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INTRODUCTION — Staphylococcus aureus is a leading cause of community-acquired and hospital-acquired bacteremia. Patients with S. aureus bacteremia can develop a broad array of complications that may be difficult to recognize initially and can increase morbidity. Mortality rates of 20 to 40 percent have been described [1,2]. Mortality appears to be higher with methicillin-resistant (MRSA) compared with methicillin-sensitive S. aureus (MSSA) bacteremia [1,2].
Treatment failure (ie, death within 30 days following treatment, persistent bacteremia >10 days after initiation of appropriate therapy, or recurrence of bacteremia within 60 days of discontinuing therapy) is fairly common in patients with S. aureus bacteremia, particularly in the setting of infection due to MRSA .
Issues related to the clinical approach to S. aureus bacteremia in adults will be reviewed here. Issues related to clinical manifestations of S. aureus infection are discussed separately. The epidemiology, risk factors, and complications of S. aureus bacteremia and treatment of methicillin-resistant or vancomycin-resistant S. aureus infections are discussed separately. (See "Clinical manifestations of Staphylococcus aureus infection in adults".)
CLINICAL APPROACH — The clinical approach to S. aureus bacteremia consists of careful history and physical examination, infectious disease consultation, and diagnostic evaluation including echocardiography and additional imaging as needed.
History and physical examination — A careful history and physical examination is essential. For circumstances in which the source of bacteremia is uncertain, patients should be questioned carefully regarding potential portals of entry including recent skin or soft tissue infection and presence of indwelling prosthetic devices (including intravascular catheters, orthopedic hardware, and cardiac devices).
Patients should also be questioned regarding symptoms that may reflect metastatic infection, which can occur in up to 30 percent of cases . These include bone or joint pain (particularly back pain, suggesting vertebral osteomyelitis, discitis, and/or epidural abscess), protracted fever and/or sweats (suggestive of endocarditis), abdominal pain (particularly left upper quadrant pain, which may reflect splenic infarction), costovertebral angle tenderness (which may reflect renal infarction or psoas abscess), and headache (which may reflect septic emboli).
The physical examination should include careful cardiac examination for signs of new regurgitant murmurs or heart failure. A vigorous search should be undertaken for the clinical stigmata of endocarditis, including evidence of small and large emboli with special attention to the fundi, conjunctivae, skin, and digits. A neurologic evaluation should be undertaken for evidence of focal neurologic impairment; it is also important as a baseline examination should neurologic deficits develop later. These issues are discussed further separately. (See "Clinical manifestations and evaluation of adults with suspected native valve endocarditis", section on 'Clinical manifestations'.)
Serial bedside examinations are critical for detection of complications that may develop after initial evaluation and during the course of treatment. Metastatic seeding may occur within the first few days of hospitalization, although in some cases it may not come to clinical attention for several weeks. In several case series, only 39 percent of 133 patients with bacteremic S. aureus vertebral osteomyelitis  and 57 percent of 35 patients with epidural abscess  had a diagnosis on admission related to the spine. Failure to identify such complications of S. aureus bacteremia may lead to catastrophic complications (eg, death, paralysis)  or relapsing bacteremia due to inadequate treatment .
Infectious disease consultation — Bedside infectious disease consultation is an important component of management for patients with S. aureus bacteremia and should occur whenever feasible [9-16]. In one retrospective study comparing bedside consultation with telephone consultation for management of 342 patients with S. aureus bacteremia, bedside consultation was associated with a significantly lower 90-day mortality (9 versus 29 percent; odds ratio [OR] 0.25; 95% CI 0.13-0.51) . Another study noted that, even among patients treated with an appropriate duration of therapy, significantly fewer relapses were observed among those who received bedside consultation (6 versus 18 percent) .
Several other studies have also demonstrated that bedside consultation by an infectious diseases specialist is associated with better outcomes including fewer deaths, fewer relapses, and lower readmission rates than telephone consultation or no consultation [12-14]. These findings underscore the importance of serial examinations evaluating for metastatic infection and/or clues to the source of bacteremia.
