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The Golden Grapes of Wrath – Staphylococcus aureus Bacteremia: A Clinical Review

  • John C. Lam
    Correspondence
    Requests for reprints should be addressed to John C. Lam, MD, Division of Infectious Diseases, Department of Medicine, University of California Los Angeles, 52-215 Center for Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095-1688.
    Affiliations
    Division of Infectious Diseases, Department of Medicine, University of California Los Angeles
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  • William Stokes
    Affiliations
    Provincial Laboratory for Public Health, Alberta Precision Laboratories, Alberta, Canada

    Department of Pathology and Laboratory Medicine

    Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada
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Open AccessPublished:September 27, 2022DOI:https://doi.org/10.1016/j.amjmed.2022.09.017

      Abstract

      Staphylococcus aureus bacteremia is common and associated with fatality rates approximating 25%. We provide a brief overview of S. aureus bacteremia from a clinical and microbiological lens and review the relevant evidence and literature gaps in its management. Using a case-based approach, evidence and clinical judgement are meshed to highlight and justify the 5 core interventions that ought to be performed for all cases of S. aureus bacteremia: 1) appropriate anti-staphylococcal therapy, 2) screening echocardiography, 3) assessment for metastatic phenomena and source control, 4) decision on duration of antimicrobial therapy, and 5) Infectious Diseases consultation.

      Keywords

      Clinical Significance
      • Staphylococcus aureus is responsible for a diverse burden of human diseases.
      • S. aureus bacteremia is common, and has fatality rates approximating 25%.
      • S. aureus’ affinity for foreign material and antimicrobial resistance renders S. aureus bacteremia treatment challenging.
      • In patients with S. aureus bacteremia, the following interventions should be undertaken: 1) appropriate anti-staphylococcal therapy, 2) screening echocardiography, 3) assessment for metastatic phenomena and source control, 4) decision on duration of antimicrobial therapy, 5) Infectious Diseases consultation.

      Clinical Cases

      Case 1

      A 78-year-old woman is hospitalized with hypoxemia. Index blood cultures (BCx) did not isolate a pathogen. A diagnosis of congestive heart failure was made and she improved with diuresis. Four days later she developed swelling and tenderness at her peripheral intravenous line site. BCx yielded methicillin-sensitive Staphylococcus aureus (MSSA) and her intravenous line was removed. There are no other sites of infection and repeat BCx taken 2 days after antibiotic initiation are negative.

      Case 2

      A 45-year-old man with lumbar degenerative disc disease presents with a 2-day history of low back pain after sustaining a musculoskeletal injury from lifting furniture 1 week ago. Accompanied by fevers and chills, his examination is relevant for L5 vertebral tenderness. BCx are positive for MSSA. Plain radiographs and magnetic resonance imaging (MRI) of his lumbar spine are unremarkable.

      Case 3

      A 29-year-old woman who injects drugs is hospitalized for left knee pain and methicillin-resistant S. aureus (MRSA) bacteremia. Clinical assessment reveals a tender, swollen joint with limited range of motion. Synovial fluid culture from an irrigation and debridement of her left knee yields MRSA. A transthoracic echocardiogram (TTE) reveals a 0.5 cm × 0.5 cm vegetation on her tricuspid valve with moderate tricuspid regurgitation. Despite 8 days of therapeutic vancomycin, serial BCx remain positive for MRSA. Computed tomography (CT) of her chest, abdomen, and pelvis is unremarkable.
      Questions to consider for each patient:
      • 1.
        What other investigations should be considered?
      • 2.
        What is the role of echocardiogram?
      • 3.
        What choice, route, and duration of antibiotic(s) should be administered?
      • 4.
        What is the role of Infectious Diseases (ID) consultation?

