INTRODUCTION — Issues related to treatment of bacteremia in adults caused by methicillin-resistant Staphylococcus aureus (MRSA) will be reviewed here.
General issues related to S. aureus bacteremia are discussed further separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults".)
Other issues related to MRSA are discussed further separately:
Issues related to management of patients with infection due to S. aureus with reduced vancomycin susceptibility are discussed in detail separately. (See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)
Antibiotics for the treatment of invasive MRSA infections are summarized in the table (table 1). Vancomycin or daptomycin are the agents of choice for treatment of invasive MRSA infections . The optimal approach to the use of other agents with activity against MRSA is unclear; further study is needed. Considerations in selecting an alternative agent include baseline susceptibility testing prior to antibiotic administration and individual patient circumstances (including the type of infection, underlying comorbidities, allergies or drug intolerance, and concurrent medications). Vancomycin susceptibility is an important issue in the decision-making process.
Patients with an S. aureus infection due to an isolate with a vancomycin MIC ≥2 mcg/mL may not respond to therapy as well as those with infection due to an isolate with a lower MIC. In such cases, poor clinical response to vancomycin therapy should prompt use of daptomycin or another agent. (See 'Borderline vancomycin susceptibility' below and "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)
Inappropriate drugs for monotherapy of MRSA bacteremia include fluoroquinolones, trimethoprim-sulfamethoxazole (TMP-SMX), and tigecycline [3-7]. In a randomized trial including 91 patients with MRSA bacteremia treated with high-dose TMP-SMX or vancomycin, high-dose TMP-SMX did not achieve non-inferiority .
MANAGEMENT OF MRSA BACTEREMIA — Treatment of MRSA bacteremia consists of prompt source control (such as removal of implicated vascular catheters and/or drainage of purulent collections if present); this is crucial for a successful therapeutic outcome. Prompt initiation of appropriate antimicrobial therapy is also important. Decisions regarding continuation of antibiotic therapy are in large part determined by the initial clinical response. Issues related to antibiotic selection for treatment of MRSA bacteremia are discussed below.
General issues related to evaluation and management of S. aureus bacteremia and the duration of antibiotic therapy (which depends on the source of infection) are discussed in detail separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults".)
Issues related to treatment of MRSA endocarditis are discussed separately. (See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Methicillin resistant' and "Antimicrobial therapy of prosthetic valve endocarditis", section on 'Staphylococci'.)
Initial antibiotic therapy — Issues related to empiric treatment of S. aureus bacteremia (prior to the availability of susceptibility data) are discussed separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Empiric treatment'.)
Vancomycin susceptibility breakpoints — Vancomycin MIC breakpoints for S. aureus are defined as follows (preferably determined by E-tests): susceptible = MIC ≤2 mcg/mL, intermediate = MIC 4 to 8 mcg/mL, and resistant = MIC ≥16 mcg/mL . The European Committee on Antimicrobial Susceptibility Testing (EUCAST) vancomycin breakpoints for S. aureus are as follows: susceptible = MIC ≤2 mg/L and resistant = MIC >2 mg/L. (See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)
Vancomycin susceptible isolates — For initial treatment of a documented MRSA bacteremia, we are in agreement with the 2011 guidelines issued by the Infectious Diseases Society of America (IDSA), which recommend vancomycin or daptomycin (table 1) . Vancomycin is the agent for which there is the greatest cumulative clinical experience for the treatment of MRSA bacteremia. Due to risk of nephrotoxicity, vancomycin requires serum concentration monitoring, particularly in the setting of renal dysfunction. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults".)
Daptomycin is an acceptable alternative to vancomycin for treatment of MRSA bacteremia, particularly in the setting of known or suspected high vancomycin minimum inhibitory concentration (MIC >1 mcg/mL); it is more costly than vancomycin and is associated with myopathy, so it requires serum creatine kinase monitoring [2,8-11].
In areas where teicoplanin is available, some use it as the drug of choice for initial therapy of S. aureus bacteremia, while others favor its use for patients intolerant to vancomycin . The optimal approach to use of the relatively new agents with activity against MRSA (eg, telavancin, ceftaroline, oritavancin, dalbavancin, delafloxacin) for treatment of bacteremia is uncertain; further study is needed.
