Staphylococcus aureus

Paul G. Auwaerter, M.D.

MICROBIOLOGY

CLINICAL

SITES OF INFECTION

Some common presentations, list by no means comprehensive.

TREATMENT

General considerations

  • In severely ill, or risk for MRSA, empiric coverage traditionally with vancomycin IV, although daptomycin, ceftaroline or linezolid among others would potentially service depending on the clinical presentation.
  • Anti-staphylococcal penicillins and cefazolin appear superior to vancomycin and other lipo/glycopeptides, if susceptible.
  • For hospital-acquired staphylococcal bacteremia, most ID clinicians obtain echocardiography. Highly suggested for
    • Patients with ESRD or on hemodialysis
    • Vertebral osteomyelitis, discitis or epidural abscess
    • Intravascular or intracardiac device
    • Prolonged bacteremia, ≥ 4d.
  • Severe MRSA infections with vancomycin MIC 1.5-2.0 (so-called hVISA) not responding to vancomycin therapy, consider an alternative agent (e.g., daptomycin or ceftaroline).
    • Several studies have worse clinical outcomes with vancomycin in these settings. This remains controversial.
  • Vancomycin does have dose-related nephrotoxicity especially with maintaining 15-20 ug/mL troughs.
    • More recent evidence suggests troughs are not an ideal surrogate for a target AUC:MIC ≥400 , with many patients able to achieve a goal AUC:MIC with troughs less than 15 mg/L.
  • Daptomycin: caution for use with vancomycin MIC > 1.0, especially if switching from vancomycin therapy due to higher rates of non-susceptibility of daptomycin and clinical failures.
    • Check daptomycin MICs.
  • VISA and VRSA infections remain rare, which is much different than with the Enterococcus (VRE).
    • VRSA: vancomycin MIC ≥16 µg/mL due to resistance genes (vanA operon, codes enzymes that modify or eliminate the vancomycin binding site, derived from VRE.
    • First identified in 2002, only 14 isolates described (2015)[17].

Bacteremia

  • Perform detailed history and physical to detect the source and if metastatic spread has occurred. Infectious diseases consultation is recommended in most cases.
    • Remove foci of infection whenever possible; remove implicated venous catheter if present.
    • May occur without apparent focus or entry site.
    • Evaluate if without focus for endocarditis (TTE (transthoracic echocardiography)/TEE (transesophageal echocardiography), mycotic aneurysms or other deep infection, e.g., abscess, spinal involvement (discitis, vertebral osteomyelitis, epidural abscess).
    • Rule out endocarditis with echocardiography (TTE/TEE).
    • Mortality rates of up to 20-40% (MRSA > MSSA).
    • The appropriate duration of therapy improves outcomes.
      • Risks for poor outcomes include age, SOFA score, cirrhosis.
  • Treatment:
    • MSSA: superiority of β-lactams make clear favorite over vancomycin.
      • Preferred:
      • Alternatives:
        • For non-life-threatening PCN allergy: cefazolin 2g IV q8h
          • Cefazolin can be given to hemodialysis patients: 2 gm after dialysis if next dialysis in 2 days and 3 gm after dialysis if next dialysis in 3 days.
          • Note: inoculum effect may occur in MSSA Type A Bla that hydrolyze beta-lactam bonds of cefazolin but not oxacillin or nafcillin. Perhaps 10-30% may exhibit inoculum effect and this could be associated with worse outcomes.
          • Other cephalosporins or beta-lactams:
            • Some limited data suggest outcomes may be worse with cefuroxime or ceftriaxone compared to semi-synthetic penicillins.
            • MSSA Type C Bla inoculum effect can contribute to worse outcomes if using ampicillin/sulbactam or piperacillin/tazobactam.
        • Consider oxacillin/nafcillin desensitization for life-threatening Type 1 PCN allergy (hives/anaphylaxis).
        • Severe beta-lactam allergy:
    • MRSA or life-threatening PCN allergy:
      • Preferred:
        • Vancomycin 15 mg/kg q 8-12h
          • Consider loading dose for severe infections: guidelines recommend 25-35 mg/kg, although at Johns Hopkins, favor 20-25 mg/kg, particularly in patients with any baseline or anticipated renal dysfunction.
          • Subsequent dosing guided by AUC/MIC monitoring or checking vancomycin serum trough levels.
        • Daptomycin 6-10 mg/kg IV daily
          • FDA approved for S. aureus bacteremia and right-sided endocarditis, preferred in most instances; some experts recommend higher doses 8-10 mg/kg daily for severe infections.
          • Suggested agent for MRSA isolates with MIC > 1.0 µg/nL.
          • If using after vancomycin failure, daptomycin non-susceptibility may develop compared to the original isolate.
            • Recheck of daptomycin susceptibility from the latest MRSA isolate recommended.
      • Alternatives: for severe allergy or treatment failure, consider infectious diseases consultation. Little robust data to guide choices. Unclear if monotherapy or combination therapy is needed for salvage therapy (see below). With the exception of daptomycin, none of the below regimens are FDA-approved for the treatment of bacteremia.
        • Linezolid 600mg IV/PO q12h
          • Not FDA approved for S. aureus bacteremia, black box warning has to do with increased mortality seen in patients with Gram-negative, not Gram-positive bacteremia.
        • Ceftaroline 600mg IV q8h
        • Teicoplanin 6-12 mg/kg IV once daily
          • Not available in the U.S.
        • Telavancin 10 mg/kg IV q24h
        • TMP/SMX 5 mg/kg IV q8-12h
      • No routine role for employing aminoglycosides or rifampin in combination.
      • MRSA isolates with MIC ≥ 2 µg/mL may be associated with worse outcomes if treated with vancomycin.
        • If such patients are not responding well to vancomycin, consider switch to an alternative, e.g, daptomycin or combination therapy (see salvage therapy section).
  • Duration of therapy:
    • Bacteremia: 28d is the standard course of therapy.
      • Short-course therapy, 14d only if the following criteria are met:
        • Endocarditis is ruled out by TTE +/- TEE (transesophageal echocardiography)
        • No implanted prostheses (e.g., prosthetic valves, cardiac devices, or arthroplasties)
        • Blood cultures drawn 2-4 days after the initial cultures were negative, the patient defervesces within 72 hours of appropriate therapy
        • No evidence of metastatic infection
        • Some avoid short courses in patients that meet short-course criteria but have multiple co-morbidities, e.g., diabetes, liver or advanced renal disease, immunosuppression.
      • Perform blood cultures q 24-48h until clearance of bacteria documented.
    • Endocarditis or epidural abscess: 42d minimum.

