Staphylococcus aureus infective endocarditis and septic pulmonary embolism after septic abortion

INTRODUCTION

Infective endocarditis (IE) is one of the most devastatingmanifestations of S. aureus infection. It can occur inpreviously well individuals with no pre-existing cardiacabnormality. Between 20% and 65% of cases of S. aureusinfective endocarditis (SAIE) are fatal, and a significantproportion of survivors are left with permanent sequelaedue to local invasion of cardiac structures, embolizationof vegetations, or metastatic infection. Prosthetic valveendocarditis caused by S. aureus is associated with a veryhigh mortality, and surgery is often required for asuccessful outcome.

EPIDEMIOLOGY OF S. AUREUSINFECTIVE ENDOCARDITIS

A retrospective study of SAIE in Denmark over 5 yearsestimated the incidence of the disease at four cases permillion people per year.1 Several prospective and retro-spective studies have documented an increase in the inci-dence of both S. aureus bacteraemia (SAB) and SAIEworldwide,2,3 and the proportion of all endocarditis casesthat are due to S. aureus also appears to be increasing.For example, in one prospective study at a large US insti-tution, the proportion of endocarditis cases due toS. aureus increased almost 7-fold between 1993 and1999.4 In recent reports (including one from the large

International Collaboration on Endocarditis), S. aureuswas found to be responsible for 25% to 68% of cases ofnative valve endocarditis in adults,5–10 and it was thecausative organism in 10% to 30% cases of prostheticvalve endocarditis.7,8,10

Possible reasons for the increase in the incidence ofSAIE include the increased use of invasive proceduresand intravascular devices, an increase in the prevalenceof intravenous drug use (IVDU), and improvements indiagnostic techniques.3 The proportion of SAIE that isacquired in the healthcare setting also appears to beincreasing;1,2,4,11 however, community-acquired SAIEstill comprises the majority of cases in most recentstudies.1,12–14

Risk factors for SAIE identified in prospective studiesinclude intravenous drug use, diabetes mellitus, hospital-ization, increasing age, prior cardiac surgery, pre-existingvalvular heart disease, previous endocarditis, thepresence of an intravascular device and male gender.15

S. aureus has been identified as an independent riskfactor for mortality in large prospective studies of infec-tive endocarditis due to all causes.4

Endocarditis in patients with S. aureus bacteraemia(SAB)Reported rates of endocarditis in patients with SAB havevaried between 0% and 64%, due to variations in studypopulations, case definitions, imaging modalities,autopsy rates and reporting bias.11,16–29 In earlier studies,endocarditis was considered to be uncommon whenSAB was acquired in hospital or when a primary focusfor the bacteraemia (such as an intravascular catheter)was present.17,21–23 However, more recent prospective

AbstractS. aureus infective endocarditis (SAIE) is a serious infec-tion associated with considerable morbidity andmortality.There is evidence that the incidence of SAIE isincreasing. As its clinical features are non-specific, SAIEmust be suspected in every case of S. aureus bacteraemia,whether it is associated with an obvious source or not.The optimal antimicrobial agent(s) and duration of treat-ment for SAIE are currently not known, but on the basisof present evidence, a minimum of 2 weeks of antimicro-bial therapy is recommended for ‘right-sided’ SAIE, aminimum of 4 weeks for uncomplicated ‘left-sided’SAIE, and a minimum of 6 weeks for complicated ‘left-sided’ or prosthetic valve SAIE. Although there is no

evidence to suggest that combination therapy with a cell-wall active agent (e.g. flucloxacillin) and an aminogly-coside decreases mortality in SAIE, combination therapyshould be considered during the initial 3–5 days oftherapy as it can shorten the duration of bacteraemia. Incomplicated or prosthetic valve SAIE, early and closeliaison with cardiology and cardiothoracic surgeryservices is essential. Rapid identification and suscepti-bility testing of the infecting organism are important indetermining the choice of definitive antimicrobialtherapy. (Intern Med J 2005; 35: S25–S44)

Key words: Staphylococcus aureus, infectiveendocarditis, endocarditis, evidenced-based guidelines.

Internal Medicine Journal 2005; 35: S25–S44

Staphylococcus aureus infective endocarditis: diagnosis andmanagement guidelines

R. J. MURRAY

Department of Microbiology and Infectious Diseases, Royal Perth Hospital, Perth,Western Australia, Australia

Correspondence to: Ronan J. Murray, Department ofMicrobiology and Infectious Diseases, Royal PerthHospital, GPO Box X2213, Perth,WA 6847, Australia.Email: [email protected]

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studies of SAB using echocardiography and well-validated diagnostic criteria have demonstrated thatendocarditis is present in up to 25% of all cases of SAB,regardless of whether a portal of entry is identified orwhere the bacteraemia is acquired.11,24,25,27,28 In onerecent study, 52% of cases of SAIE were associated witha removable focus of infection and 46% were nosocomi-ally acquired.13 Because of the relationship between SABand SAIE, it has been proposed that S. aureus bacter-aemia be added to major criteria for the diagnosis ofinfective endocarditis as a modification to the existingDuke criteria (see further below).30

The incidence of SAIE in patients with SAB inAustralasia is not known. In three recent Australianstudies that included a total of 435 patients with SAB,endocarditis was reported in 2% to 32% of cases.31–33 Inone of these studies, it was noted that transoesophagealechocardiography was performed in only 23% of cases ofSAB, suggesting that SAIE may be underdiagnosed.33

S. aureus infective endocarditis in intravenous drugusersInfective endocarditis is a common cause of morbidityand mortality in intravenous drug users (IVDUs),34,35

and S. aureus is the most common cause of infectiveendocarditis in this patient group.7,34–38 The proportionof all cases of SAIE that occurs in IVDUs varies between0% and 65% depending on the population studied.7,10,22,39

The high rate of SAIE in this population is likely due toSAB resulting from unhygienic injection practices inindividuals colonized with S. aureus.40–42

Most IVDUs who develop SAIE have no underlyingcardiac abnormality.7,38,43 SAIE in these patients is morelikely to affect the tricuspid or pulmonary valves (‘right-sided’ infective endocarditis) than the aortic or mitralvalves (‘left-sided endocarditis’), although involvementof both sides of the heart can occur simultaneously.7,22,38

HIV infection is associated with a significantlyincreased risk of endocarditis in IVDUs, but not in thenon-IVDU population.44,45 This risk increases with thedegree of immune suppression, and mortality from

infective endocarditis is significantly higher in HIV-infected patients with CD4+ T-cell counts of ≤200/mm3

or AIDS.44 In non-immunosuppressed HIV-infectedpatients, the clinical course of SAIE and its response toantimicrobial therapy is similar to that in IVDUs withoutHIV infection.46,47

CLINICAL FEATURES OF S. AUREUSINFECTIVE ENDOCARDITIS

The common symptoms and signs of SAIE are shown inTable 1. Splinter haemorrhages, Osler’s nodes, Janewaylesions and Roth’s spots are uncommon findings, butperipheral embolic lesions are common (Fig. 1A–D).34

In patients with SAB, clinical features are neither sensi-tive nor specific for SAIE.13 In large retrospective studiesof SAB, endocarditis was only found at postmortemstudy in a significant percentage of cases.1,48

Early studies of SAIE found that an identifiable portalof entry for S. aureus was apparent in only a minority ofcases.17,23 However, a more recent study suggested that94% of patients with SAIE had an identifiable portal ofentry.11 Intravenous vascular access devices (IVADs)have been implicated as a frequent portal of entry forS. aureus.11,13,18,24,25,49

Cardiac manifestationsS. aureus produces extracellular toxins which can resultin rapid and extensive tissue damage and abscess forma-tion. The typical feature of infective endocarditis, theendocardial vegetation, consists of aggregates of plate-lets, fibrin and organisms which adhere to heart valves orto endocardium in the path of regurgitant jets of blood.Progression of the infection can result in a number ofdeleterious sequelae. Acute valvular dysfunction due toperforation or dehiscence results in acute severe conges-tive cardiac failure, which is the most common cause ofdeath from SAIE. Perivalvular abscesses can originatefrom parts of the prosthetic valve attached to the heartand can rapidly extend into the myocardium, resulting inconduction abnormalities or aneurysmal dilatation.