      Epidemiology and Relevance

      S. aureus is a colonizer of mucous membranes, skin, and gastrointestinal tract, carried by up to 80% of the population. Nasal carriage of S. aureus is most common, and increases with health care exposure, diabetes, dialysis, substance drug use, and human immunodeficiency virus infection.
      • Kluytmans J
      • van Belkum A
      • Verbrugh H
      Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks.
      While most carriers of S. aureus do not go on to develop illness, colonization often precedes infection.
      S. aureus bacteremia remains a common cause of bloodstream infection. It has an annual population-based incidence rate upwards of 50 cases/100,000 population and mortality rate approximating 20%-30% in developed countries despite effective antibacterial therapies and source control strategies.
      • van Hal SJ
      • Jensen SO
      • Vaska VL
      • Espedido BA
      • Paterson DL
      • Gosbell IB
      Predictors of mortality in Staphylococcus aureus bacteremia.
      In contrast, 30-day mortality from an acute myocardial infarction approximates 10%.
      • Krumholz HM
      • Normand ST
      • Wang Y
      Twenty-year trends in outcomes for older adults with acute myocardial infarction in the United States.
      In the United States, prevalence of MRSA amongst S. aureus clinical isolates is upwards of 50% and significant enough to justify empiric MRSA treatment in S. aureus bacteremia. However, rates continue to decrease with rigorous infection control measure implementations.
      • Kourtis AP
      • Hatfield K
      • Baggs J
      • et al.
      Vital signs: epidemiology and recent trends in methicillin-resistant and in methicillin-susceptible Staphylococcus aureus bloodstream infections – United States.
      In comparison, both Canada and Europe have lower MRSA prevalence, although European MRSA prevalence increases substantially with decreasing latitude (eg, <5% in Northern European countries compared with over 25% among Southern Europe).

      European Centre for Disease Prevention and Control (ECDC). Surveillance atlas of infectious diseases. Available at:https://atlas.ecdc.europa.eu/public/index.aspx?Dataset=27&HealthTopic=4. Accessed June 19, 2022.

      Patients with S. aureus bacteremia have a spectrum of clinical presentations; some are asymptomatic with incidentally identified primary bacteremia, while others have a sustained bloodstream infection complicated by embolic phenomena. The mechanism of disease from S. aureus is not well understood and thought to be mediated by the relationship between host susceptibility and pathogen virulence factors.
      Despite the lethality of S. aureus bacteremia, there remain no contemporary uniform guidelines to inform clinical practice. Rather, the evidence that guides the treatment of patients with S. aureus bacteremia focus on specific questions (eg, comparison of antibacterials, comparison of cardiac imaging modalities) rather than S. aureus bacteremia as an entity in itself.
      • Thwaites GE
      • Edgeworth JD
      • Gkrania-Klotsas E
      • et al.
      Clinical management of Staphylococcus aureus bacteraemia.
      ,
      • Lam JC
      • Gregson DB
      • Somayaji R
      • et al.
      Forgoing transesophageal echocardiogram in selected patients with complicated Staphylococcus aureus bacteremia.
      Regardless, a series of diagnostic and therapeutic investigations should be performed in all patients with S. aureus bacteremia. These include: 1) appropriate anti-staphylococcal therapy, 2) screening echocardiography, 3) assessment for metastatic phenomena and source control, 4) decision on duration of antimicrobial therapy, and 5) ID consultation (Figure).
      Figure
      FigureProposed flow diagram for Staphylococcus aureus bacteremia management. May differ depending on recommendations by local ID consultants.
      Abx = antibiotic; BCx = blood culture; CT = computed tomography; CV = cardiovascular; ID = Infectious Diseases; CXR = chest X-ray study; IE = infective endocarditis; IV = intravenous; MRI = magnetic resonance imaging; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-susceptible Staphylococcus aureus; PET-CT = positive emission tomography-computed tomography; TEE = transesophageal echocardiogram; SAB = s.aureus bacteremia; TTE = transthoracic echocardiogram.