Endocarditis, native valve

  • Perform detailed history and physical to detect a potential source and metastatic spread.
  • Diagnostic and therapeutic considerations: most use Duke criteria (see endocarditis module), positive blood cultures documented.
    • Remove or drain foci of infection whenever possible.
    • Obtain brain and CNS vessel imaging if neurologic symptoms or persistent headache present.
    • Consult cardiac surgery if the patient has persistently positive blood cultures, evidence of heart failure or ongoing embolic disease.
      • Evaluation is especially recommended if vegetation > 10mm, new heart block, worsening heart failure, persistent fevers.
    • Obtain MRI w/ contrast spinal imaging if back pain present to assess for discitis, vertebral osteomyelitis or epidural abscess.
    • Echocardiography recommended, TTE as initial with TEE if moderate to high clinical suspicion, difficult TTE imaging of prosthetic valves.
  • Treatment: per 2015 AHA guidelines
    • General notes:
      • Gentamicin: no longer recommended for native valve endocarditis (right- or left-sided, MSSA or MRSA).
      • The utility of combination, empiric therapy (e.g., vancomycin + cefazolin) is not well evidenced.
      • Endocarditis caused by PCN-susceptible isolates should still be treated with antistaphylococcal abx (nafcillin, oxacillin, cefazolin) since many labs not able to detect PCN susceptibility.
      • Clindamycin is not recommended due to the increased risk of relapse.
      • Routine use of rifampin is not recommended due to observations of worsened outcomes with combination therapy.
    • MSSA, native valve, left-sided:
      • Preferred:
      • Alternatives:
        • If highly penicillin-allergic: consider allergy consultation or desensitization as beta-lactam therapy preferred. If a history of rash or minor reactions, use cefazolin
        • Vancomycin 15 mg/kg IV q 8-12h
          • Vancomycin trough ~ 15 υg/mL
        • Daptomycin 8-10 mg/kg IV q 24h
          • Dosing is higher than FDA-approved 6 mg/kg.
        • If a brain abscess is present, nafcillin or oxacillin is favored rather than cefazolin (which has poor CNS penetration).
    • MSSA, native valve, right-sided involvement ONLY: pt w/o AIDS, vascular prosthesis or embolic disease other than septic pulmonary emboli.
      • Preferred: oxacillin or nafcillin 2g IV q4h
      • Alternative: daptomycin 6 mg/kg IV q 24
      • Duration: 2 wks
      • The use of synergistic gentamicin is no longer recommended for short-course therapy as no impact on outcomes and is associated with nephrotoxicity.
    • Alternate oral regimen: only for IDU, TV MSSA endocarditis.
      • Ciprofloxacin 750 mg PO twice daily PLUS rifampin 300 mg PO twice daily for 28 days, if isolate proven susceptible to both agents.
      • Many experts state that though this is a well-studied regimen, concern for the emergence of FQ-resistance deems this a problematical choice.
    • Alternate, if life-threatening penicillin allergy:
    • MRSA, native valve, right- or left-sided involvement:
      • Preferred: vancomycin 15 mg/kg IV q12h
      • Alternative: daptomycin ≥ 8 mg/kg IV daily
        • Some experts recommend higher doses: 10-12 mg/kg daily.
      • Duration: 6 wks, consider longer if complicated infection (osteomyelitis, etc.)

Endocarditis, prosthetic valve

  • TEE recommended for all cases to evaluate for significant perivalvular abscess, leak or if other valves involved.
    • FDG-PET may be helpful in confusing situations, Ao-grafts, concomitant cardiac device presence.
  • Early evaluation for potential valve replacement suggested.
  • See diagnostic and therapeutic considerations listed above.
  • MSSA, prosthetic valve:
    • Oxacillin or nafcillin 2g IV q4h for ≥ 6 weeks PLUS gentamicin 1 mg/kg IV q8h (or 1.5 mg IV q 12h) for 1st 2 weeks PLUS rifampin 300 mg PO q8h for ≥ 6 weeks after blood cultures have cleared; confirm susceptibility to all agents.
  • MRSA, prosthetic valve:
    • Vancomycin 15 mg/kg IV q12h for ≥ 6 weeks PLUS gentamicin 1 mg/kg IV q8h (or 1.5 mg IV q 12h) for 1st 2 weeks PLUS rifampin 300 mg PO q8h for ≥ 6 weeks after blood cultures have cleared; confirm susceptibility to all agents.

Salvage therapy

  • Always consider unknown sources if persistently bacteremic.
    • If conventional evaluation by CT or MRI imaging is unhelpful, FDG-PET may help localize (especially for prosthetic valve infection[24].)
  • Little quality evidence to guide and judge the effectiveness of such switching to combination therapies. Available studies are a mix of in vitro and observational data. Drugs are often used in combination although reports of monotherapy working in such situations are also documented.