Table 1 Symptoms and signs of S. aureus infective endocarditis

Involvement Symptoms Signs

• Either left- or right-sided Fever Inflammation/pus at entry siteRigors TachycardiaMyalgias HypotensionArthralgias Metastatic infection (bone, joint, visceral)

• Left-sided Dyspnoea Heart blockCentral nervous system symptoms Oslerian manifestations†

(e.g. syncope, meningism, hemiparesis) Aortic or mitral valve regurgitationManifestations of arterial emboli (cerebral, visceral,

limb)• Right-sided Dyspnoea Tricuspid or pulmonary regurgitation

Pleuritic chest pain Lung consolidationCough with sputum EffusionHaemoptysis

†Osler’s nodes, Janeway lesions, splinter haemorrhages, Roth’s spots.

S27S. aureus infective endocarditis

Fistulae due to extension of the infection into the sinusesof Valsalva, aorta or pulmonary arteries can result inhaemodynamically significant intracardiac shunting.These events may have already occurred at the timeof diagnosis or develop at any time during the course oftherapy, and are associated with a high mortality ratewithout surgery.50

‘Right-sided’ SAIE runs a much more benign coursethan ‘left-sided’ SAIE, leading to significantly betteroutcomes from shorter treatment durations.38,51,52

Extracardiac manifestationsEmbolization of a vegetation may result in ischaemia ofthe region distal to the embolus and/or the establishmentof a metastatic focus of infection. In addition, excessiveimmune complex formation in the setting of a high-grade intravascular infection may result in organdysfunction (e.g. glomerulonephritis).

‘Left-sided’ SAIE

Embolization from the left side of the heart can affectvirtually any part of the body, but is especially seriouswhen it involves the central nervous system. In one retro-spective study, neurological events occurred in 35% ofpatients with SAIE, the most frequent of which wereunilateral hemiparesis, aphasia and meningitis. Mortalityfrom SAIE was significantly higher in patients who had

any neurological event compared with those who did nothave a neurological event (74% vs 56%, respectively),and most of these events had occurred prior to the diag-nosis of SAIE.53 Other common sites of embolizationinclude the kidneys, spleen (see Fig. 2), limbs, vertebralcolumn, epidural space and skeletal muscle (particularlythe iliopsoas complex).

Mycotic aneurysms result from metastatic infectioninvolving the arterial wall. These are most commonlyrecognized in the cerebral circulation when they rupture(resulting in intracranial haemorrhage) or thrombose(resulting in ischaemia). Most cerebral mycoticaneurysms occur in the territory of the middle cerebralartery and they may be multiple.54

Renal complications are seen in up to 50% of cases ofSAIE and occur as a result of embolic phenomena orimmune complex-medicated disease.6,7,55 Common patho-logic findings include infarction, glomerulonephritis,acute interstitial nephritis and cortical necrosis.56

‘Right-sided’ SAIE

Septic pulmonary emboli are usually multiple, small andperipheral and are rarely of haemodynamic significance.However, they can enlarge and cavitate to form lungabscesses, or rupture into the pleural space resulting inempyema formation.

PATHOLOGY TESTING

Readers are referred to the review on S. aureus bacter-aemia in this issue for details regarding blood culturecollection and result interpretation.

Serum bactericidal titre testA systematic review of the use of the serum bactericidaltitre (SBT) test in infective endocarditis found that there


Figure 1 Peripheral stigmata of infective endocarditis. (A)Splinter haemorrhage. (B) Janeway lesions. (C) Osler’s nodes.(D) Embolic lesions typical of Staphylococcus aureus. Splinterhaemorrhages and Osler’s nodes are due to antigen/antibodycomplex deposition, whereas Janeway lesions are due tomicroemboli. Frequently in S. aureus endocarditis as opposedto endocarditis due to other bacterial species, the emboli andtherefore the lesions are bigger, and splinter haemorrhages,Osler’s nodes and Janeway lesions are less frequently seen.Osler’s nodes are typically painful whereas the others are not.♣(Photographs [A]–[C] courtesy of Dr Bryan Speed,Fairfield historical collection, photograph [D] from author’scollection.)

Figure 2 Computerized tomographic scan of abdomen,showing splenic abscess in case of Staphylococcus aureusendocarditis. (Photograph courtesy of A/Prof Iain Gosbell,Department of Microbiology and Infectious Diseases,South-western Area Pathology Service, Liverpool, NSW).

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was no significant association between the test resultand either survival or bacteriological outcome, and thatsignificant variations in methodology made interpre-tation of such assays problematic.57 Consequently,measurement of the SBT is not recommended in themanagement of patients with SAIE.

Serology testsEarly studies suggested that the demonstration of anti-bodies to teichoic acid (a component of the cell wall ofstaphylococci) in serum was useful as diagnostic markerof SAIE.58 However, it was subsequently reported thatthis test is neither sensitive nor specific for SAIE.22 Thus,measurement of antistaphylococcal antibodies is notrecommended in the diagnosis or management of SAIE.

Nucleic acid detectionRecent studies have demonstrated the potential utility ofnucleic acid detection methods such as real-time poly-merase chain reaction (PCR) and peptide nucleic acidfluorescence in situ hybridization (PNA-FISH) for thedetection of S. aureus directly from positive bloodcultures.59,60 Additionally, resistance to methicillin canalso be determined on the same sample simultaneously.59

S. aureus DNA has been identified directly from heartvalves by amplification and sequencing of bacterial 16SrDNA in cases of known or suspected SAIE.61,62

Although nucleic acid detection of S. aureus is notcurrently performed routinely in most clinical labora-tories, it may become more widely available in the futureand may be a valuable adjunct in the diagnosis andmanagement of SAIE.

IMAGING PROCEDURES

EchocardiographyThe advent of echocardiography represented a signifi-cant advance in the management of infective endo-carditis. Transthoracic echocardiography (TTE) allowsdirect visualization of valvular and endocardial struc-tures, is non-invasive, rapid, widely available and can beperformed by suitably trained non-medical personnel. Inan early study of the use of TTE in patients with SAB,unsuspected infective endocarditis was found in 11% of36 hospital-acquired SAB cases.22 Although TTE hasexcellent specificity for the detection of cardiac vegeta-tions in infective endocarditis (98%), its sensitivity isonly 40% to 80%;11,63,64 therefore, a negative TTEcannot exclude infective endocarditis in patients withSAB.

Transoesophageal echocardiography (TOE) canproduce higher quality images of the heart than TTEbecause the transducers use higher ultrasonic frequen-cies, imaging in multiple planes is readily obtainable andinterference from air-filled lungs or the chest wall iseliminated. Diagnostic sensitivities of 87% to 100% andspecificities of 89% to 100% have been reported for theuse of TOE in the diagnosis of SAIE.11,63,65–69 TOE isparticularly useful in detecting small vegetations,70

‘right-sided’ endocarditis,71 non-valvular endocarditis,72

prosthetic valve endocarditis,73 and complications ofendocarditis such as paravalvular abscesses,67 papillarymuscle rupture74 and valvular perforation.75 The highnegative predicative value of TOE is of importancebecause it may allow earlier cessation of antimicrobialtherapy,24,68 a strategy that is more cost-effective thanlong-course therapy for possible SAIE in catheter-associated SAB.76 Although TOE is invasive and usuallyrequires intravenous sedation, major complications arerare.77

Echocardiography may also be useful in predictingthe outcome of treatment in patients with SAIE.Although persistence of vegetations following successfultherapy of SAIE is not predictive of late complicationssuch as recurrence or emboli,78 an increase in vegetationsize over the course of therapy may predict a groupof patients at risk for complications, independently ofpersistent bacteraemia or ongoing embolic phenom-ena.79 One prospective study showed that vegetationsvisible by TTE were more likely to embolize than vege-tations visible only by TOE.13 In studies of IVDUs withtricuspid valve SAIE, patients with vegetations that weredetectable by TTE were more likely to have a prolongedfever, develop right heart failure, and/or require tricuspidvalve surgery than those in whom vegetations were notvisible.36,80

All patients with SAB should undergo echocardio-graphy within the first 5–7 days of therapy. In addition,TOE should be performed when the TTE is suboptimaland/or non-diagnostic in community-acquired orprolonged SAB, in prosthetic valve endocarditis (PVE)or infection associated with other intracardiac devices, ifnew-onset cardiac conduction disturbance occurs, orwhere short-course therapy (2 weeks) is being consid-ered. If the clinical suspicion of infective endocarditis ishigh, but initial echocardiography is negative, it shouldbe repeated in 7–10 days.

