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Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia

Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia
Author:
Franklin D Lowy, MD
Section Editor:
Denis Spelman, MBBS, FRACP, FRCPA, MPH
Deputy Editor:
Keri K Hall, MD, MS
Literature review current through: Sep 2021. | This topic last updated: Aug 25, 2021.

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:

(See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology".)

(See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Prevention and control".)

(See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".)

(See "Methicillin-resistant Staphylococcus aureus (MRSA): Microbiology".)

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".)

GENERAL PRINCIPLES — Methicillin resistance in S. aureus is defined as an oxacillin minimum inhibitory concentration (MIC) of ≥4 mcg/mL [1].

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 [2]. 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 [7].

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 [2]. 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) [2]. 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 [12]. 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) [13]. 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 [18], and vancomycin-rifampin has been associated with hepatic adverse effects, drug interactions, and emergence of rifampin resistance [19,20].

Borderline vancomycin susceptibility

General principles — Vancomycin MIC breakpoints for S. aureus are summarized above. (See 'General principles' above.)

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 [25]. 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) [28]. 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 [31].

Clinical failures have been reported in patients without evidence of vancomycin resistance [32]; 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) [33]. (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 [34]. 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 [26]; the outcome was independent of the methicillin susceptibility and whether the patients were treated with vancomycin or a beta-lactam.

Clinical approach

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].

Switching from vancomycin to daptomycin  

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 [42]. 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]:

Daptomycin plus ceftaroline [43-49]

Vancomycin plus ceftaroline or other beta-lactams [14,50]

Daptomycin plus trimethoprim-sulfamethoxazole [51]

Ceftaroline plus trimethoprim-sulfamethoxazole [52]

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 [54].

There is no role for use of quinupristin-dalfopristin, tigecycline, or fluoroquinolones for treatment of MRSA bacteremia.

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 [46]. Another report noted enhanced bactericidal activity in vitro with combination therapy using daptomycin and ceftaroline [44].

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.

Daptomycin — Daptomycin is a cyclic lipopeptide antibiotic with concentration-dependent bactericidal activity [73,74]. (See "Daptomycin: An overview".)

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) [77]. 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 [77]. 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 [2].

Adverse effects associated with daptomycin include myopathy, peripheral neuropathy, and eosinophilic pneumonia [78]. 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 [79]. 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) [80]. Another meta-analysis noted a lower risk of nephrotoxicity with teicoplanin than with vancomycin [12].

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 [82].

Alternative agents

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 [83]. Ceftaroline has in vitro activity against staphylococci, with reduced susceptibility to vancomycin, daptomycin, or linezolid [84].

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 [89]. In addition, ceftaroline has been associated with encephalopathy in patients with severe kidney impairment [90].

Ceftobiprole is a newer drug in the same class as ceftaroline; approval by the US Food and Drug Administration is pending.

Lipoglycopeptides

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 [96].

Dalbavancin and oritavancin — Dalbavancin and oritavancin are long-acting lipoglycopeptides; data on these agents for treatment of MRSA bacteremia are limited [97]. One study reported success using dalbavancin as follow-up therapy for serious staphylococcal infections in people who inject drugs [98].

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 [54]. (See "Linezolid and tedizolid (oxazolidinones): An overview".)

Linezolid has excellent tissue distribution and may be administered parenterally or orally (table 1). Monitoring of blood counts and serum chemistries should be performed at least weekly.

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) [104]. 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 [109]. 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 [111]. 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 [116]. 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) [117].

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.)