      Microbiology

      S. aureus is a Gram-positive, facultatively anaerobic coccus with unique virulent properties. In brief, S. aureus adhesins allow migration into the bloodstream followed by attachment to biotic and abiotic surfaces. Once attached, S. aureus coagulase interacts with fibrinogen to form hardy, drug-resistant biofilms.
      • Jenkins A
      • Diep BA
      • Mai TT
      • et al.
      Differential expression and roles of Staphylococcus aureus virulence determinants during colonization and disease.
      Toxins produced by S. aureus can lyse leukocytes and evade host immune systems. Certain S. aureus strains, particularly within community-acquired MRSA, produce Panton-Valentine leukocidin (PVL), a cytolytic toxin associated with granulocyte destruction. The presence of PVL can be associated with severe, deep-seated S. aureus infections in hosts with high inflammatory markers but relative leukopenia.
      • Dohin B
      • Gillet Y
      • Kohler R
      • et al.
      Pediatric bone and joint infections caused by Panton-Valentine leukocidin-positive Staphylococcus aureus.
      While in vitro data of S. aureus strains with PVL suggests a benefit with usage of adjunctive toxin inhibitory antibiotics such as rifampin, clindamycin, or linezolid, clinical benefit has not been reflective of the same.
      • Dumitrescu O
      • Badiou C
      • Bes M
      • et al.
      Effect of antibiotics, alone and in combination, on Panton-Valentine leukocidin production by a Staphylococcus aureus reference strain.
      S. aureus is seldom considered nonpathogenic when identified in BCx. Risk factors associated with S. aureus contamination are not well defined. In our experience, pseudobacteremia is more common among patients with papulosquamous skin disease (eg, eczema, psoriasis). If contamination is suspected, close follow-up with clinical monitoring and serial BCx is advised.
      Time to BCx positivity may predict speciation, severity, and etiology of staphylococcal bacteremia. For example, 1/4 positive BCx for Gram-positive cocci in clumps after 24 hours are more likely to be coagulase-negative Staphylococci, whereas S. aureus BCx positivity within 14 hours is associated with endovascular infection, persistent bacteremia, and metastatic complications.
      • Kahn F
      • Resman F
      • Bergmark S
      • et al.
      Time to blood culture positivity in Staphylococcus aureus bacteraemia to determine risk of infective endocarditis.
      Time to positivity difference of ≥2 hours between BCx taken from central lines and those taken from peripheral sites are suggestive of central-line-associated bloodstream infection.
      Bacteremia with MRSA is associated with poorer clinical outcomes compared with MSSA; likely due to increased virulence and drug-resistance. The dysfunction of the accessory gene regulator (agr), a protein that modulates S. aureus virulence factors, is a key contributor to virulence of MRSA. Its dysfunction is associated with prolonged bacteremia via increasing glycopeptide (e.g. vancomycin) resistance through various mechanisms including adhesin overexpression.

      Chong YP, Park SJ, Kim HS, et al. Persistent Staphylococcus aureus bacteremia: a prospective analysis of risk factors, outcomes, and microbiologic and genotypic characteristics of isolates. Medicine (Baltimore). 2013;92(2):98-108.

      Antimicrobial resistance to vancomycin in S. aureus can develop in 3 main ways: modifications of S. aureus’ cell wall, “minimal inhibitory concentration (MIC) creep,” and acquisition of vanA plasmids.
      Vancomycin (or glycopeptide)-intermediate S. aureus (VISA or GISA) and heterogenous VISA (hVISA) strains are less susceptible to vancomycin due to increasing cell wall thickness. Compared with VISA, the number of S. aureus subpopulations in hVISA have variable ranges of vancomycin susceptibility. In contrast, MIC creep is not a method of resistance per se but represents a phenomenon of increasing vancomycin MICs among S. aureus over time. Compared with an MIC <2 ug/mL, isolates of MRSA with a MIC of 2 ug/mL treated with vancomycin may be associated with unfavorable clinical outcomes and be precursors to VISA and hVISA.
      • van Hal SJ
      • Lodise TP
      • Paterson DL
      The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis.
      However, interpretation of vancomycin “MIC creep” and its clinical relevance remains varied. Both the American and European susceptibility guidelines continue to recommend MRSA isolates with a MIC of 2 ug/mL susceptible to vancomycin, although some centers may report caution with vancomycin use in these cases. Vancomycin MICs between 4 and 8 ug/mL (VISA, hVISA) and MIC ≥16 ug/mL (VRSA) are reported as indeterminate and resistant, respectively. Vancomycin resistance is rare and most commonly mediated by acquisition of vanA plasmids from vancomycin resistant Enterococci. VanA confers resistance by altering the peptide target of glycopeptides.
      Even less common is resistance to daptomycin, tigecycline, linezolid, and anti-MRSA beta-lactams (ceftobiprole, ceftaroline) among S. aureus strains. Increasing MICs to vancomycin and daptomycin appears to decrease the MICs for anti-MRSA beta-lactams and is referred to as the “see-saw effect.” It is thought that the beta-lactam decreases cell membrane positive charge, thereby enhancing daptomycin binding.
      • Molina KC
      • Morrisette T
      • Miller MA
      • Huang V
      • Fish DN
      The emerging role of β-lactams in the treatment of methicillin-resistant Staphylococcus aureus bloodstream infections.
      Clinical studies examining the combination of beta-lactams with vancomycin or daptomycin have shown improved time to MRSA blood clearance but increased rates of acute kidney injury.
      • Tong SY
      • Davis JS
      • Eichenberger E
      • Holland TL
      • Fowler VG
      Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management.