Combination therapy with beta-lactam agents lacking activity against MRSA are not recommended [13,14]. In a randomized trial including more than 300 patients with MRSA bacteremia, addition of an antistaphylococcal beta-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) to standard antibiotic therapy (intravenous vancomycin or daptomycin) was not associated with significant improvement in the primary composite end point of 90-day mortality, persistent bacteremia at day 5, relapse, or treatment failure (absolute difference -4.2%, 95% CI -14.3 to 6.0 percent) . A majority of patients received vancomycin with or without an antistaphylococcal penicillin. Nephrotoxicity occurred more frequently among patients treated with combination therapy (23 versus 6 percent), primarily in those receiving flucloxacillin or cloxacillin, leading to early termination of the trial. Further study of combination therapy with daptomycin and ceftaroline is needed [15-17].
Combination therapy with vancomycin and gentamicin or rifampin has also been associated with adverse effects; vancomycin-gentamicin has been associated with an increased risk of nephrotoxicity , and vancomycin-rifampin has been associated with hepatic adverse effects, drug interactions, and emergence of rifampin resistance [19,20].
Borderline vancomycin susceptibility
Some studies suggest a worse clinical outcome associated with vancomycin therapy for infection due to MRSA with vancomycin MIC ≥2 mcg/mL [21-27], while others do not [28-31]. One meta-analysis observed increased mortality among patients with MRSA bacteremia treated with vancomycin when the vancomycin MIC was ≥2 mcg/mL (by E-test; odds ratio [OR] 1.7, 95% CI 1.3-2.2); increased mortality was not observed in cases with vancomycin MIC ≤1.5 mcg/mL . However, a subsequent meta-analysis of patients with S. aureus bacteremia found no difference in mortality between patients whose isolate had high vancomycin MIC (≥1.5 mg/L) and those whose isolate had low vancomycin MIC (<1.5 mg/L) . In addition, a prospective cohort study including 429 patients with S. aureus bacteremia noted that there was no association between vancomycin MIC and 30- or 90-day mortality .
Clinical failures have been reported in patients without evidence of vancomycin resistance ; some of these failures have occurred in patients with heteroresistant infection (in which subpopulations of organisms have higher vancomycin MICs, although it is uncertain whether heteroresistance is a cause of vancomycin treatment failure) . (See "Overview of antibacterial susceptibility testing", section on 'Heteroresistance'.)
A retrospective cohort study including 170 patients with MRSA bacteremia with vancomycin MICs 1.5 to 2 mcg/mL compared the efficacy of vancomycin with daptomycin . Vancomycin was associated with a higher rate of treatment failure (24 versus 11 percent) and a higher rate of renal complications (23 versus 9 percent).
There may be other factors (apart from vancomycin MIC) that contribute to clinical outcome; in one study including 532 patients with S. aureus bacteremia, those with infection due to strains with vancomycin MIC (by E-test) >1.5 mcg/mL had poorer outcomes than those infected with strains with vancomycin MIC ≤1.5 mcg/mL ; the outcome was independent of the methicillin susceptibility and whether the patients were treated with vancomycin or a beta-lactam.
●General principles −- In general, if the vancomycin MIC approaches the limit of the susceptible range (2 mcg/mL) and there is a poor initial clinical response (eg, persistent bacteremia), vancomycin should be discontinued and treatment switched to daptomycin [35-37]. Combination therapy is an alternative approach; some investigators support the use of initial combination therapy in high-risk patients, including those with endovascular infections, end-stage renal disease, or signs of sepsis.
For patients with infection due to S. aureus isolates approaching the limit of the susceptible range (2 mcg/mL) who are not responsive to or are intolerant of vancomycin and daptomycin, there are several potential alternative approaches. In such circumstances, the approach to antibiotic selection is uncertain; definitive trials are lacking. It is unknown whether combination therapy or monotherapy is warranted [38,39].
•Supporting evidence − Early adjustment of treatment from vancomycin to daptomycin is supported by a retrospective study including more than 7400 patients with MRSA bacteremia in which the 30-day survival was superior among patients switched from vancomycin to daptomycin within three days of treatment onset (hazard ratio [HR] 0.48; 95% CI 0.25-0.92); the survival advantage did not persist beyond this early window [40,41].
•Susceptibility testing − Caution is required when treating S. aureus infection with daptomycin in the setting of vancomycin failure; infrequently, S. aureus nonsusceptibility to daptomycin has been observed when bacteremia has persisted in spite of vancomycin therapy . Therefore, repeat testing of the S. aureus isolate associated with vancomycin failure should be performed to ensure daptomycin susceptibility. In addition, breakthrough staphylococcal bacteremia in patients treated with daptomycin may reflect emergence of daptomycin nonsusceptibility in the infecting isolate; this possibility should be evaluated by performing susceptibility studies on the breakthrough isolate.