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  45. Barber KE, Werth BJ, Rybak MJ. The combination of ceftaroline plus daptomycin allows for therapeutic de-escalation and daptomycin sparing against MRSA. J Antimicrob Chemother 2015; 70:505.
  46. Sakoulas G, Moise PA, Casapao AM, et al. Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. Clin Ther 2014; 36:1317.
  47. Mehta S, Singh C, Plata KB, et al. β-Lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives. Antimicrob Agents Chemother 2012; 56:6192.
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  49. Holland TL, Davis JS. Combination Therapy for MRSA Bacteremia: To ß or Not to ß? Clin Infect Dis 2020; 71:11.
  50. Barber KE, Rybak MJ, Sakoulas G. Vancomycin plus ceftaroline shows potent in vitro synergy and was successfully utilized to clear persistent daptomycin-non-susceptible MRSA bacteraemia. J Antimicrob Chemother 2015; 70:311.
  51. Claeys KC, Smith JR, Casapao AM, et al. Impact of the combination of daptomycin and trimethoprim-sulfamethoxazole on clinical outcomes in methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother 2015; 59:1969.
  52. Fabre V, Ferrada M, Buckel WR, et al. Ceftaroline in Combination With Trimethoprim-Sulfamethoxazole for Salvage Therapy of Methicillin-Resistant Staphylococcus aureus Bacteremia and Endocarditis. Open Forum Infect Dis 2014; 1:ofu046.
  53. Polenakovik HM, Pleiman CM. Ceftaroline for meticillin-resistant Staphylococcus aureus bacteraemia: case series and review of the literature. Int J Antimicrob Agents 2013; 42:450.
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  55. Corey GR, Rubinstein E, Stryjewski ME, et al. Potential role for telavancin in bacteremic infections due to gram-positive pathogens: focus on Staphylococcus aureus. Clin Infect Dis 2015; 60:787.
  56. Stryjewski ME, Lentnek A, O'Riordan W, et al. A randomized Phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study. BMC Infect Dis 2014; 14:289.
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  59. Kuehl R, Morata L, Boeing C, et al. Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study. Lancet Infect Dis 2020; 20:1409.
  60. Tenover FC, Moellering RC Jr. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Infect Dis 2007; 44:1208.
  61. Hussain FM, Boyle-Vavra S, Shete PB, Daum RS. Evidence for a continuum of decreased vancomycin susceptibility in unselected Staphylococcus aureus clinical isolates. J Infect Dis 2002; 186:661.
  62. Song JH, Hiramatsu K, Suh JY, et al. Emergence in Asian countries of Staphylococcus aureus with reduced susceptibility to vancomycin. Antimicrob Agents Chemother 2004; 48:4926.
  63. Graziani AL, Lawson LA, Gibson GA, et al. Vancomycin concentrations in infected and noninfected human bone. Antimicrob Agents Chemother 1988; 32:1320.
  64. Lamer C, de Beco V, Soler P, et al. Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients. Antimicrob Agents Chemother 1993; 37:281.
  65. Albanèse J, Léone M, Bruguerolle B, et al. Cerebrospinal fluid penetration and pharmacokinetics of vancomycin administered by continuous infusion to mechanically ventilated patients in an intensive care unit. Antimicrob Agents Chemother 2000; 44:1356.
  66. Choice of antibacterial drugs. Treat Guidel Med Lett 2007; 5:33.
  67. Mohr JF, Murray BE. Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2007; 44:1536.
  68. LaPlante KL, Rybak MJ. Impact of high-inoculum Staphylococcus aureus on the activities of nafcillin, vancomycin, linezolid, and daptomycin, alone and in combination with gentamicin, in an in vitro pharmacodynamic model. Antimicrob Agents Chemother 2004; 48:4665.
  69. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34:1227.
  70. Stryjewski ME, Szczech LA, Benjamin DK Jr, et al. Use of vancomycin or first-generation cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis 2007; 44:190.
  71. Kim SH, Kim KH, Kim HB, et al. Outcome of vancomycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2008; 52:192.