Soft tissue infections

  • Surgical drainage for any collection. For cutaneous abscess, I&D may be sufficient.
    • Recent RCT did suggest better outcomes if clindamycin or TMP/SMX were used in addition to I&D[16][15].
  • For non-purulent cellulitis, this usually is due to β-hemolytic streptococci rather than S. aureus.
  • Antibiotics indicated for severe/rapidly progressive infections, signs and symptoms of systemic illness, diabetes or other significant immunosuppression, advanced age, location of abscess in an area where complete drainage is difficult, lack of response to initial I&D (also assess for the need for additional I&D, surgical consultation for necrotizing fasciitis), extensive abscess-associated cellulitis.
  • If antibiotics are employed, obtaining cultures is recommended helping guide therapy.
  • Treatment:
  • Recurrent soft tissue infections: education regarding hand hygiene and personal hygiene (e.g., regular bathing, no sharing of personal items, clean personal sporting equipment, avoid shaving).
    • Clean high-touch areas in contact with bare skin (e.g., counters, sinks, doorknobs, tubs, toilet seats, etc) with commercial cleaners or dilute bleach.
    • Indications for decolonization include recurrent infection despite optimal hygiene or household transmission. Evaluate contacts for evidence of S. aureus infection. Routine screening cultures of nares are not recommended.
    • Consider decolonization for recurrent soft tissue infections: potential approaches include (both index patient ± contacts/household)
      • Mupirocin 2% ointment to nares twice daily for 5-10 days. Some repeat for a period of months, e.g, the first five days of each month.
      • Mupirocin 2% as above + chlorhexidine (Hibiclens) washes daily for 5-14d or dilute bleach bath (1 tsp/gallon, ¼ cup per 13 gallons) twice weekly x ~3 months.
      • Oral antibiotics are not usually recommended. Some use if the above measures fail. Typically choose one drug from the oral MRSA regimen above plus rifampin (e.g., doxycycline 100mg twice daily + rifampin 600mg daily x 7-10d).
  • Some clinicians add rifampin to oral agents for MRSA for patients with recurrent soft tissue infections; rifampin should NEVER be used as monotherapy; the efficacy of this strategy is unproven and rifampin is associated with significant drug interactions so we do not recommend it in most cases.

Pneumonia

  • Consider MRSA pneumonia in any patient with severe CAP (e.g., ICU admission, necrotizing/cavitary disease, empyema) pending sputum or blood culture results.
  • Treatment: use susceptibilities to help guide final choice. Linezolid may have better PK/PD data in lungs compared to vancomycin; the study shows better initial clinical success than vancomycin, but similar 60d mortality[23].
  • Daptomycin cannot be used for pulmonary infections because it is inactivated by surfactant.
  • Drain or proceed with thoracic surgical consultation for empyema.
  • Duration of therapy: 7-21d course, depending on severity; many cases of ventilator-associated pneumonia can be treated for 8d; necrotizing pneumonia usually requires longer courses ≥ 14d; bacteremic pneumonia, at least 14d.

Bone/joint infections

  • Osteomyelitis (OM)
    • MRI with gadolinium is often the best study to employ to diagnose infection in vertebral bones, discs or feet. CT or if plain films positive, sufficient for larger bones.
    • Drainage and debridement of devitalized bone should be done if possible.
    • No clear data to suggest preference regarding the parenteral or oral route of antibiotics. The European OVIVA trial suggested non-inferiority with the use of 1 wk IV then oral antibiotics compared to all parenteral; however, few MRSA infections in this study.
    • Treatment:
    • Some add rifampin to any of the above dosings as 600mg once daily or 300-450mg PO twice daily. If the patient is bacteremic, only add rifampin after bacteremia clears to avoid the emergence of resistance.
    • Duration: unclear best course, many choose 6-8 wks, the IDSA vertebral osteomyelitis guideline suggests 6 wks.
      • Some treat for additional 4-12 wks especially if OM of longstanding nature or if complete debridement not achieved, ESRD patient or hardware is present that also may require consideration of suppressive therapy.
      • ESR/CRP may be used to follow response.
  • Septic arthritis
    • Always drain or debride joint.
      • Repeat closed drainage as needed or open drainage, no clear preference.
      • Consult orthopedics for open drainage
    • Treatment: select from MSSA or MRSA choices as above.
    • Duration: 4-6 wks
  • Prosthetic joint infection: see the module for additional details.
    • Early (< 2 mos post-op) or acute hematogenous infection w/ stable joint < 3wks symptoms:
      • Debride/washout joint and retain.
      • Select abx guided by susceptibilities, from OM choices above + rifampin 600mg or 300-450mg PO twice daily x 2-6 wks.
    • Late (> 2 mos post-op): or if unstable, later-onset infection or > 3wks symptoms--remove hardware and administer abx as above.
    • Duration: 6 wks (or until inflammatory markers normalize), may consider suppressive therapy.

CNS

  • Meningitis:healthcare-associated or community-acquired
    • MSSA: nafcillin or oxacillin 2g IV q4h.Meningitis=
    • MRSA:
      • Preferred: vancomycin 15-20 mg/kg IV 12h (consider loading dose; guidelines recommend 25-30 mg/kg, although we favor 20-25 mg/kg, particularly in patients with any baseline renal dysfunction). Strive for trough level ~20 µg/mL.
      • Alternatives:
      • Some add rifampin 600mg PO/IV q24 or 300-450mg IV/PO q12h.
      • Refractory infection: consider intrathecal vancomycin, 5-20mg daily.
    • Duration: 14d.
  • CNS shunt infection: remove the device. Replace only when CSF cultures are sterile.
  • Brain abscess, subdural empyema, epidural abscess:
    • Consult neurosurgery urgently for drainage.
    • MSSA or MRSA: choices as above
      • Would not use cefazolin for MSSA given poor CNS penetration.
    • Duration: 4-6 wks

Toxic Shock Syndrome

  • See Staphylococcal TSS module for details.
  • Remove focus of staphylococcal colonization or infection.
  • Stabilize blood pressure w/ aggressive hydration +/- pressors.
  • MSSA: oxacillin or nafcillin 2g IV q4h PLUS clindamycin 600mg IV q8h.
  • MRSA: vancomycin 15-20 mg/kg IV q12h PLUS clindamycin 600mg IV q8h (if susceptible) or linezolid 600 mg IV/PO q12h.
  • Consider intravenous immunoglobulin infusions, though data most supportive for streptococcal TSS.