●Use of combination antibiotic therapy – As noted above, the optimal approach to use of combination antibiotic therapy for treatment of MRSA bacteremia is uncertain. Possible combination regimens include [37,38]:
Data supporting use of combination therapy are discussed below. (See 'Persistent bacteremia: Salvage therapy' below.)
●Alternative monotherapy regimens − Possible monotherapy regimens include telavancin, ceftaroline, and linezolid [53-55]. Telavancin monotherapy may prove effective for treatment of MRSA bacteremia (thus far, data are limited); in a phase II trial of telavancin for treatment of bacteremia including 17 patients, cure rates were comparable for telavancin and standard therapy (88 versus 89 percent) [55,56].
Dalbavancin and oritavancin are long-acting lipoglycopeptides; data on these agents for the treatment of MRSA bacteremia are limited as are data on ceftaroline monotherapy [46,53]. Linezolid and tedizolid are bacteriostatic (vancomycin, daptomycin, ceftaroline, and telavancin are bactericidal), and toxicity limits prolonged use .
●Vancomycin-intermediate and vancomycin-resistant isolates − The approach to treatment of S. aureus bacteremia caused by isolates with vancomycin MIC ≥4 is discussed separately. (See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin", section on 'Infection due to VISA or VRSA'.)
Follow-up blood cultures — After initiation of treatment for MRSA bacteremia, blood cultures should be repeated to document clearance of bacteremia. Persistent bacteremia (ie, >2 to 3 days) has been associated with increased morbidity and mortality [57-59].
Failure to clear bacteremia within 48 hours after initiation of therapy should prompt further evaluation as follows:
●Clinical evaluation for occult focus of infection that may require drainage. Persistent foci of infection (such as a deep-seated bone infection, abscess, retained prosthetic device, or endovascular source of infection) should be eliminated if feasible.
●Careful review of antibiotic susceptibility data; antibiotic susceptibility studies should be performed on the breakthrough isolate.
Repeated isolation of S. aureus from normally sterile sites despite seemingly appropriate therapy should prompt suspicion for emergence of an S. aureus isolate with reduced susceptibility to vancomycin during therapy, even if the MIC of the original isolate was within the susceptible range [21,60-62].
Suspected antibiotic failure should prompt antibiotic adjustment at three days of persistent bacteremia [2,35,36,38,57]. The approach is as described above for borderline vancomycin susceptibility. (See 'Borderline vancomycin susceptibility' above.)
Issues related to management of infection due to S. aureus isolates with vancomycin MIC >2 are discussed separately. (See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)
Persistent bacteremia: Salvage therapy — Patients with persistent MRSA bacteremia (2 to 3 days) are at increased risk of metastatic infections and death [57,58]. In these patients, we favor combination therapy with daptomycin (dosed at 8 to 10 mg/kg rather than 6 mg/kg intravenously daily) and ceftaroline [37,43,46].
This approach is supported by several studies [15-17,43,46,48,49]. In one small case series that included 26 patients whose MRSA isolates had diminished daptomycin susceptibility, after persistent bacteremia for a median of 10 days on previous antimicrobial therapy, the median time to clearance of bacteremia with daptomycin and ceftaroline was two days . Another report noted enhanced bactericidal activity in vitro with combination therapy using daptomycin and ceftaroline .
DRUGS WITH ACTIVITY AGAINST MRSA
Antibiotics of choice
Vancomycin — Vancomycin is a bactericidal glycopeptide antibiotic that inhibits cell wall synthesis; it is the antibiotic agent for which there is the greatest cumulative clinical experience for treatment of bacteremia caused by MRSA. Tissue penetration is highly variable and depends on the degree of inflammation [63-65].
Vancomycin has a relatively good safety profile and favorable pharmacokinetics that facilitate convenient administration [66,67]. Monitoring vancomycin levels is necessary due to the risk of nephrotoxicity. Dosing is discussed separately. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults".)
Vancomycin kills staphylococci more slowly than do beta-lactam antibiotics in vitro and is clearly inferior to beta-lactams for treatment of methicillin-susceptible S. aureus bacteremia and infective endocarditis [23,68-72].
Alternatives to vancomycin should be considered in the setting of adverse effects due to vancomycin or infection with a pathogen with nonsusceptibility to vancomycin.
Dosing for bloodstream infections (as approved by the US Food and Drug Administration) consists of 6 mg/kg intravenously (IV) once daily; some experts favor doses of 8 to 10 mg/kg IV once daily. These higher doses may be warranted in critically ill patients [75,76].