Other imaging proceduresPulmonary metastatic complications are common inpatients with ‘right-sided’ SAIE (see Fig. 3A,B).They donot in themselves dictate a change in management, butthey can progress to cavitation or rupture into the


Figure 3 Pulmonary abscesses secondary to tricuspidendocarditis due to community MRSA. (A) Chest X-ray. (B).Computerized tomographic scan of chest. (Photographcourtesy of A/Prof Iain Gosbell, Department of Microbiologyand Infectious Diseases, South-western Area PathologyService, Liverpool, NSW).


pleural space resulting in empyema. All patients with‘right-sided’ SAIE should therefore undergo chest radio-graphy (CXR) at the time of diagnosis, and this shouldbe repeated if symptoms or signs of pulmonaryembolism develop during or after therapy. If the CXRdoes not show any abnormality in a patient withsymptoms and signs suggestive of pulmonary embolism,computerized tomography (CT) of the chest should beperformed as it is a more sensitive (though more expen-sive and less widely available) test for the demonstrationof septic embolic lesions.81

Imaging to detect systemic metastatic complicationsshould be performed according to any symptoms andsigns that are elicited on patient history and examina-tion. A CT scan of the brain should be performed onpatients with focal neurological signs. Patients withsymptoms and signs of meningitis should have a cere-brospinal fluid examination once space-occupyingcerebral lesions or raised intracranial pressure have beenexcluded by clinical examination and cerebral imaging.

USE OF THE DUKE CRITERIA FORDIAGNOSIS OF S. AUREUSINFECTIVE ENDOCARDITIS

In 1994, a set of diagnostic criteria (known as the Dukecriteria) were developed for the diagnosis of infectiveendocarditis.82 The Duke criteria have been validated ina wide variety of populations and settings, and have beenshown to be both sensitive (>80%) and highly specific(>98%) for the diagnosis of infective endocarditis incomparison with the ‘gold standard’ of pathologicalconfirmation.3,30,82,83 Recently, several modifications havebeen proposed to increase the sensitivity of the Dukecriteria for detecting infective endocarditis (Table 2),including making SAB a major criterion.30

ANTIMICROBIAL THERAPY OFS. AUREUS INFECTIVEENDOCARDITIS

Recently published guidelines on the management ofSAIE provide differing recommendations regardingthe choice and dosages of antimicrobial agents and theduration of treatment.83–86 In the main, these recommen-dations are based largely on expert opinion or consensusrather than high-quality evidence from randomised,controlled clinical trials. Animal models are commonlyused in the evaluation of antimicrobial agents of poten-tial value for the treatment of SAIE, but efficacy in thesemodels does not always correlate with clinical outcomeswhen these agents are used in humans.

Although a number of prospective, randomisedcontrolled trials have compared various antimicrobialagents (alone or in combination) for the treatment ofSAIE, many of these trials are of limited value because ofnon-uniform definitions of endocarditis, small samplesizes, high dropout rates, and variations in drug dosages,administration routes, therapy duration and outcomemeasures. Because no prospective, randomised controlledtrials have determined the optimal duration of therapy for

SAIE, recommendations regarding treatment duration arelargely derived from retrospective studies, consensusopinion, or previously published recommendations.

β-Lactam antibiotics

Penicillins

Over 90% of S. aureus isolates in Australia are resistantto penicillin due to the production of penicillinase.87

When an isolate of S. aureus obtained from a patientwith infective endocarditis is susceptible to penicillin,benzylpenicillin (penicillin G) is considered the agent ofchoice, despite the lack of controlled clinical trials demon-strating its efficacy.

The semisynthetic antistaphylococcal β-lactamsnafcillin and oxacillin are bactericidal in animal modelsof S. aureus endocarditis.88–92 Flucloxacillin anddicloxacillin are the only agents from this group that areavailable in Australasia and are the agents of choice forthe treatment of SAIE due to penicillinase-producingmethicillin-susceptible S. aureus (MSSA) (Tables 3,4),although it should be emphasized that they have notbeen as thoroughly studied as other agents of thisantimicrobial group.Traditionally, they are administeredby bolus injection, but continuous infusion therapy isbeing increasingly utilized, particularly in the outpatientsetting93,94 (see section on outpatient antimicrobialtherapy for SAIE below). As peripheral vein thrombo-phlebitis is common with the use of intravenousdicloxacillin, it should always be administered via acentral venous catheter.

Because penicillins are more active against suscep-tible staphylococci than other cell-wall active agents (e.g.cephalosporins and glycopeptides), they should beconsidered first-line agents for susceptible isolates,except for patients with penicillin hypersensitivity.Patients who report an unconfirmed history of hyper-sensitivity to penicillins should be considered forimmediate-type hypersensitivity skin testing if this isavailable.95

Cephalosporins

The first-generation cephalosporins cephalothin andcephazolin demonstrate bactericidal activity againstMSSA in vitro. In animal models of SAIE, these agentswere of similar efficacy to the semisynthetic peni-cillins.91,92,96 While neither has been systematicallystudied in clinical trials, they are often used for the treat-ment of SAIE caused by MSSA in patients with non-immediate hypersensitivity to penicillins. Some in vitrostudies have shown that cephazolin is more susceptible toenzymatic hydrolysis by type A β-lactamases producedby some strains of S. aureus, particularly when highnumbers of organism are present (as is the case in acardiac vegetation),97,98 and clinical failures of cephazolintreatment of SAIE have been reported.99–101 Cephalothinis therefore preferred to cephazolin for the treatment ofSAIE, but if ‘high inoculum’ MIC testing or molecularcharacterization of the β-lactamase genes of the infectingstrain of S. aureus demonstrate that cephazolin is activeagainst that strain, then cephazolin may be used.101


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The third-generation cephalosporin ceftriaxone is apotentially attractive agent because it is active againstS. aureus in vitro and is administered as a once-dailybolus injection. It has been used for the treatment ofstaphylococcal endocarditis, but as clinical failures arenot uncommon, despite its use in combination withgentamicin,102 it is not recommended for the treatmentof SAIE.