  72. Lodise TP Jr, McKinnon PS, Levine DP, Rybak MJ. Impact of empirical-therapy selection on outcomes of intravenous drug users with infective endocarditis caused by methicillin-susceptible Staphylococcus aureus. Antimicrob Agents Chemother 2007; 51:3731.
  73. Boucher HW, Sakoulas G. Perspectives on Daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 2007; 45:601.
  74. Humphries RM, Pollett S, Sakoulas G. A current perspective on daptomycin for the clinical microbiologist. Clin Microbiol Rev 2013; 26:759.
  75. Falcone M, Russo A, Venditti M, et al. Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis 2013; 57:1568.
  76. 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; 49:177.
  77. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653.
  78. Skiest DJ. Treatment failure resulting from resistance of Staphylococcus aureus to daptomycin. J Clin Microbiol 2006; 44:655.
  79. Dare RK, Tewell C, Harris B, et al. Effect of Statin Coadministration on the Risk of Daptomycin-Associated Myopathy. Clin Infect Dis 2018; 67:1356.
  80. Wood MJ. The comparative efficacy and safety of teicoplanin and vancomycin. J Antimicrob Chemother 1996; 37:209.
  81. Finch RG, Eliopoulos GM. Safety and efficacy of glycopeptide antibiotics. J Antimicrob Chemother 2005; 55 Suppl 2:ii5.
  82. Gemmell CG, Edwards DI, Fraise AP, et al. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother 2006; 57:589.
  83. Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2011; 52:1156.
  84. Sader HS, Flamm RK, Jones RN. Antimicrobial activity of ceftaroline tested against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin from U.S. hospitals, 2008 to 2011. Antimicrob Agents Chemother 2013; 57:3178.
  85. Vazquez JA, Maggiore CR, Cole P, et al. Ceftaroline Fosamil for the Treatment of Staphylococcus aureus Bacteremia Secondary to Acute Bacterial Skin and Skin Structure Infections or Community-Acquired Bacterial Pneumonia. Infect Dis Clin Pract (Baltim Md) 2015; 23:39.
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  87. Cosimi RA, Beik N, Kubiak DW, Johnson JA. Ceftaroline for Severe Methicillin-Resistant Staphylococcus aureus Infections: A Systematic Review. Open Forum Infect Dis 2017; 4:ofx084.
  88. Destache CJ, Guervil DJ, Kaye KS. Ceftaroline fosamil for the treatment of Gram-positive endocarditis: CAPTURE study experience. Int J Antimicrob Agents 2019; 53:644.
  89. Furtek KJ, Kubiak DW, Barra M, et al. High incidence of neutropenia in patients with prolonged ceftaroline exposure. J Antimicrob Chemother 2016; 71:2010.
  90. Martin TCS, Chow S, Johns ST, Mehta SR. Ceftaroline-associated Encephalopathy in Patients With Severe Renal Impairment. Clin Infect Dis 2020; 70:2002.
  91. Pace JL, Krause K, Johnston D, et al. In vitro activity of TD-6424 against Staphylococcus aureus. Antimicrob Agents Chemother 2003; 47:3602.
  92. King A, Phillips I, Kaniga K. Comparative in vitro activity of telavancin (TD-6424), a rapidly bactericidal, concentration-dependent anti-infective with multiple mechanisms of action against Gram-positive bacteria. J Antimicrob Chemother 2004; 53:797.
  93. Higgins DL, Chang R, Debabov DV, et al. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2005; 49:1127.
  94. Saravolatz LD, Stein GE, Johnson LB. Telavancin: a novel lipoglycopeptide. Clin Infect Dis 2009; 49:1908.
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  97. Tobudic S, Forstner C, Burgmann H, et al. Dalbavancin as Primary and Sequential Treatment for Gram-Positive Infective Endocarditis: 2-Year Experience at the General Hospital of Vienna. Clin Infect Dis 2018; 67:795.
  98. Bryson-Cahn C, Beieler AM, Chan JD, et al. Dalbavancin as Secondary Therapy for Serious Staphylococcus aureus Infections in a Vulnerable Patient Population. Open Forum Infect Dis 2019; 6:ofz028.
  99. Moellering RC. Linezolid: the first oxazolidinone antimicrobial. Ann Intern Med 2003; 138:135.
  100. Weigelt J, Itani K, Stevens D, et al. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005; 49:2260.
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Topic 3164 Version 74.0