Selected Drug Comments

Drug

Recommendation

Amoxicillin/clavulanate

Good activity against MSSA and other Gram+ organisms (not MRSA). Useful for skin and skin structure infections when some Gram (-) and anaerobic coverage is also desirable (bite, mixed abscess). Not recommended for S. aureus bacteremia or endocarditis.

Ampicillin/sulbactam

Good activity against MSSA and other Gram+ organisms (not MRSA). Useful for skin and skin structure infections when some Gram (-) and anaerobic coverage is also desirable (bite, mixed abscess). Not recommended for S. aureus bacteremia or endocarditis.

Cefazolin

A first-generation cephalosporin antibiotic with excellent general Gram+ activity except for enterococci and MRSA. A practical alternative for S. aureus endocarditis or bacteremia therapy when CNS involvement is not suspected (only 1-4% penetration into CSF)

Clindamycin

A good choice for skin and skin structure infections due to S. aureus, though for CA-MRSA susceptibilities to clindamycin vary by geographic location. Erythromycin resistance predicts inducible clindamycin resistance in many isolates; thus, the microbiology lab should perform a D-test to assess for clindamycin susceptibility. Excellent oral absorption, although GI intolerance (including C. difficile) is more likely with higher doses. Not recommended for S. aureus bacteremia or endocarditis.

Minocycline

A good choice for skin and skin structure infections due to S. aureus, particularly CA-MRSA; poorer anti-streptococcal activity. Has the best in vitro Gram+ activity of the tetracyclines. Side effects include photosensitivity, reversible vestibular dysfunction, and blue skin discoloration. Often used for long-term suppressive therapy in orthopedic infections, sometimes in combination with rifampin. Not recommended for S. aureus bacteremia or endocarditis.

Nafcillin

Well-established agent for serious systemic S. aureus infections (not MRSA). No dose adjustment for renal failure. The main toxicity is neutropenia. The agent is administered intravenously q4h or by a pump for home therapy.

Oxacillin

Well-established agent for serious systemic S. aureus infections (not MRSA). No dose adjustment for renal failure. The main toxicity is the elevation of hepatic enzymes. The agent is administered intravenously q4h or by a pump for home therapy.

Piperacillin/tazobactam

Activity against MSSA and other Gram+ organisms (not MRSA) as well as most Gram (-) organisms. Useful for broad-spectrum empiric therapy when MSSA, streptococcus, enterococcus, Gram (-), and anaerobic coverage is desirable. Not generally recommended for S. aureus bacteremia or endocarditis due to lack of robust clinical data, but probably would work if not expressing BlaC. [J Antimicrob Chemo 1993;Suppl A 97-104, bacteremia 15/17 cured, 2 failures ascribed to lack of source control] [7].

Quinupristin/dalfopristin

Combination streptogramin antibiotic is active against MRSA and Vancomycin-resistant Enterococcus faecium. E. faecalis is intrinsically resistant. Not FDA approved for S. aureus bacteremia. Must be given IV via a central line because of phlebitis risk. Other side effects are severe arthralgia and myalgia. Has a variety of drug-drug interactions mediated via the cytochrome P450 system. No dose adjustment is required for renal or hepatic insufficiency.

Rifampin

Excellent bactericidal agent against S. aureus but SHOULD NEVER BE USED AS MONOTHERAPY because of the rapid development of resistance. Can be used in combination with fluoroquinolones, TMP/SMX, clindamycin, or minocycline after a course of appropriate IV therapy for complicated bone and joint infections requiring long-term therapy/suppression. Also used as part of combination therapy for PVE. No robust studies have proven beneficial role independently, and some have suggested use equates with poorer outcomes.

Trimethoprim/sulfamethoxazole

A good choice for skin and skin structure infections due to S. aureus, particularly CA-MRSA; poor anti-streptococcal activity. Use compared to vancomycin has been studied in a cohort of injection drug users with MSSA and MRSA infections with good clinical results, particularly with MRSA. Not usually recommended for S. aureus bacteremia or endocarditis except in salvage situations in conjunction with infectious diseases consultation. A recent study of severe S. aureus infection suggested TMP-SMX was not inferior and those receiving had higher mortality compared to vancomycin[18]. Some studies support the treatment of bacteremia, and if so, would use higher dosing (5mg q 8, trimethoprim)[36].

Vancomycin

  • Active against MRSA and MSSA (but less effective so if MSSA, prefer beta-lactam therapy for serious infections).
    • The clinical failure rate is higher for staphylococcal endocarditis treated with vancomycin than with alternate beta-lactam agents. Use is thus reserved for MRSA or for patients with documented severe beta-lactam allergy.
  • Must be given IV (no oral absorption).
  • When using this agent it is prudent to follow serum trough levels (aiming for a trough of 15-20 mcg/ml for serious infections). No single dose should exceed 2g. Loading dose can be considered in patients who are critically ill.
  • Trough concentrations are the most accurate method to guide dosing; obtain after steady-state likely following 4th or 5th dose. For routine SSTI infections, 1g q12h dosing should be adequate.
  • For serious infections, trough suggested 15-20 mcg/mL, with 20 mcg/mL goal if CNS.
    • These trough numbers are through to correlate with an AUC of 400mg*hr/L but reports suggest increased rates of nephrotoxicity.
  • 2020 Vancomycin Guideline suggests instead using AUC/MIC since it is the primary PK/PD target for glycopeptides.
    • The guideline recommends a target AUC between 400 and 600 mg*hour/L for MRSA infections (assuming MIC 1 mg/L)in adults and pediatrics
    • These AUC targets should be achieved early in the course (24-48h).
    • However, barriers including education, lack of resources and costs may limit the uptake of AUC/MIC-based monitoring. Many institutions have remained with vancomycin trough monitoring.
      • Needs include two vancomycin levels within the same dosing interval: first is 1-2h after the end of infusion, the second is 4-6h after one half-life has passed (about 4-6h in patients with normal renal function). These values are needed to calculate a patient-specific elimination rate and volume of distribution. Then a second vancomycin dose may be calculated.
      • A helpful explanation of AUC/MIC monitoring can be found in this link.
    • Note: AUC/MIC monitoring recommendations pulled from MRSA infections; therefore, uncertain how it applies to other pathogens including MSSA.