Glycopeptide antibiotics

Vancomycin

Vancomycin is bactericidal against staphylococci in vitro,but killing is significantly slower than with the β-lactam

agents.103,104 In animal and artificial models of SAIE,vancomycin has proved to have similar efficacy to anti-staphylococcal penicillins for MSSA infection,88,90,105 andit can sterilize cardiac vegetations containing methicillin-resistant S. aureus (MRSA).90 However, contrary to earlyclinical reports suggesting good outcomes whenvancomycin was used for SAIE caused by MSSA, failurerates of around 30% have been reported.103,106–109 Aretrospective study of the use of vancomycin in IVDUswith predominantly ‘right-sided’ SAIE caused by MRSAsuggested that 28 days of therapy was curative in themajority of cases,110 but bacteraemia may persist forseveral days despite apparently adequate therapy.34,111

Vancomycin is currently the agent of choice for the


Table 2 Modified Duke criteria for the diagnosis of S. aureus infective endocarditis (adapted from Li et al.30)

Diagnosis Criteria

• Definite infective endocarditis(a) Pathological criteria 1. S. aureus demonstrated by culture or histological examination of

a vegetation, a vegetation that has embolised, or an intracardiac abscess specimen; or

2. Pathological lesions, vegetation or intracardiac abscess confirmed by histological examination showing active endocarditis

(b) Clinical criteria 1. 2 major criteria; or2. 1 major criterion and 3 minor criteria; or3. 5 minor criteria

• Possible infective endocarditis 1. 1 major criterion and 1 minor criterion; or2. 3 minor criteria

• Rejected 1. Firm alternative diagnosis explaining evidence of infective endocarditis

2. Resolution of infective endocarditis syndrome with antibiotic therapy for ≤4 days; or

3. No pathological evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy for = 4 days; or

4. Does not meet criteria for possible infective endocarditis, as above

Major criteria Minor criteriaS. aureus identified from 2 separate blood cultures; or Predisposition: predisposing heart condition or intravenous drug useS. aureus identified from persistently positive blood Fever: temperature >38°C

cultures, defined as follows: Vascular phenomena: major arterial emboli, septic pulmonary at least 2 positive cultures of blood samples collected infarcts, mycotic aneurysm, intracranial haemorrhage,

>12 h apart; or conjunctival haemorrhages, and Janeway’s lesionsall of 3 or a majority of ≥4 separate cultures of blood Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s

(with the first and last sample drawn at least 1h apart) spots, rheumatoid factorEvidence of endocardial involvement: Microbiologic evidence: positive blood culture for S. aureus but 1. Echocardiogram positive for infective endocarditis,† does not meet a major criterion as noted above, or serological

defined as follows: evidence of active infection with S. aureusoscillating intracardiac mass on valve or supporting

structures, in the path of regurgitant jets, or onimplanted material in the absence of an alternative anatomic explanation; or

abscess; ornew partial dehiscence of prosthetic valve2. New valvular regurgitation (worsening or changing of

pre-existent murmur not sufficient)

†Transoesophageal echocardiography is recommended in patients with prosthetic valves, rated at least ‘possible infective endocarditis’ by clinicalcriteria, or those with complicated infective endocarditis (e.g. paravalvular abscess). Transthoracic echocardiography is recommended as the firsttest in other patients.


treatment of SAIE caused by MRSA, or for the minorityof cases of SAIE caused by MSSA when the patient hasdemonstrated intolerance of or severe hypersensitivity toβ-lactam agents. However, as treatment failure in SAIEhas recently been described in association with the emer-gence of S. aureus with reduced vancomycin suscepti-bility (SA-RVS) while on vancomycin therapy, closeobservation and surveillance blood cultures should beperformed if it is used in the treatment of SAIE.112,113

Vancomycin has been administered by continuousinfusion in small studies that included patients withserious infections caused by Gram-positive cocci,including S. aureus.114,115 Continuous infusion vanco-mycin therapy may be considered in patients who do notrespond to bolus therapy and in those who are suitablefor outpatient intravenous antimicrobial therapy.

Teicoplanin

Teicoplanin has bactericidal activity against S. aureus invitro. In animal models of SAIE, teicoplanin was inferiorto nafcillin and cloxacillin in MSSA infection andinferior to vancomycin for MRSA infection,90,116 and inanother study, resistance emerged during therapy insome animals.117 Teicoplanin penetrates poorly into the

centre of vegetations in comparison with β-lactams andaminoglycosides,118 and an artificial model of SAIEdemonstrated sterilization only with very high doses.105

Uncontrolled, non-randomised studies of teicoplaninin the treatment of SAIE have reported unacceptablefailure rates, particularly when low doses were used.119–123

In a randomised, double-blind trial comparingvancomycin (30 mg/kg/day) with teicoplanin (12 mg/kgfor the first day, then 6 mg/kg/day) for the treatment ofSAB, all four patients with ‘left-sided’ SAIE in theteicoplanin group failed on therapy, resulting in discontin-uation of the trial.124 In another small trial that comparedhigh-dose teicoplanin (up to 20 mg/kg/day) withcloxacillin and gentamicin for the treatment of ‘right-sided’ SAIE in IVDUs, four of six patients receivingteicoplanin failed on therapy.122 Similarly, in a retrospec-tive study, the use of teicoplanin as ‘salvage therapy’ forSAIE resulted in only six of 13 patients achieving cure.123

Adverse effects of teicoplanin such as rash and fever werecommon in some of these studies, particularly whenhigher doses were used.121,123,125 In addition, resistance toteicoplanin has emerged during therapy for SAIE.117

Teicoplanin should only be used in rare cases of SAIEwhere patients are intolerant of both β-lactam agents


Table 3 Recommendations for the treatment of ‘right-sided’ native valve endocarditis caused by S. aureus

Clinical setting Recommended antimicrobial therapy†

• Methicillin-susceptible S. aureus Flucloxacillin/dicloxacillin 2 g IV q4h for 14 days plusgentamicin 1 mg/kg IV q8h for the first 3 to 5 days

If isolate is susceptible to penicillin Substitute for flucloxacillin/dicloxacillin: Benzylpenicillin 1.8 g IV q4h

If non-severe penicillin hypersensitivity‡ Substitute for flucloxacillin/dicloxacillin: Cephalothin 2 g IV q4h • Severe penicillin hypersensitivity‡ or methicillin-resistant Vancomycin 15 mg/kg IV q12h for 28 days plus gentamicin

S. aureus 1 mg/kg IV q8h for the first 3 to 5 days• Intravenous therapy not possible; compliance with oral Rifampicin 300 mg PO q12h plus ciprofloxacin 750 mg

therapy can be assured PO q12h for 28 days• Intolerance of or hypersensitivity to vancomycin Discuss therapy with an Infectious Diseases Physician/Clinical

(for methicillin-resistant S. aureus) or to both β-lactams Microbiologist. Possible alternatives to β-lactams/ and vancomycin (for methicillin-susceptible S. aureus) vancomycin include:

Teicoplanin 800 mg IV q12h for first 24h, then 800 mg daily;orLinezolid 600 mg IV/PO q12h; orQuinupristin/dalfopristin 7.5 mg/kg IV q8h

• Outpatient intravenous antimicrobial therapy Discuss therapy with an Infectious Diseases Physician/Clinical Microbiologist. Options include:

Flucloxacillin 8–12 g/day by continuous infusion; orVancomycin 2 g/day by continuous infusion

Note: if any exclusion criteria are present (see footnote), treatment duration is as for ‘left-sided’ endocarditis (refer Table 4).Exclusion criteria for ‘short-course’ treatment of ‘right-sided’ native valve endocarditis caused by S. aureus include: (1) infectioncaused by methicillin-resistant S. aureus; (2) hypersensitivity to (or intolerance of) penicillins and cephalosporins; (3) prosthetic valve infection;(4) co-existent ‘left-sided’ infective endocarditis; (5) extrapulmonary metastatic infection (e.g. meningitis, osteomyelitis, septic arthritis,empyema); or (6) polymicrobial infection.†Doses and dose intervals of the following antimicrobial agents should be adjusted according to the patient’s renal function and therapeutic drugmonitoring results:

– gentamicin: aim for a trough serum concentration of <1 mg/L– vancomycin: aim for a trough serum concentration of 15-20 mg/L (intermittent dosing) or at least 20 mg/L (continuous infusion)– teicoplanin: aim for a trough serum concentration of >20 mg/L– flucloxacillin: as there are significant variations in methodology, refer to local laboratory data for interpretation.

‡Immediate-type hypersensitivity skin testing for penicillins should be considered when there is no clearly documented history of hypersensitivity.