      Appropriate Anti-Staphylococcal Therapy

      Empiric S. aureus Bacteremia Therapy

      Empiric antibiotic selection in S. aureus bacteremia is critical. Vancomycin monotherapy in MSSA bacteremia is associated with worse clinical outcomes compared with anti-staphylococcal beta-lactams.
      • McConeghy KW
      • Bleasdale SC
      • Rodvold KA
      The empirical combination of vancomycin and a β-lactam for Staphylococcal bacteremia.
      When susceptibilities of S. aureus bacteremia are not yet known, patients with S. aureus bacteremia should be treated with combined anti-staphylococcal beta-lactam and anti-MRSA agent. De-escalation and appropriate monitoring should be performed once susceptibilities are known.

      MSSA Bacteremia

      Anti-staphylococcal penicillin or cefazolin are preferred and clinically superior to broad-spectrum antibiotics with anti-staphylococcal coverage in MSSA bacteremia. While piperacillin/tazobactam and non-first-generation cephalosporins have activity against MSSA, their use in MSSA bacteremia is associated with higher mortality and worse outcomes.
      • Beganovic M
      • Cusumano JA
      • Lopes V
      • LaPlante KL
      • Caffrey AR
      Comparative effectiveness of exclusive exposure to nafcillin or oxacillin, cefazolin, piperacillin/tazobactam, and fluoroquinolones among a national cohort of veterans with methicillin-susceptible.
      Some exceptions may include febrile neutropenia with mixed infections where broad spectrum anti-staphylococcals may be favored over combination beta-lactam therapy.
      • Aleissa MM
      • Gonzalez-Bocco IH
      • Zekery-Saad S
      • et al.
      The relationship between antibiotic agent and mortality in patients with febrile neutropenia due to Staphylococcal bloodstream infection: a multicenter cohort study.
      In patients with S. aureus bacteremia who require additional Gram-negative or anaerobic therapy, we recommend discussion with ID to optimize the patient's antimicrobial regimen without sacrificing ideal anti-staphylococcal coverage.
      We recommend cefazolin as first-line therapy for MSSA bacteremia. Anti-staphylococcal penicillins have similar efficacy to cefazolin but are associated with higher rates of adverse events, including interstitial nephritis.
      • Flynt LK
      • Kenney RM
      • Zervos MJ
      • Davis SL
      The safety and economic impact of cefazolin versus nafcillin for the treatment of methicillin-susceptible Staphylococcus aureus bloodstream infections.
      It was traditionally believed that anti-staphylococcal penicillins were superior for penetration of the central nervous system compared with cefazolin, but a growing body of pharmacokinetic studies is reassessing this dogma—and highlighting that cefazolin is a viable option in treating MSSA bacteremia with central nervous system involvement.
      • Novak AR
      • Krsak M
      • Kiser TH
      • et al.
      Pharmacokinetic evaluation of cefazolin in the cerebrospinal fluid of critically ill patients.

      MRSA Bacteremia

      Intravenous vancomycin or daptomycin are appropriate for MRSA bacteremia, depending on the clinical scenario. Vancomycin is challenging to dose, as reaching therapeutic levels and steady state depends on a host's volume of distribution and renal function. Traditionally, vancomycin trough concentrations of 15-20 mg/L were thought to achieve sufficient serum vancomycin concentrations to eradicate MRSA. However, contemporary guidelines recommend targeting an area under the curve (AUC) over 24 hours to MIC (AUC/MIC) between 400 and 600 mg/h/L (assuming a vancomycin MIC of 1 mg/L) to minimize vancomycin toxicity.
      • Rybak MJ
      • Le J
      • Lodise TP
      • et al.
      Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.
      Compared with monitoring vancomycin trough concentrations, AUC-guided therapeutic drug monitoring is labor intensive and requires additional time-critical phlebotomies. Accordingly, some institutions recommend monitoring vancomycin levels to achieve a less restrictive trough concentration of 10-20 mg/L as an alternate strategy to balance drug efficacy against drug toxicity in settings that lack the resources to do AUC-guided monitoring.
      • Stewart J
      • Jorgensen S
      • Dresser L
      • et al.
      A Canadian perspective on the revised 2020 ASHP–IDSA–PIDS–SIDP guidelines for vancomycin AUC-based therapeutic drug monitoring for serious MRSA infections.
      The increasingly recognized limitations of vancomycin have prompted usage of daptomycin as an anti-staphylococcal for MRSA bacteremia. Daptomycin is a lipopeptide antibiotic that inserts and disrupts the integrity of the staphylococcal cell wall, leading to rapid depolarization and bacterial cell death. Initial studies demonstrated noninferiority when comparing daptomycin with vancomycin in MRSA bacteremia.
      • Fowler VG
      • Boucher HW
      • Corey GR
      • et al.
      Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus.
      Daptomycin is an acceptable agent for MRSA bacteremia and may confer advantages over vancomycin in isolates with an MIC ≥2.
      Linezolid is an oxazolidinone, a bacteriostatic protein synthesis inhibitor with enhanced in vitro activity in MRSA toxin-producing isolates. While linezolid is reliably utilized for MRSA meningitis, skin and soft tissue infection, and pneumonia, usage in bacteremia has been associated with higher mortality when compared with daptomycin or vancomycin.
      • Usery JB
      • Vo NH
      • Finch CK
      • Cleveland KO
      • Gelfand MS
      • Self TH
      Evaluation of the treatment of methicillin-resistant Staphylococcus aureus bacteremia.
      Thus, daptomycin and vancomycin remain preferred agents in MRSA bacteremia.
      Monitoring parameters and considerations of anti-staphylococcal agents are summarized in Table 1.
      Table 1Anti-Staphylococcal Drugs for Staphylococcus aureus Bacteremia
      Common or Severe Adverse ReactionsRegular Monitoring (weekly)Considerations
      Cefazolin
      Consider higher dosing for elevated body mass index (3 g IV every 8 hours) in adults over 100 kg in weight, assuming a normal creatinine clearance.