Linezolid

  • An oxazolidinone antibiotic is available both orally and intravenously with activity against both MSSA and MRSA as well as VRE. No dose alteration is required in renal or hepatic insufficiency.
  • Not FDA approved for S. aureus bacteremia.
  • Side effects include thrombocytopenia, anemia, neutropenia as well as optic neuritis and irreversible peripheral neuropathy. Side effects are more common in patients receiving the drug for > 3 weeks.
  • Because it is a monoamine oxidase inhibitor (MAO-I), it should not be used with MAO-Is and should be used with caution with serotonergic drugs (SSRIs) given case reports of serotonin syndrome. Patients on both drugs should be monitored for mental status changes, myoclonus, diaphoresis and other symptoms of serotonin syndrome. If the concern of serotonin effect may consider instead tedizolid which has a much lower risk of interaction.

Daptomycin

  • A lipopeptide antibiotic FDA approved for MSSA and MRSA bacteremia and right-sided endocarditis and complicated skin and skin structure infections due to MSSA, MRSA, GAS, and VSE.
  • It is inactivated by pulmonary surfactant and cannot be used for pneumonia.
  • The dose is 6 mg/kg/day when used for S. aureus bacteremia or endocarditis and 4 mg/kg/day when used for skin infections. Many experts recommend higher doses (8-10 mg/kg daily) for MRSA bacteremia and endocarditis. Dose reduction required for CrCl < 30mL/min (same doses but administered every other day).
  • The main side effect is myopathy; CK must be checked at least weekly.
  • Cases of the emergence of resistance during therapy have been reported, particularly in patients without source control who have received prior vancomycin; monitor for recurrent positive blood cultures during therapy.

Doxycycline

A good choice for skin and skin structure infections due to S. aureus, particularly CA-MRSA but has poor anti-streptococcal activity. Side effects include photosensitivity (patients should be warned to avoid the sun). Often used for long-term suppressive therapy in orthopedic infections, sometimes in combination with rifampin. Not recommended for S. aureus bacteremia or endocarditis.

Tigecycline

FDA approved for skin and soft tissue infections. Low serum levels make this a drug not typically employed for bacteremia. FDA warning issued based on a review of clinical trials warned of increased mortality with its use.

Telavancin

  • Lipoglycopeptide was initially FDA approved for SSTI on the basis of non-inferiority studies compared to vancomycin. Unclear if lower MRSA MIC of telavancin compared to vancomycin has clinical significance.
  • May cause red man syndrome and should not be used in pregnancy.
  • Maybe slightly more nephrotoxic than vancomycin.
  • After an absence, the drug is now again available in the US.
  • In 2013 FDA approved the drug to be used for HAP but only when other alternatives are not suitable, i.e., not a first-line agent. Concern with the drug is that studies have suggested a substantially higher rate of mortality in patients with diabetes or renal failure compared to those treated with vancomycin.

Ceftaroline

New-generation cephalosporin with MRSA activity as well as Gram-negative spectrum similar to ceftriaxone. FDA approved for CAP and SSTIs, but some clinicians using off-label with success in the treatment of difficult MRSA infections including persistent bacteremia (typically dosed 600mg IV q 8 +/- another agent [e.g., TMP/SMX] in salvage situations).

Tedizolid

Oral and parenteral oxazolidinone FDA approved for short-course therapy (6d) for skin and skin structure infections. Utility for bacteremia or other Gram-positive infections is unclear but has activity against both MSSA and MRSA. Would consider higher dosing 400 mg daily for serious infections if used. The drug has a much lower risk of potential induction of serotonin syndrome compared to linezolid.

Dalbavancin

Long-acting glycopeptide, FDA approved for skin and soft tissue infections. Little data regarding use for bacteremia or other causes.

Oritavancin

Long-acting glycopeptide, FDA approved for skin and soft tissue infections. No data regarding use for bacteremia or other causes.

FOLLOW UP

OTHER INFORMATION

Basis for recommendation

  1. Berbari EF, Kanj SS, Kowalski TJ, et al. Executive Summary: 2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults. Clin Infect Dis. 2015;61(6):859-63.  [PMID:26316526]

    Comment: Guidance document suggesting 6 wks of parenteral or highly bioavailable oral therapy for native (no hardware) vertebral osteomyelitis. First-line choices for MSSA, recs include nafcillin, oxacillin, cefazolin or ceftriaxone. For MRSA, vancomycin or daptomycin.

  2. 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. Circulation. 2015;132(15):1435-86.  [PMID:26373316]

    Comment: Most recent guidelines addressing S, aureus endocarditis.

  3. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis. 2014;59(2):147-59.  [PMID:24947530]

    Comment: The latest set of guidelines from the Infectious Diseases Society of America incorporates recommendations for MRSA infections.

  4. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011;52(3):285-92.  [PMID:21217178]

    Comment: Guidelines looking at the MRSA compendium of diseases with recommendations that also include vancomycin dosing recommendations.