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and vancomycin. If it is used for the treatment of SAIE,trough serum concentrations must be regularly measuredand a level of >20 mg/L should be maintained.126

Other antimicrobial agents

Clindamycin

Clindamycin demonstrates bacteriostatic activity againstS. aureus in vitro. Animal model data have indicated thatpersistent bacteraemia and relapse are common withclindamycin therapy, and that relapses are often associ-ated with an increase in the minimum inhibitory concen-tration (MIC) for this agent.88 High failure rates werereported when clindamycin was administered via intra-muscular injection in IVDUs with ‘right-sided’SAIE.127,128 Consequently, this agent is not recom-mended, either alone or in combination, for the treat-ment of SAIE.

Fluoroquinolones

Ciprofloxacin, moxifloxacin and gatifloxacin have bacte-ricidal activity against S. aureus in vitro, penetrate wellinto tissues, and are active against stationary phasebacteria. Animal models of SAIE have demonstrated thatciprofloxacin is as effective as nafcillin for MSSA, and aseffective as vancomycin for MRSA infection.129–131

However, resistance emerges rapidly when it is used asmonotherapy for the treatment of S. aureus infection.132

There are limited animal model or human data for thenewer fluoroquinolones (e.g. moxifloxacin, gatifloxacin)

in the treatment of SAIE.133,134 Currently, these agentsare not recommended as single agent therapy for thetreatment of SAIE.

Rifampicin

Rifampicin has rapid bactericidal activity againstS. aureus in vitro, good bioavailability after oral dosing,penetrates into cardiac vegetations, and has demon-strated bactericidal activity against organisms associatedwith foreign material.135 However, resistance emergedrapidly when it was used as monotherapy for SAIE inanimal models.88,136 Thus, monotherapy with rifampicinis not recommended for the treatment of SAIE.

Fusidic acid

Fusidic acid has bactericidal activity against S. aureus invitro and has good oral bioavailability. However, resis-tance emerges rapidly when this agent is used asmonotherapy for staphylococcal infection.137 There havebeen no prospective, randomised clinical trials of the useof fusidic acid, either alone or in combination, in thetreatment of SAIE.138 Some retrospective studies havesuggested that its use in combination with a β-lactamagent results in better outcomes in SAIE,20,139,140 but asingle large retrospective study of SAB did not demon-strate a significant survival benefit with this combinationin comparison with flucloxacillin monotherapy.141

The intravenous formulation of fusidic acid commonlycauses jaundice and elevated hepatic enzyme levels, whichlimits its usefulness.140 Fusidic acid should not be used


Table 4 Recommendations for the treatment of ‘left-sided’ native valve endocarditis caused by S. aureus


• Methicillin-susceptible S. aureus Flucloxacillin/dicloxacillin 2 g IV q4h for 28–42 days plus gentamicin 1 mg/kg IV q8h for the first 3 to 5 days

If isolate is susceptible to penicillin Substitute for flucloxacillin/dicloxacillin:Benzylpenicillin 1.8 g IV q4h

If non-severe penicillin hypersensitivity‡ Substitute for flucloxacillin/dicloxacillin:Cephalothin 2 g IV q4h

• Severe penicillin hypersensitivity‡ or Vancomycin 15 mg/kg IV q12h for 28–42 days plus gentamicin 1 mg/kg IV methicillin-resistant S. aureus q8h for the first 3 to 5 days

• Intolerance of or hypersensitivity to vancomycin Discuss therapy with an Infectious Diseases(formethicillin-resistant S. aureus) or to both Physician/Clinical Microbiologist.β-lactams andvancomycin (for methicillin- Alternatives to β-lactams/vancomycin include:susceptible S. aureus) Teicoplanin 800 mg IV q8h for first 24 h, then 800 mg daily; or

Linezolid 600 mg IV/PO q12h; orQuinupristin/dalfopristin 7.5 mg/kg IV q8h

• Outpatient intravenous antimicrobial therapy Discuss therapy with an Infectious Diseases Physician/Clinical Microbiologist.

Options include:Flucloxacillin 8–12 g/day by continuous infusionVancomycin 2 g/day by continuous infusion

†Doses and dose intervals of the following antimicrobial agents should be adjusted according to the patient’s renal function and therapeutic drugmonitoring results:




as monotherapy for SAIE and there is no convincingevidence to suggest that its addition to β-lactam therapyconfers benefit.

Co-trimoxazole (trimethoprim/sulfamethoxazole;TMP-SMX)

Co-trimoxazole has bactericidal activity against most(but not all) strains of S. aureus in vitro.142 In animalmodels of SAIE, cotrimoxazole was inferior tocloxacillin, vancomycin and teicoplanin for both MSSAand MRSA, with valve sterilization rates and mortalitycomparable to untreated animals.116 In a prospective,randomised controlled trial comparing co-trimoxazolewith vancomycin for the treatment of IVDUs withserious S. aureus infection (almost half of which were dueto MRSA), co-trimoxazole was found to be inferior tovancomycin in the group as a whole, with most clinicalfailures occurring in those patients who had ‘right-sided’SAIE due to MSSA. In addition, there was a non-significant trend towards a longer duration of bacteraemiaand increased adverse events in the co-trimoxazole-treated group.143 At present therefore there is insufficientevidence to recommend the use of co-trimoxazole for thetreatment of SAIE.

Quinupristin/dalfopristin

Quinupristin/dalfopristin demonstrates bacteriostaticactivity against staphylococci, including most strains thatare resistant to macrolides and lincosamides.144 Animalmodel data have suggested that quinupristin/dalfopristinmay be effective for the treatment of SAIE,144,145 andsynergistic bactericidal activity has been demonstratedwhen it was combined with β-lactams,146 vancomycin,147

or rifampicin148 in experimental MRSA endocarditis.There are currently no prospective randomised,controlled clinical trials of quinupristin/dalfopristin forthe treatment of SAIE. Although a multicentre,randomised, controlled trial that compared quinupristin/dalfopristin with vancomycin for the treatment ofcatheter-related bacteraemia due to MRSA suggestedequivalence,149 a multinational, non-randomised studyof the use of quinupristin/dalfopristin for the treatmentof MRSA infection refractory to standard therapydescribed clinical failure in five of 11 patients with endo-carditis, including two with proven bacteriologicalfailure.150

Quinupristin/dalfopristin is not currently recom-mended for the first-line treatment of SAIE, but may beconsidered in those patients with SAIE due to MRSAwho are intolerant of vancomycin, who have persistentbacteraemia despite appropriate first-line therapy, or inpatients with endocarditis due to SA-RVS, vancomycin-intermediate S. aureus (VISA), or vancomycin-resistantS. aureus (VRSA).

Linezolid

Linezolid belongs to the oxazolidinone class of antimi-crobial agents and is active against virtually all strains ofS. aureus in vitro. Linezolid was able to sterilize vege-tations as effectively as vancomycin in some studies of

animal models of methicillin-susceptible and methicillin-resistant SAIE,151,152 but not in others.153 It was notsynergistic with rifampicin in an animal model studyof MSSA infective endocarditis,154 or with vancomycinfor MRSA infective endocarditis.153 There are norandomised, controlled clinical trials of linezolid inSAIE, and only limited non-controlled clinical experi-ence has been reported in the literature.155–157 There havealready been reports of linezolid treatment failure inSAIE155,156 and resistance has developed during thecourse of treatment for serious MRSA infection.158

Currently, there is insufficient evidence to recom-mend the use of linezolid as first-line therapy in thetreatment of SAIE, but its use may be considered inthose patients with SAIE due to MRSA who are refrac-tory to or intolerant of vancomycin, or in patients withendocarditis due to SA-RVS, vancomycin-intermediateS. aureus (VISA) or vancomycin-resistant S. aureus(VRSA).