Diagnostic evaluation — In general, blood cultures positive for S. aureus should be respected as a clinically significant finding that should prompt clinical evaluation and initiation of empiric therapy. All patients with S. aureus bacteremia should undergo echocardiography to evaluate for presence of endocarditis. Additional diagnostic imaging should be tailored to findings on history and physical examination. (See "Clinical manifestations and evaluation of adults with suspected native valve endocarditis" and "Clinical manifestations and evaluation of adults with suspected native valve endocarditis", section on 'Echocardiography'.)
Echocardiography — All patients with S. aureus bacteremia should undergo echocardiography to evaluate for presence of endocarditis [17,18]. Transthoracic echocardiography (TTE) should be performed first ; identification of a vegetation on TTE usually obviates the need for transesophageal echocardiography (TEE), although TTE is not sufficient for ruling out infective endocarditis (IE) [19,20]. The results of echocardiography are useful even when the study is negative, as the absence of IE may impact decisions about the duration of antimicrobial therapy. In one series including 103 patients with S. aureus bacteremia, the diagnosis of endocarditis was established by TTE and TEE in 7 versus 25 percent of cases, respectively .
The indications for TEE in patients with S. aureus bacteremia and no evidence of vegetation on TTE are controversial. TEE is substantially more sensitive than TTE for identification of valvular vegetation [20,22-24]; it is most sensitive when performed five to seven days after the onset of bacteremia [25,26]. In the setting of high clinical suspicion for IE and a negative echocardiogram, a repeat study is warranted. However, TEE has associated costs and risks. Major complications such as esophageal perforation occur in approximately 1 in 5000 transesophageal echocardiographies .
Pursuit of TEE is especially important in the setting of risk factors for IE including [19,28]:
●Persistent S. aureus bacteremia despite appropriate antimicrobial therapy
●Unknown duration of bacteremia (ie, community-acquired infection)
●Presence of cardiac prosthetic material
●Presence of predisposing valvular abnormality
●Absence of evident removable source of bacteremia
●Evidence of infection involving the back (osteomyelitis, discitis, and/or epidural abscess)
●Presence of peripheral stigmata for IE
●Intravenous drug use
It may be reasonable to forgo TEE for circumstances in which all of the following conditions are met [17,29-31]:
●Nosocomial acquisition of bacteremia
●Sterile follow-up blood cultures within four days after the initial positive culture
●No permanent intracardiac device
●No hemodialysis dependence
●No clinical signs of endocarditis or secondary foci of infection
●Removable focus of infection removed promptly, if present
●Defervescence within 72 hours of initial positive blood culture
Echocardiography is not necessary for children with catheter-associated bacteremia who do not have other signs of endocarditis .
Imaging — Imaging should be tailored to findings on history and physical examination. Patients with back pain should be evaluated for vertebral osteomyelitis and discitis; this is discussed further separately. (See "Vertebral osteomyelitis and discitis in adults".)
Imaging of the torso (computed tomography) should be pursued for patients with abdominal pain or costovertebral angle tenderness to evaluate for presence of splenic infarct, renal infarct, psoas abscess, or other intraabdominal sites of infection. Such imaging is also appropriate for patients with documented endocarditis even in the absence of focal symptoms to evaluate for subclinical sites of metastatic infection.
Patients with headache and known or suspected IE should undergo magnetic resonance imaging of the head. (See "Clinical manifestations and evaluation of adults with suspected native valve endocarditis".)
TREATMENT — Treatment of S. aureus bacteremia includes prompt source control (such as removal of implicated vascular catheters and/or surgical drainage of abscess if present) and antimicrobial therapy . (See "Diagnosis of intravascular catheter-related infections".)
Selection of antimicrobial therapy depends on culture and susceptibility results as discussed in the following sections.
Empiric treatment — Empiric treatment should consist of antimicrobial therapy with activity against methicillin-resistant S. aureus (MRSA) when positive blood cultures with gram-positive cocci are observed and should be continued until culture and susceptibility become available. Empiric treatment consists of vancomycin (15 to 20 mg/kg/dose every 8 to 12 hours, not to exceed 2 g per dose); daptomycin (6 mg/kg intravenously once daily) is an acceptable alternative agent. Once susceptibility results are available, if the isolate is methicillin-susceptible S. aureus (MSSA), antibiotic treatment should be deescalated to a beta-lactam agent (such as nafcillin, oxacillin, or cefazolin) as discussed below.
The optimal approach to empiric therapy in the setting of S. aureus bacteremia prior to availability of culture and susceptibility data is uncertain. We favor empiric antimicrobial therapy with activity against MRSA; some favor empiric antimicrobial therapy with activity against both MRSA and MSSA [34-36]. There are data suggesting that administration of vancomycin monotherapy with deescalation to a beta-lactam agent may result in worse outcomes than empiric treatment for both MRSA and MSSA among patients with the highest risk of morbidity and mortality from S. aureus infections [34,37,38], including patients with severe sepsis, probable endocarditis, or presence of a prosthetic or intravascular device [34,39]. However, a retrospective study including more than 5000 patients with MSSA bacteremia who received empiric monotherapy with a beta-lactam or vancomycin noted no difference in all-cause 30-day mortality, even though there was a significantly better outcome for the same cohort of patients who received definitive therapy with a beta-lactam from day 4 to 14 of treatment . Further study of empiric antimicrobial therapy with activity against both MRSA and MSSA is needed.
Methicillin-susceptible S. aureus (MSSA) — Treatment of MSSA bacteremia generally consists of a beta-lactam agent such as nafcillin (2 g IV every four hours), oxacillin (2 g IV every four hours), or flucloxacillin (2 g IV every six hours) . If the isolate is penicillin sensitive, penicillin (4 million units intravenously [IV] every four hours) is the drug of choice for S. aureus bacteremia ; however, the majority of isolates are penicillin resistant .
A first-generation cephalosporin such as cefazolin (2 g IV every eight hours) is an acceptable alternative in patients with hypersensitivity to the preceding agents. In some cases, cefazolin may be more practical and better tolerated for continuation of intravenous therapy in outpatient settings [44,45]. Adequately powered prospective clinical trials comparing the efficacy of various beta-lactam agents including cefazolin for treatment of MSSA bacteremia are not available; retrospective data suggest that cefazolin and antistaphylococcal penicillins are equally effective for treatment of S. aureus bacteremia [46,47]. Findings from one retrospective study suggested that patients who received cefazolin had a lower risk of mortality and similar risk of recurrent infection compared with those who received oxacillin or nafcillin ; however, interpretation of the findings is limited by potential confounding.
Vancomycin is less effective for treatment of S. aureus bacteremia than beta-lactam agents and should not be administered as primary therapy for methicillin-sensitive strains unless the use of a beta-lactam agent is precluded by drug intolerance [49-58]. Patients with MSSA bacteremia and a reported penicillin allergy should have treatment guided by allergy history (cefazolin may be given if history excludes anaphylactic features) or, if available, full allergy evaluation with skin testing . In an observational study of 505 patients with S. aureus bacteremia, nafcillin was superior to vancomycin for preventing relapse or persistent MSSA bacteremia; the failure rate was 4 versus 20 percent . In another study of 294 patients with S. aureus bacteremia, vancomycin therapy was associated with a higher risk of relapse (odds ratio 4.1; 95% CI 1.5-11.6) .
Alternative agents for the treatment of S. aureus should be reserved for patients intolerant to beta-lactams and vancomycin and should be guided by the results of susceptibility testing. The use of these agents is discussed further separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia", section on 'Bacteremia due to MRSA'.)
Patients whose infection requires treatment with an alternative agent should preferably be treated by clinicians who are experts in the treatment of infectious diseases and who are familiar with the available (and limited) literature on the efficacy, dosing, and side effects of such therapy. The use of all alternative agents is limited because of the development of resistance or an increased rate of adverse effects during therapy.