Daptomycin was demonstrated to be noninferior to an antistaphylococcal penicillin or vancomycin plus low-dose gentamicin for treatment of S. aureus bacteremia in a trial including 246 patients with S. aureus bacteremia (89 patients with MRSA bacteremia) . At the time of the trial, the comparator regimen was standard of care; however, synergistic aminoglycosides are no longer routinely used for treatment of S. aureus infection given their association with renal dysfunction. A successful outcome was observed for 44 percent of patients who received daptomycin and 42 percent of patients who received antistaphylococcal penicillin or vancomycin plus low-dose gentamicin (absolute difference 2.4 percent; 95% CI -10.2 to 15.1 percent).
Some retrospective studies suggest that outcomes of MRSA bacteremia may be improved with early switching from vancomycin to daptomycin (within three days of treatment onset) for definitive therapy, especially if treatment failure is suspected [40,41]; this warrants further study.
Daptomycin should not be used for treatment of MRSA bacteremia associated with pneumonia. (See "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Methicillin-resistant S. aureus'.)
The daptomycin minimum inhibitory concentration may increase during therapy and may be influenced by prior exposure to vancomycin . Therefore, daptomycin susceptibility testing must be performed prior to therapy and repeated in the event of positive cultures obtained during therapy, particularly if prolonged therapy is administered and/or there is microbiological evidence of persistent infection during therapy .
Adverse effects associated with daptomycin include myopathy, peripheral neuropathy, and eosinophilic pneumonia . Serial measurements of serum creatine kinase should be monitored at least weekly, and daptomycin should be discontinued in patients with symptomatic myopathy and creatine phosphokinase (CPK) ≥5 times the upper limit of normal (ULN) or in asymptomatic patients with CPK ≥10 times the ULN. (See "Daptomycin: An overview".)
A retrospective review of patients treated with daptomycin reported that coadministration of daptomycin with statins may be associated with myopathy and rhabdomyolysis . Discontinuation of statin therapy during daptomycin administration, especially when therapy will be prolonged (≥14 days), may be prudent, unless there is a compelling need to continue statin therapy (such as a recent cardiovascular event).
Teicoplanin (in areas where available) — Teicoplanin is a bacteriostatic glycopeptide with similar spectrum of activity and efficacy as vancomycin [80,81]. It has a longer half-life than vancomycin and can be administered once daily with more rapid infusion rates than vancomycin. It can also be given intramuscularly.
Teicoplanin tends to be better tolerated than vancomycin. In one meta-analysis including 1276 patients, the efficacy of teicoplanin and vancomycin was similar, but there were significantly fewer episodes of vancomycin infusion reaction and other adverse events in patients treated with teicoplanin (14 versus 21 percent) . Another meta-analysis noted a lower risk of nephrotoxicity with teicoplanin than with vancomycin .
Teicoplanin is not available in the United States. In areas where it is available, some favor its use for patients with intolerance to vancomycin, while others use it as the drug of choice for initial therapy of gram-positive pathogens .
Ceftaroline — Ceftaroline is a fifth-generation cephalosporin administered as a prodrug whose active metabolite has bactericidal activity against MRSA and vancomycin-intermediate S. aureus (VISA) as well as some gram-negative pathogens . Ceftaroline has in vitro activity against staphylococci, with reduced susceptibility to vancomycin, daptomycin, or linezolid .
Data for use of ceftaroline for treatment of MRSA bacteremia are limited to small retrospective case series [53,85-87]. For treatment of bacteremia, we favor administration of ceftaroline every 8 hours (table 1), which is more frequent than dosing for other indications such as pneumonia or skin and skin structure infections [87,88].
Prolonged use of ceftaroline has been associated with neutropenia; monitoring of hematologic parameters is warranted for patients taking ceftaroline >7 days . In addition, ceftaroline has been associated with encephalopathy in patients with severe kidney impairment .
Telavancin — Telavancin is a semisynthetic lipoglycopeptide that inhibits cell wall synthesis and disrupts cell membrane permeability [91-95]. It is bactericidal against MRSA, VISA, and vancomycin-resistant S. aureus. It has a half-life of seven to nine hours, permitting once-daily dosing. Telavancin should be avoided in patients at risk for nephrotoxicity. Telavancin has a higher rate of toxicity than vancomycin (including taste disturbance, nausea, vomiting, and renal dysfunction) and has been associated with teratogenicity. There is increasing experience with the use of telavancin in treating a variety of infections .