Combination antimicrobial therapyBased on in vitro and animal model evidence of syner-gistic bactericidal activity, combination therapy with twoor more antimicrobial agents has been used in SAIE withthe aim of improving outcomes and/or shortening theduration of treatment. In a New Zealand study of152 cases of staphylococcal endocarditis (mostly due toS. aureus) that involved valve surgery, there was no signif-icant difference in the rate of valve sterilization whensingle-agent therapy was compared with any combina-tion therapy in native valve endocarditis. However, anykind of combination therapy was six times more likely toresult in valve sterilization in prosthetic valve staphylo-coccal endocarditis when compared with single-agenttherapy.159

Cell-wall active agents plus aminoglycosides

Aminoglycosides are frequently used in combinationwith cell-wall active agents (β-lactams and glyco-peptides) in the treatment of serious staphylococcalinfections. Various combinations of agents have provedsynergistic against S. aureus in in vitro studies,105,160,161

and have demonstrated enhanced killing of organismswithin vegetations when compared with monotherapywith cell-wall active agents in animal models ofSAIE.88,89,162,163 An early retrospective study did not showany reduction in mortality when gentamicin was addedto an antistaphylococcal β-lactam agent for the treat-ment of SAIE.39 Although a multicentre, prospective,randomised clinical trial of nafcillin (for 6 weeks) versuscombination therapy with nafcillin (for 6 weeks) andgentamicin (for 2 weeks) for SAIE demonstrated that theaddition of gentamicin significantly reduced the durationof bacteraemia, there was no significant difference incure rates or mortality, and more nephrotoxicity wasseen with the combination regimen.164

Several clinical trials have compared combinationantistaphylococcal β-lactam/aminoglycoside therapyto antistaphylococcal β-lactam monotherapy for SAIEin IVDUs with predominantly ‘right-sided’ disease(Table 5).46,109,122,164–167 There were significant variations


MurrayS34


Tabl

e5

Sum

mar

y of

the

res

ults

of

pros

pect

ive

stud

ies

of c

ell-

wal

l act

ive

antim

icro

bial

age

nts

with

or

with

out

amin

ogly

cosi

des

in t

he t

reat

men

t of

S.a

ureu

sin

fect

ive

endo

card

itis

in in

trav

enou

s dr

ug u

sers

(IV

DU

s)

Aut

hor

No.

of p

tsR

ando

mis

edT

TE

/TO

ET

reat

men

tD

urat

ion

(day

s)C

ure

rate

†(%

)M

orta

lity

(%)

Cha

mbe

rs e

tal.

(198

8)11

070

‡N

oYe

sN

afci

llin

1.5

g q4

h or

1494

0V

anco

myc

in§30

mg/

kg/d

+to

bram

ycin

1m

g/kg

tid

Tor

res-

Tor

tosa

eta

l.(1

994)

165

72N

oYe

sC

loxa

cilli

n 2

g q4

h +

1493

0.7

amik

acin

7.5

mg/

kg b

idA

bram

s et

al.

(197

9)16

725

Yes

No

Ant

ista

phyl

ococ

cal β

-lac

tam

¶28

100

0A

ntis

taph

yloc

occa

l β-l

acta

m+

2810

00

gent

amic

in 1

mg/

kg t

id14

For

tun

etal

.(1

995)

122

16††

Yes

Yes

Clo

xaci

llin

2g

q4h

+ge

ntam

icin

14

880

1.5

mg/

kg t

id14

Tei

copl

anin

10

mg/

kg b

id,

333

0th

en 6

mg/

kg b

id,t

hen

47

mg/

kg d

aily

21R

iber

a et

al.

(199

6)46

90‡‡

Yes

Yes

Clo

xaci

llin

2g

q4h

1489

2.5

Clo

xaci

llin

2g

q4h

+ge

ntam

icin

14

86*

5.5*

1m

g/kg

tid

7F

ortu

n et

al.

(200

1)16

634

§§Ye

sYe

sC

loxa

cilli

n 2

g q4

h+

gent

amic

in

1410

00

1m

g/kg

tid

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anco

myc

in 5

00m

g qi

d+

gent

amic

in

1460

01

mg/

kg t

id14

Tei

copl

anin

24

mg/

kg d

ay 1

,the

n 1

70**

012

mg/

kg/d

+ge

ntam

icin

14

1m

g/kg

tid

14

*P=

NS;

**P

=0.

03 f

or c

loxa

cilli

n ve

rsus

gly

cope

ptid

e (t

eico

plan

in a

nd v

anco

myc

in).

† Clin

ical

and

/or

bact

erio

logi

cal c

ure.

‡ 17

patie

nts

excl

uded

fro

m f

inal

ana

lysi

s.§ V

anco

myc

in a

rm o

f th

e st

udy

term

inat

ed e

arly

bec

ause

of

clin

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fai

lure

s.¶ P

enic

illin

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cep

halo

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g/da

y.††

2 pa

tient

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clud

ed f

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‡‡16

pat

ient

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clud

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rom

eff

icac

y an

alys

is.

§§3

patie

nts

excl

uded

fro

m f

inal

ana

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s.d,

day;

h,ho

ur;p

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atie

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TO

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in design, inclusion and exclusion criteria, and choiceand duration of antimicrobial therapy in these trials, butoverall, they suggest that the addition of an aminoglyco-side to a cell-wall active agent does not appear to be ofbenefit, and that antistaphylococcal β-lactams appearsuperior to glycopeptides (alone or in combination withaminoglycosides) for the treatment of SAIE caused byMSSA.

Once-daily aminoglycoside therapy is commonly usedfor infections due to Gram-negative organisms. However,as the efficacy and safety of once-daily dosing has notbeen directly compared with traditional three-times-daily dosing in the treatment of SAIE, it is currently notrecommended. Because of an increased potential fornephro- and ototoxicity when vancomycin is adminis-tered in combination with an aminoglycoside, thiscombination should be used with caution.168

Ciprofloxacin plus rifampicin

The combination of ciprofloxacin with rifampicin hasproved effective in animal models of SAIE, despiteconcerns regarding in vitro antagonism.131,169 A regimenconsisting of ciprofloxacin 300 mg twice daily intra-venously for up to 7 days followed by 750 mg twice dailyorally plus rifampicin 300 mg twice daily orally for a totalof 28 days achieved a 100% cure rate in a small prospec-tive, non-randomised study of 10 IVDUs with ‘right-sided’ SAIE.170 A prospective, open, randomised trialthat compared oral ciprofloxacin 750 mg twice daily andoral rifampicin 300 mg twice daily with intravenousoxacillin or vancomycin for 2 weeks combined withgentamicin 2 mg/kg three times daily for the first 5 daysfor the treatment of ‘right-sided’ SAIE in 85 IVDUsreported fewer clinical failures and significantly lesstoxicity in the group receiving ciprofloxacin andrifampicin.47 However, clinical failure associated withresistance to both agents has been reported with the useof this combination.171,172

At present, the combination of ciprofloxacin andrifampicin should be reserved for patients with uncom-plicated ‘right-sided’ SAIE who are unwilling or unableto receive intravenous therapy, and who will becompliant with oral therapy (or be willing to receive oraltherapy under direct supervision).

Vancomycin plus rifampicin

An early report described favourable outcomes followingthe addition of rifampicin to vancomycin in patients withSAIE who were failing therapy.173 Subsequently, arandomised, controlled clinical trial that comparedvancomycin (1 g twice daily) to vancomycin (1 g twicedaily) plus rifampicin (600 mg once daily orally) for4 weeks in 42 patients with SAIE caused by MRSA (themajority of whom were IVDUs with probable ‘right-sided’ disease) demonstrated no difference in outcomebetween the two groups.111 The emergence of rifampicinresistance has been described with this combination.174

Cell-wall active agents plus aminoglycosides plus rifampicin

The combination of vancomycin, rifampicin andgentamicin proved more effective than vancomycin

alone, vancomycin and gentamicin, or vancomycin andrifampicin in an animal model of endocarditis caused byS. epidermidis.175 A retrospective study of S. epidermidisprosthetic valve endocarditis suggested that therapy witha cell-wall active agent combined with an aminoglyco-side and/or rifampicin was more likely to be curativethan therapy with a cell-wall active agent alone, whethersurgery was performed during therapy or not.176 Theseresults have been extrapolated to the management ofprosthetic valve infective endocarditis caused byS. aureus in previously published guidelines. In theabsence of evidence from prospective, randomisedcontrolled trials, and given the significant mortality asso-ciated with this infection, both gentamicin andrifampicin should be given in combination with anantistaphylococcal β-lactam (for MSSA) or vancomycin(for MRSA) in prosthetic valve endocarditis caused byS. aureus.

Treatment of prosthetic valve S. aureus infectiveendocarditisProsthetic valve endocarditis (PVE) due to S. aureus isassociated with mortality rates of more than 40%.15,177–179

Intracardiac and extracardiac complications arecommon. ‘Early’ PVE caused by S. aureus occurs lessthan 12 months after valve surgery, and is usually theresult of contamination of the surgical field at the time ofor shortly after surgery. ‘Late’ PVE occurs more than12 months after valve surgery and results from seeding ofthe prosthesis from bacteraemia originating at a distantsite (e.g. an intravascular catheter). Both types of PVEoccur equally on bioprosthetic or mechanical valves.Close and early consultation with a cardiologist, cardio-thoracic surgeon and an infectious disease physician orclinical microbiologist is essential in PVE due toS. aureus. Transoesophageal echocardiography shouldalways be performed, as it is more sensitive for the detec-tion of intracardiac complications than TTE and allowsplanning of subsequent surgery.

No randomised, controlled clinical trials have beenperformed to determine the optimal antimicrobial treat-ment or the timing of surgery in prosthetic valve SAIE.Although data from clinical trials are lacking, there isgeneral agreement that combination antimicrobialtherapy using agents with bactericidal activity and withgood activity in association with prosthetic materialshould be used for the treatment of prosthetic valveSAIE (Table 6). If surgical specimens are negative onculture, the total duration of therapy should be at least6 weeks. If surgical specimens are culture-positive forS. aureus, or if an active intracardiac infection is found(e.g. myocardial abscess, annulus infection or pseudo-aneurysm), then treatment should continue for aminimum of 6 weeks following surgery. A large retro-spective study of ‘left-sided’ prosthetic valve SAIEsuggested that early valve replacement surgery lessenedmortality, even in the absence of intracardiac or extrac-ardiac complications,15 and similar findings were seen ina small prospective study which reported that four offour patients who had surgery for prosthetic valve SAIE


MurrayS36

survived compared with two of 11 who did not.177

However, these studies would have been biased towardsfavourable outcomes in patients who underwent surgery,since patients with a poor prognosis at presentation maynot have been selected for surgery.

Outpatient parenteral antimicrobial therapy(OPAT) for S. aureus infective endocarditisThere have been no randomised, controlled clinical trialscomparing the efficacy and safety of OPAT to inpatienttherapy for SAIE. Several studies of OPAT for deep-seated staphylococcal infections have included smallnumbers of patients with SAIE.93,94,180–184 However, someauthorities have advised against OPAT for SAIE becauseof the significant risk of complications related to theinfection.185 The likelihood of an embolic event in SAIEis significantly higher than in streptococcal infectiveendocarditis.186 The risk of endocarditis-related compli-cations is considered to be highest in the first 2 weeks oftherapy, and the risk of line or antimicrobial-relatedadverse effects is highest between 2 and 6 weeks oftherapy.187 However, hospitalization does not preventcomplications from SAIE, and it is not known whetheroutcomes are worse if complications occur when thepatient is not hospitalized.184

A variety of antimicrobial regimes have been used forOPAT of SAIE with reported success, including ceftri-axone and gentamicin, teicoplanin and continuousinfusion flucloxacillin.93,94,180,182,188 The optimal choice ofagent and method of delivery varies significantlybetween institutions, but it is important that the choice

of antimicrobial agent is not compromised for the sakeof earlier hospital discharge and healthcare savings. Ifcontinuous infusion therapy is to be given, the stabilityof the antimicrobial agent at conditions in which it isto be stored and administered must be known.Flucloxacillin is stable in solution for up to 7 days at 4°C;however, dicloxacillin is unstable in solution at roomtemperature and is therefore unsuitable for OPAT. Asserum flucloxacillin concentrations may vary signifi-cantly when it is administered by infusion (due to varia-tions in renal function and other factors), measurementof serum flucloxacillin concentrations may be useful inguiding dosing during therapy.93,189 Vancomycin is alsostable in solution for several days and may be given as aninfusion or bolus therapy for OPAT. Continuous infusiontherapy should always be administered via a centralvenous catheter.

Careful selection of patients for OPAT is critical.185

Contraindications include active cardiac infection oruntreated metastatic infection, congestive cardiac failure,uncontrolled arrhythmias, a previous arterial embolicevent, inability to establish central venous access, no tele-phone at home, no ready access to the hospital or patientunwillingness to receive outpatient therapy. Relativecontraindications include prosthetic valve endocarditis, ahistory of intravenous drug use, and lack of reliable trans-portation. Patients with SAIE being considered for OPATshould receive at least the initial 10–14 days of therapy inhospital and should be assessed by a cardiologist, acardiothoracic surgeon, and an infectious diseases physi-cian or clinical microbiologist prior to discharge.


Table 6 Recommendations for the treatment of prosthetic valve endocarditis caused by S. aureus


• Methicillin-susceptible S. aureus Flucloxacillin/dicloxacillin 2 g IV q4h for 42 days plus rifampicin 600 mg IV/PO daily for 42 days plus gentamicin 1 mg/kg IV q8h for the first 14 days

If isolate is susceptible to penicillin Substitute for flucloxacillin/dicloxacillin:Benzylpenicllin 1.8 g IV q4h

If non-severe penicillin hypersensitivity‡ Substitute for flucloxacillin/dicloxacillin:Cephalothin 2 g IV q4h

• Severe penicillin hypersensitivity‡ or Vancomycin 15 mg/kg IV q12h for 42 days plus rifampicin 600 mg methicillin-resistant IV/PO S. aureus daily for 42 days plus gentamicin 1 mg/kg

IV q8h for the first 14 days• Intolerance of or hypersensitivity to vancomycin (for Discuss therapy with an Infectious Diseases

methicillin-resistant S. aureus) or to both β-lactams Physician/Clinical Microbiologist. Alternatives to and vancomycin (for methicillin-susceptible S. aureus) β-lactams/vancomycin include:

Teicoplanin 800 mg IV q12h for first 24 h, then 800 mg daily; orLinezolid 600 mg IV/PO q12h; orQuinupristin/dalfopristin 7.5 mg/kg IV q8h

• Outpatient intravenous antimicrobial therapy Not currently recommended

Note: urgent transoesophageal echocardiography and early referral to a cardiothoracic surgeon is essential.†Doses and dose intervals of the following antimicrobial agents should be adjusted according to the patient’s renal function and therapeutic drugmonitoring results:




TREATMENT OF CARDIAC ANDEXTRACARDIAC COMPLICATIONSOF S. AUREUS INFECTIVEENDOCARDITIS

Cardiac complicationsRegular and careful serial clinical examination of allpatients with SAIE is essential to detect the onset ofcomplications that may need surgical intervention. Serialechocardiography should be performed in patients withclinical and/or initial echocardiographic evidence ofcomplications, particularly in aortic valve SAIE wheresudden onset of severe valvular regurgitation may resultin acute severe pulmonary oedema requiring emergencysurgery.

Because intraventricular conduction disturbancesare common in patients with SAIE complicated byparavalvular infection,190 electrocardiography (ECG)should be performed at diagnosis and serially in patientswith persistent fever, heart failure or arrhythmias.191

Paravalvular extension of the infection is an indicationfor urgent surgical intervention. In prosthetic valveSAIE, small paravalvular leaks or other abnormalitieson echocardiography may predate the onset of endo-carditis; therefore, a comparison of echocardiographicfindings with previous results should be performedwhenever possible to establish their significance. Aspersistent bacteraemia may be the only indicator ofparavalvular infection, patients with bacteraemiapersisting for 7 days or more following the commence-ment of appropriate therapy should be evaluated forcardiac complications with transoesophageal echocardio-graphy, so that any surgically remediable cardiac lesionsare identified.

Extracardiac complicationsThe management of embolic events in ‘left-sided’ SAIEdepends on the site and size of the embolus. Such eventsare managed conservatively, unless there is occlusion ofan artery that perfuses a critical structure such as a limbor the heart, in which case immediate intervention maybe required.

Patients with SAIE who have neurological symptomsor signs at the time of diagnosis or during the course oftherapy should undergo imaging to determine the cause,location and extent of any lesion. The initial imagingmodality is usually computerized tomography (CT)because it is readily available in most institutions, can beperformed rapidly, and provides reliable informationregarding the nature and location of cerebral lesions inmost cases. In certain circumstances, magnetic reso-nance (MR) imaging (with or without MR angiography)may be indicated instead of or subsequent to CTimaging. As valve replacement surgery is relativelycontraindicated in the presence of a recent large cerebralembolic event (particularly if there is haemorrhagictransformation), most surgeons delay surgery for at least7–14 days to lessen the likelihood of precipitating orworsening the neurological deficit with subsequent anti-coagulant therapy. However, the consequences of

delaying surgery in patients with congestive cardiacfailure caused by SAIE are not insignificant and must bebalanced against this risk.

Mycotic aneurysms usually present with intracerebralor subarachnoid haemorrhage or as a stroke.54 Onereport has suggested that mycotic aneurysms causedby S. aureus are more likely to rupture.192 If cerebralimaging demonstrates a subarachnoid or intracerebralhaemorrhage, or clinical signs that suggest possibleaneurysm formation are present (e.g. headache orcranial nerve palsies without identifiable cause), thencerebral angiography should be considered. If ananeurysm is demonstrated, the patient should bereferred to a neurosurgeon or an interventional neuro-radiologist for consideration of surgical or percutaneousintervention.191

Embolization of vegetations into the pulmonarycirculation rarely requires surgical intervention.However, secondary infective complications such as lungabscess or empyema may require percutaneous and/oropen surgical drainage in addition to prolongation ofantimicrobial therapy longer than the recommended2 weeks for uncomplicated disease. Serial pulmonaryimaging (using chest X-ray and/or CT) may be requiredin patients with these complications or in those who donot respond as expected to antimicrobial therapy.

Significant metastatic infective foci such as visceralabscesses, empyemata or septic arthritis should betreated by percutaneous or open drainage withoutdelay to prevent further complications, increase thelikelihood of therapeutic success, and decrease the like-lihood of recurrence. Patients who may be at higher riskfor metastatic infection include those with prostheticjoints and those in whom the period of bacteraemia isprolonged.

SURGERY FOR S. AUREUS INFECTIVEENDOCARDITIS

The role of surgery in native or prosthetic valve SAIE hasnot been examined in randomised clinical trials. Severalretrospective studies have reported more favourableoutcomes in patients with SAIE who underwent surgerycompared with those that did not.193–199 However, thesestudies may have been biased towards better outcomesfor surgically treated patients, because patients with ahigher likelihood of survival and fewer comorbiditiesmay be more likely to be operated on. The need forsurgical intervention in SAIE needs to be individualizedfor each patient and should be reviewed if the clinicalstate deteriorates. All resected tissue from surgery shouldbe submitted for pathological and microbiological exam-ination to confirm the diagnosis of SAIE and to deter-mine the activity and extent of the infection at the timeof surgery.

The operative technique and choice of prosthesisemployed for the surgical treatment of SAIE depends onseveral factors, including the site and extent of the infec-tion, the availability of homografts or xenografts, and theexpertise of the surgeon. Specific recommendations arebeyond the scope of this review.


MurrayS38

‘Left-sided’ SAIEIn patients with ‘left-sided’ SAIE, surgery should beconsidered in the presence of haemodynamically signifi-cant valvular regurgitation (New York Heart Associationstage III or IV congestive cardiac failure), large and/orhighly mobile vegetations, vegetations of ≥1 cm on theanterior mitral valve leaflet, paravalvular extension of theinfection, rupture of the sinus of Valsalva, mechanicalobstruction of a valve by vegetations, or duration ofbacteraemia ≥7 days despite appropriate therapy.Surgery may also be considered for those patients whohave experienced one or more embolic significant events.Vegetectomy combined with valve repair may be possiblewhen a single leaflet of the mitral valve is involved.200

‘Right-sided’ SAIE‘Right-sided’ SAIE generally has a more benign coursethan ‘left-sided’ disease, and vegetation size does notappear to correlate with failure of antimicrobialtherapy.80 There is, however, a high rate of recurrenceof ‘right-sided’ endocarditis in IVDUs who continueto inject drugs.38 Therefore, a conservative approach tosurgical management in ‘right-sided’ SAIE is oftenfollowed. Surgery may be considered for patients with‘right-sided’ SAIE who have persistent or recurrentbacteraemia or ongoing significant septic emboli despiteadequate therapy. Valvulectomy is usually performed ifthe patient is able to tolerate the resulting severetricuspid regurgitation.38,201,202 Subsequent prosthesisinsertion may be required in patients who develop severechronic tricuspid regurgitation.201

Prosthetic valve S. aureus endocarditisSurgery should be considered in all cases of prostheticvalve endocarditis caused by S. aureus and should beperformed as early as possible.191

ANTITHROMBOTIC THERAPY INS. AUREUS INFECTIVE ENDOCARDITIS

Animal models of SAIE have suggested that antiplateletagents such as aspirin and/or ticlodipine can significantlyreduce vegetation size and, when given with vancomycin,can sterilize vegetations more quickly.203–205 Administra-tion of aspirin to animals prior to the establishment ofSAIE resulted in decreased adherence of S. aureus tovegetations, fibrin and platelets, in addition to reductionsin vegetation size and bacterial density within thevegetation and the kidneys.203 However, as there havebeen no clinical trials of antiplatelet therapy in SAIE todate, it is not currently recommended.

Continuation of anticoagulation therapy in patientswith prosthetic valve SAIE is controversial. A smallretrospective study of ‘left-sided’ SAIE that comparedpatients with PVE (90% of whom were on anticoagulanttherapy) with patients with native valve endocarditis(none of whom were on anticoagulant therapy) foundthat there was no difference in the proportion of patientswho suffered from cerebral embolic events between the

groups. However, mortality was significantly higher inpatients with PVE (71% vs 31%), and most deaths inthis group were due to cerebral embolic complications,most commonly intracerebral haemorrhage.The authorsrecommended that anticoagulant therapy be withheldfor 7 days in patients with prosthetic valve SAIE.206

Other groups have recommended continuation of long-term anticoagulant therapy in patients with PVE, butdelaying valve surgery for at least 7 days if a CT scan ofthe brain demonstrates a large infarction.207

ACKNOWLEDGEMENTSThe author would like to thank: the Australian Society for Antimicro-bials and Australasian Society for Infectious Diseases, who provided allthe financial support for the costs of production and publication of thiswork; Professor John Turnidge and Associate Professor Keryn Chris-tiansen of the Australian Society for Antimicrobials, for devising theconcept of writing guidelines for the treatment of deep-seated staphy-lococcal infections and for assistance with various aspects of publica-tion; Associate Professor Iain Gosbell, Department of Microbiologyand Infectious Diseases, South-western Area Pathology Service, Liver-pool, NSW, for convening the ASA Staphylococcus aureusWorking Partyand co-ordinating the writing of the body of manuscripts, editing thismanuscript, and providing the photographs used in Figs 2 and 3A,B;Dr Bryan Speed, for providing the photographs from the FairfieldHospital Historical Collection, used in Fig. 1A–C; Mr Trevor Speight,Medical Editor, Medicines Information Co. Ltd, Auckland, NZ, forfinal editing and formatting of this manuscript; and the members of theAustralasian Society for Infectious Diseases who provided peer reviewof this work.

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Staphylococcus aureus infective endocarditis and septic pulmonary embolism after septic abortion

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