Synergistic aminoglycosides — Routine combination of aminoglycosides with antistaphylococcal penicillins or vancomycin for treatment of S. aureus bacteremia is not warranted. Although in vitro and experimental models of endocarditis have demonstrated that combination therapy facilitates more rapid killing of MSSA than monotherapy, the evidence for clinically significant benefit is minimal.
This was illustrated by a randomized trial of 48 patients with MSSA native valve endocarditis . Although patients who received nafcillin plus gentamicin for the first two weeks of therapy had more rapid clearing of bacteremia than those who received nafcillin alone, cure rates were comparable and combination nafcillin and gentamicin therapy was associated with a higher incidence of renal dysfunction. (See "Antimicrobial therapy of native valve endocarditis", section on 'Staphylococci'.)
Subsequently, a randomized trial including 236 patients with S. aureus bacteremia and endocarditis demonstrated that daptomycin monotherapy is not inferior to low-dose gentamicin plus an antistaphylococcal penicillin or vancomycin; those in the standard therapy arm experienced significantly more renal impairment than those in the daptomycin arm . An investigation of safety data from the trial noted significantly greater reduction in creatinine clearance among those who received initial low-dose gentamicin than those who did not (22 versus 8 percent, respectively) .
Methicillin-resistant S. aureus (MRSA) — The treatment of patients with bacteremia due to MRSA is discussed separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia", section on 'Bacteremia due to MRSA'.)
Mortality appears to be higher with MRSA compared with MSSA bacteremia [1,2]. This was illustrated in a review of 438 patients with S. aureus bacteremia, 193 of whom had MRSA infection . The patients with MRSA infection had a significantly higher mortality rate at 90 days, except for those with pneumonia, an effect that persisted after adjustment for confounders (34 versus 20 percent, adjusted hazard ratio 1.8, 95% CI 1.2-3.0).
Follow-up cultures — Once the diagnosis of S. aureus bacteremia has been established and treatment has been initiated, blood cultures should be repeated to document clearance of bacteremia. Failure to clear bacteremia within 48 hours after initiation of therapy should prompt further evaluation, including evaluation of susceptibility data to ensure appropriate antibiotic selection and dosing, as well as clinical evaluation for occult focus of infection that may require drainage or other intervention beyond antimicrobial therapy alone.
DURATION OF THERAPY — The duration of therapy for S. aureus bacteremia depends on the etiology of infection . Determination of treatment duration requires differentiation of patients with uncomplicated S aureus bacteremia (who may be cured with 14 days of intravenous therapy from the first negative blood culture) from patients with complicated S. aureus bacteremia (who require longer duration of intravenous treatment) .
In general, a patient may be presumed to have uncomplicated S. aureus bacteremia if all of the following criteria are met [18,32,63]:
●Infective endocarditis has been excluded via echocardiography. (See 'Echocardiography' above.)
●No indwelling devices (such as prosthetic heart valves or vascular grafts) are present.
●Follow-up blood cultures drawn two to four days after initiating intravenous antistaphylococcal therapy and removing the presumed focus of infection (if present) are negative.
●The patient defervesced within 48 to 72 hours after initiating intravenous antistaphylococcal therapy and removal of the presumed focus of infection (such as debridement of soft tissue infection or intravascular catheter removal).
●There is no evidence of metastatic staphylococcal infection on physical examination.
Patients with S. aureus bacteremia and cardiac valvular abnormalities with no vegetation on transesophageal echocardiography (TEE) may be treated with 14 days of antimicrobial therapy. These patients should have negative surveillance blood cultures within 72 hours after initiation of appropriate antimicrobial therapy and no signs of systemic staphylococcal infection.
Patients with S. aureus bacteremia who do not meet all of the above criteria should be presumed to have a deep focus of infection, warranting intravenous treatment for longer than two weeks. The duration of therapy for such patients depends on the nature of the underlying infection, as discussed in the following sections:
●Infective endocarditis (see "Antimicrobial therapy of native valve endocarditis")
●Cardiac device infection (see "Infections involving cardiac implantable electronic devices")
●Osteomyelitis (see "Vertebral osteomyelitis and discitis in adults")
●Prosthetic joint infection (see "Prosthetic joint infection: Treatment")
●Septic arthritis (see "Septic arthritis in adults")
Issues related to the likelihood of hardware seeding during S. aureus bacteremia are discussed further separately. (See "Clinical manifestations of Staphylococcus aureus infection in adults", section on 'Prosthetic joint infection'.)
PROGNOSIS — Mortality rates of 20 to 40 percent have been reported in most case series of patients with S. aureus bacteremia; these rates have not changed over the past several decades [1,64]. Mortality is higher among patients with underlying comorbidities, methicillin-resistant S. aureus (MRSA) infection (odds ratio [OR] 9.3; 95% CI 1.5-59.2), and/or time to positivity of blood cultures ≤12 hours (OR 6.9; 95% CI 1.1-44.7) [65-67].
The presence of prosthetic material or devices in a patient with S. aureus increases the risk of relapsed infection. This was illustrated in a series of 294 patients with S. aureus bacteremia; relapses occur more frequently among patients with an indwelling foreign body (83 versus 21 percent) . The median time to relapse after the first detected bacteremic episode in patients with retained foreign bodies was 69 days (range 35 to 89 days).
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●Basics topics (see "Patient education: Sepsis in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS
●The clinical approach to S. aureus bacteremia consists of careful history and physical examination, infectious disease consultation, and diagnostic evaluation including echocardiography and additional imaging as needed. (See 'Clinical approach' above.)
●Patients should be questioned regarding potential portals of entry, presence of indwelling prosthetic devices, and symptoms that may reflect metastatic infection. These include bone or joint pain (particularly back pain, suggesting vertebral osteomyelitis, discitis, and/or epidural abscess) and protracted fever and/or sweats (suggestive of endocarditis). (See 'History and physical examination' above.)
●The physical examination should include cardiac examination for signs of new murmurs or heart failure. A search should be undertaken for clinical stigmata of endocarditis, including evidence of small and large emboli. Serial bedside examinations are critical for detection of complications that may develop after initial evaluation and during the course of treatment. (See 'History and physical examination' above.)
●We recommend bedside infectious disease consultation for management of patients with S. aureus bacteremia (Grade 1B); this is a critical component of management for patients with S. aureus bacteremia and is associated with better outcomes including fewer deaths, fewer relapses, and lower readmission rates. (See 'Infectious disease consultation' above.)
●In general, blood cultures positive for S. aureus should be respected as a clinically significant finding that should prompt clinical evaluation and initiation of empiric therapy. All patients with S. aureus bacteremia should undergo echocardiography to evaluate for presence of endocarditis. Additional diagnostic imaging should be tailored to findings on history and physical examination. (See 'Diagnostic evaluation' above.)
●In the setting of blood cultures with gram-positive cocci prior to availability of culture and susceptibility data, we suggest administration of empiric antimicrobial therapy with activity against methicillin resistant S. aureus (MRSA; rather than empiric therapy with activity against both MRSA and methicillin-susceptible S. aureus [MSSA]) (Grade 2B). Empiric treatment consists of vancomycin; daptomycin is an acceptable alternative agent. (See 'Empiric treatment' above.)
●We recommend treating MSSA bacteremia with a beta-lactam antibiotic (in preference to vancomycin or daptomycin) (Grade 1B). Regimens include penicillin, nafcillin, oxacillin, or flucloxacillin. A first-generation cephalosporin such as cefazolin is an acceptable alternative. (See 'Methicillin-susceptible S. aureus (MSSA)' above.)
●Vancomycin is less effective for treatment of S. aureus bacteremia than beta-lactam agents and should not be administered as primary therapy for methicillin-sensitive strains unless the use of a beta-lactam agent is precluded by drug intolerance. (See 'Methicillin-susceptible S. aureus (MSSA)' above.)
●The duration of therapy depends on the etiology of infection. In general, patients with bacteremia with a removable focus of infection may be treated with 14 days of intravenous therapy from the first negative blood culture. (See 'Duration of therapy' above.)
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