References

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18 : Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic.

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20 : Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by Staphylococcus aureus.

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24 : Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia.

25 : The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis.

26 : Antibiotic choice may not explain poorer outcomes in patients with Staphylococcus aureus bacteremia and high vancomycin minimum inhibitory concentrations.

27 : Effect of vancomycin minimal inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus endocarditis.

28 : Association between vancomycin minimum inhibitory concentration and mortality among patients with Staphylococcus aureus bloodstream infections: a systematic review and meta-analysis.

29 : Is high vancomycin minimum inhibitory concentration a good marker to predict the outcome of methicillin-resistant Staphylococcus aureus bacteremia?

30 : Paradoxical relationship between the clinical outcome of Staphylococcus aureus bacteremia and the minimum inhibitory concentration of vancomycin.

31 : Vancomycin MIC Does Not Predict 90-Day Mortality, Readmission, or Recurrence in a Prospective Cohort of Adults with Staphylococcus aureus Bacteremia.

32 : Clinical features of Staphylococcus aureus endocarditis: a 10-year experience in Denmark.

33 : Serious infections caused by methicillin-resistant Staphylococcus aureus.

34 : Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia With Vancomycin MIC>1 mg/L: A Multicenter Evaluation.

35 : Counterpoint: Vancomycin and Staphylococcus aureus--an antibiotic enters obsolescence.

36 : Management of persistent bacteremia caused by methicillin-resistant Staphylococcus aureus: a survey of infectious diseases consultants.

37 : Current Paradigms of Combination therapy in Methicillin-Resistant Staphylococcus aureus (MRSA) Bacteremia: Does it Work, Which Combination and For Which Patients?

38 : When sepsis persists: a review of MRSA bacteraemia salvage therapy.

39 : Bacteremia due to Methicillin-Resistant Staphylococcus aureus: New Therapeutic Approaches.

40 : Comparative Effectiveness of Switching to Daptomycin Versus Remaining on Vancomycin Among Patients With Methicillin-resistant Staphylococcus aureus (MRSA) Bloodstream Infections.

41 : Daptomycin Improves Outcomes Regardless of Vancomycin MIC in a Propensity-Matched Analysis of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections.

42 : Emergence of daptomycin resistance following vancomycin-unresponsive Staphylococcus aureus bacteraemia in a daptomycin-naïve patient--a review of the literature.

43 : Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding.

44 : Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus in a pharmacokinetic/pharmacodynamic model.

45 : The combination of ceftaroline plus daptomycin allows for therapeutic de-escalation and daptomycin sparing against MRSA.

46 : Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline.

47 : β-Lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives.

48 : Daptomycin Plusβ-Lactam Combination Therapy for Methicillin-resistant Staphylococcus aureus Bloodstream Infections: A Retrospective, Comparative Cohort Study.

49 : Combination Therapy for MRSA Bacteremia: Toßor Not toß?

50 : Vancomycin plus ceftaroline shows potent in vitro synergy and was successfully utilized to clear persistent daptomycin-non-susceptible MRSA bacteraemia.

51 : Impact of the combination of daptomycin and trimethoprim-sulfamethoxazole on clinical outcomes in methicillin-resistant Staphylococcus aureus infections.

52 : Ceftaroline in Combination With Trimethoprim-Sulfamethoxazole for Salvage Therapy of Methicillin-Resistant Staphylococcus aureus Bacteremia and Endocarditis.

53 : Ceftaroline for meticillin-resistant Staphylococcus aureus bacteraemia: case series and review of the literature.

54 : Salvage treatment for persistent methicillin-resistant Staphylococcus aureus bacteremia: efficacy of linezolid with or without carbapenem.

55 : Potential role for telavancin in bacteremic infections due to gram-positive pathogens: focus on Staphylococcus aureus.

56 : A randomized Phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study.

57 : Avoiding the perfect storm: the biologic and clinical case for reevaluating the 7-day expectation for methicillin-resistant Staphylococcus aureus bacteremia before switching therapy.

58 : Defining the Breakpoint Duration of Staphylococcus aureus Bacteremia Predictive of Poor Outcomes.

59 : Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study.

60 : The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus.

61 : Evidence for a continuum of decreased vancomycin susceptibility in unselected Staphylococcus aureus clinical isolates.

62 : Emergence in Asian countries of Staphylococcus aureus with reduced susceptibility to vancomycin.

63 : Vancomycin concentrations in infected and noninfected human bone.

64 : Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients.

65 : Cerebrospinal fluid penetration and pharmacokinetics of vancomycin administered by continuous infusion to mechanically ventilated patients in an intensive care unit.