Dalbavancin and oritavancin — Dalbavancin and oritavancin are long-acting lipoglycopeptides; data on these agents for treatment of MRSA bacteremia are limited . One study reported success using dalbavancin as follow-up therapy for serious staphylococcal infections in people who inject drugs .
Linezolid and tedizolid — Linezolid is a bacteriostatic oxazolidinone that inhibits initiation of protein synthesis at the 50S ribosome [99,100]. This drug class may have enhanced efficacy against strains producing toxins such as Panton-Valentine leukocidin, alpha-hemolysin, and toxic shock syndrome toxin 1 [101-103]. Tedizolid is a newer drug in the same class as linezolid; data on its efficacy for treatment of MRSA bacteremia are limited. Linezolid and tedizolid are bacteriostatic (vancomycin, daptomycin, ceftaroline, and telavancin are bactericidal), and toxicity limits prolonged use . (See "Linezolid and tedizolid (oxazolidinones): An overview".)
Among 220 adults with MRSA infection, linezolid and vancomycin had equivalent clinical cure rates overall (73 percent) and in the subgroup with MRSA bacteremia (56 and 50 percent, respectively) . Linezolid resistance and linezolid failure have been described [105-109].
Linezolid resistance has been observed among methicillin-resistant S. aureus isolates. The mechanism appears to be via the bacterial cfr gene, which resides in a potentially mobile genetic element . Clinical outbreaks of linezolid-resistant S. aureus have been described; reduction of linezolid use and infection control measures were associated with termination of the outbreaks [108,110].
Safety concerns limit the extended use of linezolid. Adverse effects include thrombocytopenia, anemia, lactic acidosis, peripheral neuropathy, serotonin toxicity, and ocular toxicity [111-113]. Linezolid can reversibly inhibit monoamine oxidase; when administered with serotonergic agents (particularly selective serotonin reuptake inhibitors), it can induce the serotonin syndrome (table 2) [114,115]. (See "Serotonin syndrome (serotonin toxicity)".)
Thrombocytopenia appears to occur more frequently with more prolonged therapy and in the setting of end-stage kidney disease and typically resolves after discontinuation of the drug . Peripheral neuropathy and lactic acidosis appear to occur more frequently in the setting of prolonged linezolid administration and may not resolve after drug discontinuation [112,113].
Investigational agents — Bacteriophages and endolysins are being studied for the treatment of serious MRSA infections . In one proof of concept study, including 43 patients with MRSA bacteremia/endocarditis, patients were randomly assigned to receive standard of care (SOC) or SOC plus a single infusion of exebacase (an antistaphylococcal lysin), the 14-day clinical response rate was higher in the exebacase group (74 versus 31 percent) .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Staphylococcus aureus infection".)
SUMMARY AND RECOMMENDATIONS
●Treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia consists of prompt source control (such as removal of implicated vascular catheters and/or drainage of purulent collection if present) and prompt initiation of appropriate antimicrobial therapy. (See 'Management of MRSA bacteremia' above.)
●General issues related to evaluation and management of S. aureus bacteremia, empiric treatment of S. aureus bacteremia (prior to the availability of susceptibility data), and duration of antibiotic therapy (which depends on the source of infection) are discussed separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults".)
●We recommend vancomycin or daptomycin for initial antibiotic management of MRSA bacteremia (table 1) (Grade 1B). Vancomycin is the agent for which there is the greatest cumulative clinical experience for the treatment of MRSA bacteremia; it requires serum concentration monitoring, particularly in the setting of renal dysfunction. Daptomycin is an acceptable alternative to vancomycin for treatment of MRSA bacteremia, particularly in the setting of known or suspected high vancomycin minimum inhibitory concentration (MIC >1 mcg/mL); it is costlier than vancomycin and is associated with myopathy (so requires serum creatine kinase monitoring). (See 'Initial antibiotic therapy' above.)
●Several studies suggest a worse clinical outcome associated with vancomycin therapy for infection due to MRSA with vancomycin MIC ≥2 mcg/mL, while others do not. In general, if the vancomycin MIC approaches the limit of the susceptible range (2 mcg/mL) and there is a poor initial clinical response, we suggest that vancomycin be discontinued and therapy switched to daptomycin (table 1) (Grade 2C). (See 'Borderline vancomycin susceptibility' above.)
●MRSA bacteremia may persist in the setting of persistent foci of infection or antibiotic failure. Bacteremia lasting ≥3 days is associated with increased morbidity and mortality. Persistent bacteremia should prompt careful evaluation for persistent foci of infection, as well as careful review of antibiotic susceptibility data. (See 'Follow-up blood cultures' above.)