References

  1. 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. Clin Infect Dis. 2020;71(6):1361-1364.  [PMID:32658968]

    Comment: A controversial updating of the 2009 vancomycin guideline that used vancomycin trough monitoring as a surrogate for AUC/MIC. The main issue is employing AUC/MIC curve over 24h, such that these consensus guidelines recommend a ratio of 400-600 mg*hr/L (with the assumption of a MIC of 1 mg/L) to foster clinical efficacy and safety for the treatment of MRSA.

  2. Tong SYC, Lye DC, Yahav D, et al. Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial. JAMA. 2020;323(6):527-537.  [PMID:32044943]

    Comment: Adding a beta-lactam had no improvement in outcomes in this open-label RCT.

  3. Song KH, Jung SI, Lee S, et al. Inoculum effect of methicillin-susceptible Staphylococcus aureus against broad-spectrum beta-lactam antibiotics. Eur J Clin Microbiol Infect Dis. 2019;38(1):67-74.  [PMID:30269181]

    Comment: Among 302 MSSA isolates in this South Korean study representing hospital isolates, 254 (84.1%) were positive for blaZ; types A, B, C and D were 13.6%, 26.8%, 43.4% and 0.3%, respectively. Mean HI MICs of all tested antibiotics were significantly increased and increases in HI MIC of piperacillin/tazobactam (HI, 48.14 ± 4.08 vs. SI, 2.04 ± 0.08 mg/L, p <  0.001) and ampicillin/sulbactam (HI, 24.15 ± 1.27 vs. SI, 2.79 ± 0.11 mg/L, p <  0.001) were most prominent. No MSSA isolates exhibited meropenem InE, and few isolates exhibited cefepime (0.3%) and ceftriaxone (2.3%) InE, whereas 43.0% and 65.9% of MSSA isolates exhibited piperacillin/tazobactam and ampicillin/sulbactam InE, respectively. About 93% of type C blaZ versus 45% of non-type C exhibited ampicillin/sulbactam InE (p <  0.001) and 88% of type C blaZ versus 9% of non-type C exhibited piperacillin/tazobactam InE (p <  0.001). A large proportion of MSSA clinical isolates, especially those positive for type C blaZ, showed marked ampicillin/sulbactam InE and piperacillin/tazobactam.

  4. Rieg S, von Cube M, Kaasch AJ, et al. Investigating the Impact of Early Valve Surgery on Survival in Staphylococcus aureus Infective Endocarditis Using a Marginal Structural Model Approach: Results of a Large, Prospectively Evaluated Cohort. Clin Infect Dis. 2019;69(3):487-494.  [PMID:30346527]

    Comment: Although early valve surgery is advocated by many, this series did not find significant benefit.

  5. Huang SS, Singh R, McKinnell JA, et al. Decolonization to Reduce Postdischarge Infection Risk among MRSA Carriers. N Engl J Med. 2019;380(7):638-650.  [PMID:30763195]

    Comment: Eradication leads to a 30% reduction in MRSA infection using chlorhexidine washes and nasal mupirocin for 5d q month x 6 months. An intestive regimen that may be less effective in the real world.

  6. Li HK, Rombach I, Zambellas R, et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med. 2019;380(5):425-436.  [PMID:30699315]

    Comment: Landmark trial suggests non-inferiority with use of 1 wk IV then oral therapy for pathogens causing osteomyelitis or joint infections including prosthetic, compared to all IV. Few MRSA infections though in this study from the UK. S. aureus accounted for 37.7% of all identified organisms in this 1054 patient study.

  7. Iversen K, Ihlemann N, Gill SU, et al. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. N Engl J Med. 2019;380(5):415-424.  [PMID:30152252]

    Comment: The POET study explored converting to oral therapy to complete six weeks of therapy in stable patients with left-sided endocarditis. All patients in the oral arm received at least 10d of IV therapy. Non-inferiority was demonstrated with primary outcome all-cause mortality/unplanned cardiac surgery, emboli or relapse of bacteremia. The primary composite outcome occurred in 24 patients (12.1%) in the intravenously treated group and in 18 (9.0%) in the orally treated group (between-group difference, 3.1 percentage points; 95% confidence interval, -3.4 to 9.6; P=0.40), which met noninferiority criteria.

  8. Carr DR, Stiefel U, Bonomo RA, et al. A Comparison of Cefazolin Versus Ceftriaxone for the Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia in a Tertiary Care VA Medical Center. Open Forum Infect Dis. 2018;5(5):ofy089.  [PMID:30568987]

    Comment: A small study from the VA; however, out of 71 patients, 38 received treatment with cefazolin and 33 with ceftriaxone. The overall rate of treatment failure was 40.8%, with significantly more failures among patients receiving ceftriaxone (54.5% versus 28.9%; P = .029). CTX is often used for convenience compared to more frequently dosed beta-lactams. This study gives some pause to the CTX-convenience approach.

  9. Nambiar K, Seifert H, Rieg S, et al. Survival following Staphylococcus aureus bloodstream infection: A prospective multinational cohort study assessing the impact of place of care. J Infect. 2018;77(6):516-525.  [PMID:30179645]

    Comment: Among different hospitals, mortality rates among the pooled 1851 patients with a median age of 66 years (64% male) were analyzed. Crude 90-day mortality differed significantly between hospitals (range 23-39%) which authors attributed to many factors.

  10. Holland TL, Raad I, Boucher HW, et al. Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial. JAMA. 2018;320(12):1249-1258.  [PMID:30264119]

    Comment: Randomized trial of 509 adults with staphylococcal bacteremia, use of an algorithm compared with usual care resulted in a clinical success rate of 82.0% vs 81.5%, respectively--showing little difference and similar serious adverse events occurred in 32.5% vs 28.3% of patients, a difference that was not statistically significant but with wide confidence intervals. The trial used 14 +/- 2 d for short course vs. 28-42 days for complicated. The trial suggests that staphylococcal bacteremia can be treated by the algorithm if diagnostic and therapeutic recommendations are followed. An interesting sidebar is in the uncomplicated, short-course group, the failure rate was 25-30%.