66 : Choice of antibacterial drugs.

67 : Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus.

68 : Impact of high-inoculum Staphylococcus aureus on the activities of nafcillin, vancomycin, linezolid, and daptomycin, alone and in combination with gentamicin, in an in vitro pharmacodynamic model.

69 : Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users.

70 : Use of vancomycin or first-generation cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia.

71 : Outcome of vancomycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia.

72 : Impact of empirical-therapy selection on outcomes of intravenous drug users with infective endocarditis caused by methicillin-susceptible Staphylococcus aureus.

73 : Perspectives on Daptomycin resistance, with emphasis on resistance in Staphylococcus aureus.

74 : A current perspective on daptomycin for the clinical microbiologist.

75 : Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia.

76 : Safety of high-dose intravenous daptomycin treatment: three-year cumulative experience in a clinical program.

77 : Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus.

78 : Treatment failure resulting from resistance of Staphylococcus aureus to daptomycin.

79 : Effect of Statin Coadministration on the Risk of Daptomycin-Associated Myopathy.

80 : The comparative efficacy and safety of teicoplanin and vancomycin.

81 : Safety and efficacy of glycopeptide antibiotics.

82 : Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK.

83 : Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus.

84 : Antimicrobial activity of ceftaroline tested against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin from U.S. hospitals, 2008 to 2011.

85 : Ceftaroline Fosamil for the Treatment of Staphylococcus aureus Bacteremia Secondary to Acute Bacterial Skin and Skin Structure Infections or Community-Acquired Bacterial Pneumonia.

86 : Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations.

87 : Ceftaroline for Severe Methicillin-Resistant Staphylococcus aureus Infections: A Systematic Review.

88 : Ceftaroline fosamil for the treatment of Gram-positive endocarditis: CAPTURE study experience.

89 : High incidence of neutropenia in patients with prolonged ceftaroline exposure.

90 : Ceftaroline-associated Encephalopathy in Patients With Severe Renal Impairment.

91 : In vitro activity of TD-6424 against Staphylococcus aureus.

92 : Comparative in vitro activity of telavancin (TD-6424), a rapidly bactericidal, concentration-dependent anti-infective with multiple mechanisms of action against Gram-positive bacteria.

93 : Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus.

94 : Telavancin: a novel lipoglycopeptide.

95 : Telavancin: mechanisms of action, in vitro activity, and mechanisms of resistance.

96 : Clinical Experience with Telavancin: Real-World Results from the Telavancin Observational Use Registry (TOUR™).

97 : Dalbavancin as Primary and Sequential Treatment for Gram-Positive Infective Endocarditis: 2-Year Experience at the General Hospital of Vienna.

98 : Dalbavancin as Secondary Therapy for Serious Staphylococcus aureus Infections in a Vulnerable Patient Population.

99 : Linezolid: the first oxazolidinone antimicrobial.

100 : Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections.

101 : Pleuropulmonary complications of Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus: importance of treatment with antimicrobials inhibiting exotoxin production.

102 : Successful treatment of staphylococcal toxic shock syndrome with linezolid: a case report and in vitro evaluation of the production of toxic shock syndrome toxin type 1 in the presence of antibiotics.

103 : Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus.

104 : Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections.

105 : Antimicrobial resistance to linezolid.

106 : Occurrence of MRSA endocarditis during linezolid treatment.

107 : Treatment failure of methicillin-resistant Staphylococcus aureus endocarditis with linezolid.

108 : Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit.

109 : First report of cfr-mediated resistance to linezolid in human staphylococcal clinical isolates recovered in the United States.

110 : Multicity outbreak of linezolid-resistant Staphylococcus epidermidis associated with clonal spread of a cfr-containing strain.

111 : High frequency of linezolid-associated thrombocytopenia and anemia among patients with end-stage renal disease.

112 : Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: a retrospective study.

113 : Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis?

114 : Serotonin toxicity associated with the use of linezolid: a review of postmarketing data.

115 : Linezolid and serotonergic drug interactions: a retrospective survey.

116 : Methicillin-Resistant Staphylococcus aureus in Hospitals: Latest Trends and Treatments Based on Bacteriophages.

117 : Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis.