating complication by TEE was critical to optimize patientoutcome, particularly in the setting ofS. 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 definite IE by Duke criteria using TEE

findings, only seven met clinical criteria for definite IE by TTE findings.

Importantly, only seven had physical evidence of IE on examination [60].

Investigators in Australia recently reported a similar experience. Among

52 prospectively identified consecutive patients with SAB that underwentTEE, the incidence of IE identified by TEE was 28.3%. Sixty percent of these

cases of IE were clinically occult [90]. Together, these reports suggest that

TEE provides significant 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 vegeta-

tions associated with IE, a negative TEE report in a patient with nativevalves can virtually exclude the diagnosis of IE [91,92]. For example, among

93 consecutive patients undergoing TEE to evaluate for IE, the negative pre-

dictive 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 investi-

gators have suggested that a negative TEE evaluation could help to identify

patients with intravascular catheter-associated SAB who might safelyreceive 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 define 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. Thisanalysis revealed that patients with small vegetations (10 mm) to sustain sys-

temic 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 benefit 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 identification of vegetations by TTE may also have prognostic signi-ficance for patients with SAB. In a recent prospective evaluation of patients

with S. aureus IE, patients in whom valvular vegetations were identified by

TTE were significantly 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 findings are consistent with the previous findings that injec-

tion drug users (IDUs) with S. aureus IE with tricuspid vegetations detect-

able by TTE were significantly 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 vegetationswere not visualized by TTE.

Echocardiography in SAB: TTE or TEE?

The question of which form of echocardiography to employ when evalu-

ating 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 pros-

thetic valves, and so forth), as well as the availability of the technology at a

particular institution. Heidenreich and colleagues sought to answer thisimportant question with decision tree and Markov modeling, using pub-

lished data to simulate the outcomes and costs of care for patients with sus-

pected 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 inade-quate or indicates an intermediate probability of IE [99]. Finally, the signifi-

cance 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 rando-

mized 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-effective in this application, particularly for patients at higher riskfor IE or associated complications. Such patients would include those with

prosthetic cardiac valves or other permanent cardiac devices (e.g., pacemaker

devices, implantable cardioverter defibrillators), 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 pa-

tients 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 identified by von Reyn [102] and others, and incorpo-

rated echocardiographic findings. 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 significance of some echocar-diographic findings [107], the specificity of the Duke criteria is excellent. For

example, Hoen et al. found that the specificity of the Duke criteria was 0.99

(95% CI: 0.971) among 100 retrospectively identified 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 Scientific 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 modifications to theDuke criteria in an effort to more accurately categorize patients with pos-

sible IE [109,110]. Lamas and Eykyn suggested modifications 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 com-

pared to the Duke criteria in 100 histopathologically confirmed cases of

native valve endocarditis, these modifications were more sensitive in the

identification of IE than the Duke criteria (94% versus 83%) [109]. However,

it must be recognized that this modest increase in sensitivity will be at thecost of decreased specificity. Li and colleagues suggested the following mod-

ifications to the Duke criteria: (1) the category possible IE should be

defined as having at least one major and one minor criterion or 3 minor cri-

teria, (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 toS. aureusshould 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 conductedby independent investigators will be necessary to validate these findings and

to establish the clinical utility of these proposed modifications.

Therapy

General therapeutic principles

Decisions regarding treatment are always patient-specific, relying upon

the judgment of the treating team, and must be made in light of each indi-vidual 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 domi-

nant. 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

byS. aureus, specific management depends upon the sites of involvement as

well as patient-specific 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 intra-

vascular 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 intravascular-

catheter associated SAB is unknown [114,115]. Duration of less than 10 days

of intravenous antibiotics has generally been regarded as insufficient 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 offending intra-vascular catheter is sufficient [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



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type of complication was IE. Based upon these findings, Jernigan and Farr

concluded that patients with intravascular catheter-associated SAB should

receive more than 2 weeks of intravenous antibiotics pending more definitivedata [114].

Other investigators have sought a clinically meaningful way to distin-

guish patients with uncomplicated intravascular catheter-associated SAB

from those with intravascular catheter-associated SAB and metastatic com-

plications. Among 55 retrospectively identified patients with catheter-related

SAB, Raad and Sabbagh found that an early complicated course was char-

acterized 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 clinicalevidence of metastatic infection) and favorable microbiological findings

(negative blood cultures drawn 24 days after removal of the intravascular

catheter) have been proposed as indicators to identify patients with uncom-

plicated intravascular catheter-associated SAB [27]. A recent analysis evalu-

ated 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. Impor-

tantly, patients with prosthetic valves or other prosthetic devices, clinicallyapparent metastatic infection, immunosuppression, or a history of intrave-

nous 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 effectiveness of the TEE strategy and the effective-

ness of the long-course strategy were sufficiently 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-effective. These investi-

gators concluded that for patients with clinically uncomplicated intravascu-

lar catheter-associated SAB, the use of TEE to determine therapy duration isa cost-effective alternative to either 2- or 4-week therapy [93]. While these

findings are promising, definitive recommendations regarding the manage-

ment of intravascular catheter-associated SAB await the performance of

appropriate randomized, controlled trials. Until such definitive data are

available, management should follow the recommendations of recently pub-

lished 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 invol-

vement (e.g., IE, septic arthritis, deep tissue abscess, infection involving pros-

thetic 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.



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Infected foreign bodies should almost always be removed. Although success-

ful retention of infected orthopedic prostheses has been reported in a limited

number of highly selected patients with S. aureus infections [117], this practiceshould 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 parent-

eral 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 meta-

static disease may be treated successfully with as little as 2 weeks of a variety

of intravenous antistaphylococcal therapies [122125]. The incremental ben-

efit of adding an aminoglycoside to an antistaphylococcal penicillin when

treating right-sided IE appears to be small. Although one investigation sug-gested that the addition of an aminoglycoside to nafcillin was associated

with a one day reduction in average duration of bacteremia [124], a subse-

quent investigation of 90 consecutive injection drug users with isolated

methicillin-susceptibleS. aureus IE found no difference 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 ciprofloxacin plus rifampin has also been shown

to be effective in a selected population of injection drug users with uncom-

plicated 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 first generation cephalosporin (e.g., cefazolin, 12 g IV q

8 h) is also an acceptable alternative in patients with non-life-threateningpenicillin allergy. Clindamycin [129] is associated with unacceptable relapse

rates and should not be used for the treatment ofS. aureusIE. Early experi-

ence 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



15/23

IE due to MRSA. However, its use has been associated with treatment fail-

ure rates ranging from 14% to 40% [131,132]. For this reason, investigators

recently performed a decision analysis to calculate maximum expected uti-lity 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 hyper-

sensitivity to penicillin should be skin tested, and only those patients with a

reactive skin test should be treated with vancomycin [133].

The benefits of combination therapy with an aminoglycoside have not

been established. Nonaddicts with primarily left-sided disease receivingcombination 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 ther-

apy is optional for the treatment of native valve S. aureus IE, and, if used,

should only be administered in the first 3 to 5 days to minimize nephrotoxi-

city [127].

The benefit of adding rifampin to eitherb-lactam or vancomycin therapy

is also unclear. Despite potent activity against S. aureus in vitro, patientswith 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 aggres-

sive medical and surgical management. Combination therapy with a penicil-

linase-resistant penicillin (vancomycin if infection is due to MRSA) andrifampin 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. aureusprosthetic valve IE is high (40%). Anticoagulant therapy may con-

tribute to this mortality by increasing the chances of cerebral hemorrhage.

In one retrospective analysis of 56 patients with left-sidedS. aureusIE, none

of 35 patients with native valve IE died due to central nervous system com-plications. 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 pros-

thetic valve IE.



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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-specific characteris-

tics, including the presence of other metastatic or embolic complications, the

patients comorbid illnesses, and availability and experience of the cardi-

othoracic surgical team. Nonetheless, a number of generally accepted indica-

tions for surgical intervention for IE have emerged [135]. Such indications

include congestive heart failure, uncontrolled infection, hemodynamically

significant 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 defined incompletely.

The American Heart Association Committee on IE identified the following

echocardiographic features of endocarditis as associated with a potential

need for surgical intervention: (1) persistent vegetation after systemic embo-

lization, (2) large (>1 cm) anterior mitral valve vegetations, (3) increase

in vegetation size after 4 weeks of antimicrobial therapy, (4) acute aortic

or mitral insufficiency with signs of ventricular failure, (5) valve perfora-

tion or rupture, and (6) perivalvular extension (e.g., valvular dehiscence,

rupture or fistula, or large abscess) [67].

Future directions

The increasing prevalence of resistantS. aureus has kindled intense inter-est in new treatments for this common pathogen. Two new antibiotics, qui-

nupristin/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 qui-

nupristin/dalfopristin [138] and linezolid [139] have clinical efficacy against

S. aureus. Studies are ongoing, but neither agent currently has an FDA indi-

cation for eitherS. aureusbacteremia or IE. Until the findings of these retro-

spective investigations are confirmed by well designed, prospective trials,these agents should only be considered for the treatment ofS. aureusbacter-

emia 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 initia-

tion and metastatic spread ofS. aureus, the Microbial Surface Components

Recognizing Adhesive Matrix Molecules (MSCRAMM) family of bacterial



17/23

surface adhesin proteins represents an excellent target for the development

of novel immunotherapies.Staphylococcus aureusHuman Immune Globulin

(SA-IGIV, Inhibitex, Inc.) is a purified immunoglobulin G (IgG) productderived from pooled human plasma selected for high titers of antibody to

MSCRAMMs. The MSCRAMM-specific IgG in SA-IGIV interferes with

S. aureus adherence to extracellular matrix proteins in vitro, and may

enhance opsonophagocytosis ofS. aureusby polymorphonuclear leukocytes

[140]. In an animal model ofS. aureusIE, addition of SA-IVIG to vancomy-

cin significantly increased bacterial clearance from the bloodstream when

compared to vancomycin alone (P< 0.008) [141]. An open-label, multicen-

ter 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 efforts to

reduce rates ofS. aureusinfections. StaphVax (Nabi, Inc.) is the first vaccine

with demonstrated clinical efficacy in reducing rates of staphylococcal infec-

tions. It consists of type 5 and type 8 capsular polysaccharides, the strains

accounting for more than 80% of S. aureus infections. In a recent double-

blinded, placebo-controlled Phase III clinical efficacy 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 atrisk for invasive S. aureus infections (e.g., persons with indwelling intravas-

cular catheters, persons undergoing elective surgery, and so forth).

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Staphylococcus Aureus Bacteremia and Endocarditis

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