      Cloxacillin, nafcillin, oxacillin
      Acute interstitial nephritis
      More common with anti-staphylococcal penicillins than cefazolin.


      Hematologic dyscrasias

      Rash
      More common with anti-staphylococcal penicillins than cefazolin.


      Hypersensitivity including anaphylaxis†
      CBC-diff, CrHypersensitivity cross-reaction of cefazolin with other beta-lactams is rare. Consider its use even in people with documented non-anaphylactic allergy to penicillins or other cephalosporins.

      Cloxacillin, nafcillin, oxacillin• No renal adjustment needed• Generally requires central line access due to issues with skin irritation and risk of thrombophlebitis when using a peripheral catheter
      VancomycinNephrotoxicity

      Neutropenia

      Thrombocytopenia

      DRESS
      CBC-diff, Cr, pre-vancomycin level
      Target area under the curve/minimal inhibitory concentration (MIC) of 400-600 mg/h/L (assuming a vancomycin MIC of 1 ug/mL). Alternatively, monitor vancomycin levels to achieve trough concentration of 10-20 mg/L.
      Infusion reaction: resolve by decreasing rate of infusion
      DaptomycinMyositis
      Suspend statin while on daptomycin therapy.


      Eosinophilic pneumonia
      CBC-diff, Cr, CKInhibited by pulmonary surfactant; recommend against usage in pulmonic infections
      LinezolidMyelosuppression with ≥2 weeks of use

      Lactic acidosis

      Drug interactions
      Risk of serotonin syndrome with concomitant selective serotonin reuptake inhibitors, risk of severe hypertension with concomitant monoamine oxidase inhibitor.
      CBC-diffNo renal adjustment needed

      Excellent pulmonic tissue penetratio

      Not recommended as first-line therapy in S. aureus bacteremia
      CBC-diff = complete blood count and differential; CK = creatine kinase; Cr = creatinine; DRESS = drug rash with eosinophilia and systemic symptoms.
      low asterisk Consider higher dosing for elevated body mass index (3 g IV every 8 hours) in adults over 100 kg in weight, assuming a normal creatinine clearance.
      More common with anti-staphylococcal penicillins than cefazolin.
      Target area under the curve/minimal inhibitory concentration (MIC) of 400-600 mg/h/L (assuming a vancomycin MIC of 1 ug/mL). Alternatively, monitor vancomycin levels to achieve trough concentration of 10-20 mg/L.
      § Suspend statin while on daptomycin therapy.
      Risk of serotonin syndrome with concomitant selective serotonin reuptake inhibitors, risk of severe hypertension with concomitant monoamine oxidase inhibitor.

      New Developments

      Ceftaroline and ceftobiprole are fifth-generation cephalosporins with in vitro activity against MRSA and approved for treatment of skin and soft tissue infection and community-acquired pneumonia.
      • Molina KC
      • Morrisette T
      • Miller MA
      • Huang V
      • Fish DN
      The emerging role of β-lactams in the treatment of methicillin-resistant Staphylococcus aureus bloodstream infections.
      ,
      • Mahmoud E
      • Al Mansour S
      • Bosaeed M
      • et al.
      Ceftobiprole for treatment of MRSA blood stream infection: a case series.
      Smaller studies have demonstrated promise in usage for MRSA bacteremia, particularly when clinical failure is observed with intravenous vancomycin or daptomycin. In cases of persistent bacteremia despite appropriate therapy, we recommend ID and Microbiologist consultation if ceftaroline or ceftobiprole usage is being considered due to clinical failure.
      Discussions on usage of oral anti-staphylococcal agents have become more robust over the last few years. A significant body of literature exists for usage of linezolid in select cases of S. aureus bacteremia given its excellent oral bioavailability.
      • Dagher M
      • Fowler VG
      • Wright PW
      • Staub MB
      A narrative review of early oral stepdown therapy for the treatment of uncomplicated.
      While usage of fluoroquinolone with rifampin was found to have equal efficacy to vancomycin in select cases of right-sided infective endocarditis (IE), its applicability to other cases of S. aureus bacteremia remains questionable. Usage of trimethoprim-sulfamethoxazole, tetracyclines, clindamycin, and oral beta-lactams are not advised owing to a lack of evidence.
      • Dagher M
      • Fowler VG
      • Wright PW
      • Staub MB
      A narrative review of early oral stepdown therapy for the treatment of uncomplicated.
      Based on available evidence, we recommend usage of linezolid or fluoroquinolone and rifampin only as salvage therapy when other options are not possible (eg, patients prematurely discharged from hospital with S. aureus bacteremia).

      Screening Echocardiography and Cardiac Imaging

      Echocardiography in patients with S. aureus bacteremia is supported by the European Society of Cardiology and the Infectious Diseases Society of America.
      • Habib G
      • Lancellotti P
      • Antunes MJ
      • et al.
      2015 ESC Guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM).
      ,
      • Baddour LM
      • Wilson WR
      • Bayer AS
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
      Upwards of 18% of individuals with S. aureus bacteremia IE do not have clinical stigmata.
      • Bayer AS
      • Lam K
      • Ginzton L
      • Norman DC
      • Chiu CY
      • Ward JI
      Staphylococcus aureus bacteremia. Clinical, serologic, and echocardiographic findings in patients with and without endocarditis.
      While transesophageal echocardiogram (TEE) has a higher sensitivity compared with TTE for S. aureus infective endocarditis, the specificity of both modalities is equivocal. Usage of TEE over TTE is recommended in patients with prosthetic cardiac valves or intracardiac devices. Patients with complicated S. aureus bacteremia requiring a prolonged (≥6 week) course of anti-staphylococcal therapies need not undergo a TEE so long as a TTE is done to investigate for surgical indications of native IE.
      • Lam JC
      • Gregson DB
      • Somayaji R
      • et al.
      Forgoing transesophageal echocardiogram in selected patients with complicated Staphylococcus aureus bacteremia.
      Other imaging modalities, including cardiac magnetic resonance, cardiac CT, positive emission tomography-computed tomography (PET-CT), and CT angiography can complement echocardiography. Forexample CT angiography can detect abscesses and mycotic aneurysms with diagnostic accuracy similar to that of TEE, in addition to characterizing degree of perivalvular involvement, aortic and coronary vessel anatomy, and aid in preoperative planning.
      • Habib G
      • Lancellotti P
      • Antunes MJ
      • et al.
      2015 ESC Guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM).
      ,
      • Habets J
      • Tanis W
      • van Herwerden LA
      • et al.
      Cardiac computed tomography angiography results in diagnostic and therapeutic change in prosthetic heart valve endocarditis.
      While there are no recommendations for end-of-therapy echocardiogram performance, we recommend obtaining one in select cases of IE in which relapse risk is significant. Given common persistence of valvular vegetations, repeat TTE can only be used as a new baseline, which can be compared with future TTEs if suspicion for IE relapse is high enough to warrant further investigation.

      Assessment for Metastatic Phenomena and Source Control

      Determining source and complications of S. aureus bacteremia informs diagnostic and therapeutic interventions. Directed questioning about recent procedures, trauma, or underlying comorbidities may suggest a source of S. aureus bacteremia. Similarly, the presence of foreign bodies or acute pain syndromes may identify metastatic S. aureus complications.
      Management and outcomes differ depending on the source of S. aureus bacteremia. The commonest sources of hospital-acquired and community-acquired S. aureus bacteremia are line-related and skin/soft tissue infections, respectively.
      • Tong SY
      • Davis JS
      • Eichenberger E
      • Holland TL
      • Fowler VG
      Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management.
      Upwards of 40% of individuals with S. aureus bacteremia do not have an apparent source. Pleuropulmonary, osteoarticular, and endovascular sources are also recognized, albeit in lower frequencies.
      • Tong SY
      • Davis JS
      • Eichenberger E
      • Holland TL
      • Fowler VG
      Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management.
      ,
      • Lam JC
      • Gregson DB
      • Robinson S
      • Somayaji R
      • Conly JM
      • Parkins MD
      Epidemiology and outcome determinants of Staphylococcus aureus bacteremia revisited: a population-based study.
      The urinary tract is an uncommon source of S. aureus bacteremia and may reflect hematogenous seeding as opposed to urinary infection. One in 5 patients with S. aureus bacteremia and concomitant S. aureus bacteriuria have vertebral osteomyelitis or psoas abscesses and should be closely assessed for same.
      • Stokes W
      • Parkins MD
      • Parfitt ECT
      • Ruiz JC
      • Mugford G
      • Gregson DB
      Incidence and outcomes of Staphylococcus aureus bacteriuria: a population-based study.
      Patients with S. aureus bacteremia require a meticulous physical examination followed by corresponding investigations, as dissemination to osteoarticular, vertebral, and visceral organs is common. For instance, severe headaches should prompt additional investigations for embolic seeding to the brain from endocarditis, and arthropathies should prompt arthrocentesis for assessment of septic arthritis.
      Examination for vertebral tenderness should always be conducted, as vertebral discitis can present occultly or may be erroneously attributed to mechanical back pain. Palpation of the vertebrae will elicit point tenderness over the disc involved.
      • Cornett CA
      • Vincent SA
      • Crow J
      • Hewlett A
      Bacterial spine infections in adults: evaluation and management.
      Accordingly, an MRI of the spine should be considered even if findings on clinical assessment are subtle. Repeat MRI may be considered in select circumstances of suspected acute discitis, as radiographic findings of vertebral discitis may lag behind symptoms for 10 days.
      • Ahn KS
      • Kang CH
      • Hong SJ
      • Kim BH
      • Shim E
      The correlation between follow-up MRI findings and laboratory results in pyogenic spondylodiscitis.
      PET-CT is an increasingly utilized modality in identifying metastatic complications of S. aureus bacteremia for intervention, particularly when routine investigations, including echocardiogram, are nondiagnostic despite a high pretest probability (eg, confirming vascular graft infection in an individual with unexplained persistent S. aureus bacteremia).
      • Ghanem-Zoubi N
      • Kagna O
      • Abu-Elhija J
      • et al.
      Integration of FDG-PET/CT in the diagnostic workup for Staphylococcus aureus bacteremia: a prospective interventional matched-cohort study.
      However, the expense and need for specialized radiotracers may limit the practicality of PET-CT.
      White blood cell scans have a role in evaluating embolic phenomenon except for cases with vertebral discitis, as significant uptake of leukocytes within the bone marrow conflicts interpretation.
      Achieving source control in patients with S. aureus bacteremia hastens clearance of bacteremia and reduces associated mortality.
      • Minejima E
      • Mai N
      • Bui N
      • et al.
      Defining the breakpoint duration of Staphylococcus aureus bacteremia predictive of poor outcomes.
      Endovascular devices, including central lines and intracardiac devices, should be removed in all cases of S. aureus bacteremia, where feasible. Patients with S. aureus bacteremia and prosthetic heart valves or vascular grafts should be investigated for infection. Non-endovascular material, including osteoarticular hardware, typically do not require additional investigations unless directed by clinical examination. Confirmed septic arthritis or epidural abscess require surgical consultation for irrigation and debridement. Similarly, expeditious surgical or radiological drainage are needed in cases with intramuscular or intra-abdominal dissemination. Cardiovascular Surgery consultation is valuable in all cases of S. aureus IE (Table 2
      • Pettersson GB
      • Coselli JS
      • Hussain ST
      • et al.
      2016 The American Association for Thoracic Surgery (AATS) consensus guidelines: surgical treatment of infective endocarditis: executive summary.
      ).
      Table 2Surgical Indications for Staphylococcus aureus Endocarditis
      Adapted from the 2016 American Association for Thoracic Surgery consensus guidelines.37
      IndicationClassification of Recommendations
      Left-sided endocarditisStrong
      Endocarditis induced valve dysfunction resulting in heart failureStrong
      Endocarditis induced heart block, annular or aortic abscess, or destructive penetrative lesionsStrong
      Persistent infection (characterized as persistent bacteremia or fever ≥ 5-7 days after initiation of anti-staphylococcal antibiotics)Strong
      Relapsing prosthetic valve endocarditis despite an appropriate antimicrobial courseModerate
      Recurrent emboli and persistent vegetations despite appropriate antimicrobial therapyModerate
      Vegetations >10 mm in size with clinical evidence of embolic phenomena despite appropriate antimicrobial therapyWeak
      Right-sided endocarditis with symptomatic severe valve dysfunction AND evidence of persistent infectionWeak
      low asterisk Adapted from the 2016 American Association for Thoracic Surgery consensus guidelines.
      • Pettersson GB
      • Coselli JS
      • Hussain ST
      • et al.
      2016 The American Association for Thoracic Surgery (AATS) consensus guidelines: surgical treatment of infective endocarditis: executive summary.

      Duration of Therapy

      Repeat BCx are necessary to document bacteria clearance and establish duration of therapy. At minimum, 2 weeks of intravenous anti-staphylococcal therapy from the first negative BCx is needed—and can only be considered when S. aureus bacteremia has met a series of criteria to be considered uncomplicated. Different criteria have been proposed to define the constituents of an uncomplicated S. aureus bacteremia. Based on current literature and our expert opinion, the following should be met to consider S. aureus bacteremia as uncomplicated: 1) clearance of S. aureus bacteremia and corresponding clinical defervescence within the first 48-72 hours of anti-staphylococcal therapy; 2) removable foci of infection; 3) absence of metastatic phenomena; 4) absence of endovascular foreign material (eg, prosthetic valves, cardiac devices, vascular grafts); 5) no evidence of endocarditis on echocardiogram.
      • Fowler VG
      • Olsen MK
      • Corey GR
      • et al.
      Clinical identifiers of complicated Staphylococcus aureus bacteremia.
      ,
      • Chong YP
      • Moon SM
      • Bang KM
      • et al.
      Treatment duration for uncomplicated Staphylococcus aureus bacteremia to prevent relapse: analysis of a prospective observational cohort study.
      S. aureus bacteremia is considered complicated when the aforementioned criteria are not met. At minimum, 4 weeks of intravenous anti-staphylococcal therapy from the first negative BCx is needed. Six weeks of therapy is recommended when deep-seated infection, including endocarditis or osteomyelitis, is present (Figure).

      Infectious Diseases Consultation

      ID specialist consultation is recommended in all cases of S. aureus bacteremia, given its association with improved outcomes.
      • Lam JC
      • Gregson DB
      • Robinson S
      • et al.
      Infectious diseases consultation improves key performance metrics in the management of Staphylococcus aureus bacteremia: a multicentre cohort study.
      ,
      • Turner RB
      • Valcarlos E
      • Won R
      • Chang E
      • Schwartz J
      Impact of infectious diseases consultation on clinical outcomes of patients with Staphylococcus aureus bacteremia in a community health system.
      Benefits of ID consultation have a legacy effect, with improved patient outcomes of at least 5 years.
      • Goto M
      • Jones MP
      • Schweizer ML
      • et al.
      Association of infectious diseases consultation with long-term postdischarge outcomes among patients with Staphylococcus aureus bacteremia.
      Reduction of mortality in patients with S. aureus bacteremia was more pronounced with bedside ID consultant compared with telephonic consultations.
      • Saunderson RB
      • Gouliouris T
      • Nickerson EK
      • et al.
      Impact of routine bedside infectious disease consultation on clinical management and outcome of Staphylococcus aureus bacteraemia in adults.
      The specific mechanisms in which ID consultation improves outcomes remains unclear; rendering it difficult to characterize the benefit of any unique intervention.

      Conclusion

      The significant prevalence of S. aureus bacteremia coupled with its high mortality rate behooves clinicians to be well versed in managing this bloodstream infection. Although no 2 cases of S. aureus bacteremia are the same, the management of S. aureus bacteremia should involve a series of common evidence-informed clinical considerations. Of all considerations, ID consultation remains quintessential and should be employed for all cases of S. aureus bacteremia, regardless of patient characteristics or clinical presentation.

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