  11. Daum RS, Miller LG, Immergluck L, et al. A Placebo-Controlled Trial of Antibiotics for Smaller Skin Abscesses. N Engl J Med. 2017;376(26):2545-2555.  [PMID:28657870]

    Comment: The trial suggests that the use of either clindamycin or TMP/SMX improves outcomes in patients with I&D, compared to I&D alone for abscesses that traditionally had only been drained.

  12. Talan DA, Mower WR, Krishnadasan A, et al. Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. N Engl J Med. 2016;374(9):823-32.  [PMID:26962903]

    Comment: Rather surprising results from this study are in contrast to the "no antibiotic needed" dogma for uncomplicated, drained S aureus abscesses. Study suggested higher cure rates in 507 of 630 participants (80.5%) in the trimethoprim-sulfamethoxazole group versus 454 of 617 participants (73.6%) in the placebo group (difference, 6.9 percentage points; 95% confidence interval [CI], 2.1 to 11.7; P=0.005).

  13. Walters MS, Eggers P, Albrecht V, et al. Vancomycin-Resistant Staphylococcus aureus - Delaware, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(37):1056.  [PMID:26402026]

    Comment: Reasons for the limited development of VRSA are unclear (compared to enterococci); however, only 14 isolates described since 2001. The last four have been from the state of Delaware.

  14. Paul M, Bishara J, Yahav D, et al. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: randomised controlled trial. BMJ. 2015;350:h2219.  [PMID:25977146]

    Comment: For those with severe infections including bacteremia especially, TMP/SMX did not achieve non-inferiority compared to vancomycin. Multivariable logistic regression had trimethoprim-sulfamethoxazole significantly associated with treatment failure (adjusted odds ratio 2.00, 1.09 to 3.65). The 30-day mortality rate was 32/252 (13%), with no significant difference between arms. Among patients with bacteremia, 14/41 (34%) treated with trimethoprim-sulfamethoxazole and 9/50 (18%) with vancomycin died (risk ratio 1.90, 0.92 to 3.93).

  15. Miller LG, Daum RS, Creech CB, et al. Clindamycin versus trimethoprim-sulfamethoxazole for uncomplicated skin infections. N Engl J Med. 2015;372(12):1093-103.  [PMID:25785967]

    Comment: As TMP/SMX is often thought of as better staph than strep agent, this study found no difference between clindamycin or TMP/SMX in those with either abscess, cellulitis or mixed infection. This suggests that fretting about choices if more cellulitic vs. abscess scenarios is not necessary for those with mild-moderate infections.

  16. del Río A, Gasch O, Moreno A, et al. Efficacy and safety of fosfomycin plus imipenem as rescue therapy for complicated bacteremia and endocarditis due to methicillin-resistant Staphylococcus aureus: a multicenter clinical trial. Clin Infect Dis. 2014;59(8):1105-12.  [PMID:25048851]

    Comment: Available in some European and other countries, this small study examined S aureus bacteremia or endocarditis and found that fosfomycin [2g IV q 6] + imipenem appeared to be helpful in those failing regimens including vancomycin, daptomycin and others. The success rate was 69% of the 16 patients.

  17. Kaasch AJ, Barlow G, Edgeworth JD, et al. Staphylococcus aureus bloodstream infection: a pooled analysis of five prospective, observational studies. J Infect. 2014;68(3):242-51.  [PMID:24247070]

    Comment: Five cohorts of S. aureus bacteremia with adjusted HR mortality in this group of 3346 with 30d mortality = 21%, 90d mortality = 29%.

  18. Pallin DJ, Binder WD, Allen MB, et al. Clinical trial: comparative effectiveness of cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: a randomized controlled trial. Clin Infect Dis. 2013;56(12):1754-62.  [PMID:23457080]

    Comment: Interestingly this trial did not suggest that adding an agent with activity against CA-MRSA (TMP/SMX) did not substantially improve outcomes [82% cephalexin alone, 85% combination]. This suggests that MRSA is not a typical driver of cellulitis in the absence of purulence.

  19. Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012;54(5):621-9.  [PMID:22247123]

    Comment: A fairly large trial in a difficult to study condition. RCT examined linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) x 7-14d. Enrolled pts numbered 1184, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). However, all-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was the incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%). This study suggests that the PK/PD elements favoring linezolid may in fact have clinical efficacy favorable over vancomycin but the larger 60d picture is not telling. For the very ill with the potential for added complications such as renal failure, linezolid may be the better option.

  20. Vos FJ, Kullberg BJ, Sturm PD, et al. Metastatic infectious disease and clinical outcome in Staphylococcus aureus and Streptococcus species bacteremia. Medicine (Baltimore). 2012;91(2):86-94.  [PMID:22391470]

    Comment: A study of 115 patients with staph or strep bacteremia using FDG-PET/CT technology looking for metastatic infections found foci in 84 of 115 (73%) patients: endocarditis (22 cases), endovascular infections (19 cases), pulmonary abscesses (16 cases), and spondylodiscitis (11 cases) were diagnosed most frequently. Signs or symptoms directing a diagnostic work-up were only present in 41%, suggesting that additional studies may be helpful even in absence of specific findings: for example in this study PET was the first to detect problems in 30%.

  21. van Hal SJ, Paterson DL, Gosbell IB. Emergence of daptomycin resistance following vancomycin-unresponsive Staphylococcus aureus bacteraemia in a daptomycin-naïve patient--a review of the literature. Eur J Clin Microbiol Infect Dis. 2011;30(5):603-10.  [PMID:21191627]

    Comment: One of many papers shows that daptomycin resistance may develop while on vancomycin therapy in patients with persistent bacteremia. It appears that the MRSA organisms may develop thicker cell walls, and hence be more resistant to daptomycin.

  22. Thwaites GE, Edgeworth JD, Gkrania-Klotsas E, et al. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis. 2011;11(3):208-22.  [PMID:21371655]

    Comment: Important to note that only 16 studies with < 1500 patients in RCTs form a basis for guidance in this difficult infection. Authors rightly point out that many guideline recommendations are based on observational or limited case studies. Key questions that remain to be answered in their opinion include 1) How should SAB be defined?, 2) Is identification and removal of infection focus important? 3) Should all SAB pts have echocardiography? 4) Are glycopeptides equivalent to beta-lactams? 5) Are cephalosporins equivalent to penicillins?, 6) Is teicoplanin as effective as vancomycin? 7) What is the optimum duration of treatment for SAB? 8) Is oral therapy equivalent to parenteral? 9) Is combination therapy better than monotherapy? 10) what is the role of linezolid, daptomycin and newer antimicrobials?
    Rating: Important

  23. Dhand A, Bayer AS, Pogliano J, et al. Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding. Clin Infect Dis. 2011;53(2):158-63.  [PMID:21690622]

    Comment: Authors were able to clear persistent bacteremia in 7 pts with a combination of daptomycin and oxacillin or nafcillin (2g IV q4h) in seven patients. The mechanism is not entirely clear but may be due to enhanced membrane binding of daptomycin in the presence of the beta-lactam.

  24. Simor AE. Staphylococcal decolonisation: an effective strategy for prevention of infection? Lancet Infect Dis. 2011;11(12):952-62.  [PMID:22115070]

    Comment: Best data regarding decolonization efficacy exists in pre-surgical patients and those on dialysis. Efficacy for decreasing CA-MRSA recurrent infections doesn’t yet exist in a robust fashion.
    Rating: Important

  25. Cosgrove SE, Vigliani GA, Fowler VG, et al. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis. 2009;48(6):713-21.  [PMID:19207079]

    Comment: Evidence for nephrotoxicity associated with short course synergy dose gentamicin in the treatment of S. aureus bacteremia and endocarditis.

  26. Figueroa DA, Mangini E, Amodio-Groton M, et al. Safety of high-dose intravenous daptomycin treatment: three-year cumulative experience in a clinical program. Clin Infect Dis. 2009;49(2):177-80.  [PMID:19500039]

    Comment: A single-center study evaluating the safety of higher doses of daptomycin.
    Rating: Important

  27. Fowler VG, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355(7):653-65.  [PMID:16914701]

    Comment: A landmark ID publication demonstrates that daptomycin is not inferior to standard therapy in the treatment of S. aureus bacteremia and right-sided endocarditis. Unfortunately, few companies or other agencies will fund trials of this size and complexity for evaluating antibiotic treatment of endocarditis.
    Rating: Important

  28. von Eiff C, Becker K, Machka K, et al. Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group. N Engl J Med. 2001;344(1):11-6.  [PMID:11136954]

    Comment: A German study indicates that S. aureus bacteremia appears to frequently be caused by strains of S. aureus colonizing the patient’s own nasal mucosa. An accompanying editorial emphasizes the importance of attempting to eradicate this colonization in order to control nosocomial infections but highlights the failure of most currently used agents to achieve this goal (N Engl J Med 2001; 344: 55-57)

  29. Fowler VG, Li J, Corey GR, et al. Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: experience in 103 patients. J Am Coll Cardiol. 1997;30(4):1072-8.  [PMID:9316542]

    Comment: A study demonstrated the presence of endocarditis in 25% of patients with S. aureus bacteremia when evaluated with TEE.
    Rating: Important

  30. Heldman AW, Hartert TV, Ray SC, et al. Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy. Am J Med. 1996;101(1):68-76.  [PMID:8686718]

    Comment: A study comparing standard therapy for right-sided endocarditis to oral ciprofloxacin and rifampin for 4 weeks demonstrates the efficacy of the oral regimen. This JH-based study never received widespread adoption due to the concern that FQ-based treatment could lead to the quick emergence of resistance.

  31. DiNubile MJ. Short-course antibiotic therapy for right-sided endocarditis caused by Staphylococcus aureus in injection drug users. Ann Intern Med. 1994;121(11):873-6.  [PMID:7978701]

    Comment: A review of the option of shorter course antibiotic therapy for right-sided heart infections in injection drug users.

  32. Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Ann Intern Med. 1992;117(5):390-8.  [PMID:1503330]

    Comment: A study of 101 injection drug users with S. aureus infection of whom 65% were bacteremic. The success rate for therapy of MRSA infections was equivalent for the TMP-SMX and vancomycin groups, although vancomycin was marginally more successful as a therapy in the non-MRSA group. The authors thus suggest that TMP-SMX may be a viable alternative to vancomycin for MRSA infection in this group of patients. Failures with TMP/SMX were seen only in the group with endocarditis but not those with straight (or supposedly straight) bacteremia.
    Rating: Important

  33. Tranter HS. Foodborne staphylococcal illness. Lancet. 1990;336(8722):1044-6.  [PMID:1977028]

    Comment: A review of GI tract infections caused by ingestion of certain toxin-producing strains of S. aureus.

  34. Lee BK, Crossley K, Gerding DN. The association between Staphylococcus aureus bacteremia and bacteriuria. Am J Med. 1978;65(2):303-6.  [PMID:686015]

    Comment: The classic paper describes the presence of S. aureus bacteriuria in 27% of patients with S. aureus bacteremia in the absence of obvious renal infection.

Media

S. aureus

Typical Gram Positive appearance, often with organisms in grape-like clusters.

Source: CDC

Staphylococcal boil

Typical boil or furuncle (soft tissue abscess) draining pus which grew S. aureus.

Source: CDC

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