決して甘くない MRSA bacteremia
コンビネーションはイマイチ MRSA bacteremia
We suggest initial antibiotic management of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia with intravenous vancomycin or daptomycin (Grade 2C).
Persistent bacteremia may be due to a collection, the presence of a prosthetic device, or an endovascular source of infection that requires surgery. However, if antibiotic failure seems the most likely explanation and if the minimum inhibitory concentration (MIC) approaches the limit of the susceptible range (ie, 2 mcg/mL), vancomycin should be discontinued and therapy switched to an alternative agent.
If an alternative agent for treatment of MRSA bacteremia is needed due to vancomycin intolerance or inadequate response to treatment, we suggest treating with daptomycin or linezolid (Grade 2C). Susceptibility testing should be performed; in general, we favor daptomycin over linezolid.
We recommend initial antibiotic management of MRSA osteomyelitis with intravenous vancomycin or daptomycin (Grade 1C).
In general, we are in agreement with the 2011 guidelines issued by the Infectious Diseases Society of America (IDSA), which recommend vancomycin or daptomycin for treatment of MRSA bacteremia or other invasive infections.
There are some studies that suggest a worse clinical outcome associated with vancomycin therapy for infection due to MRSA with high vancomycin MIC. Several meta-analyses have addressed this question with different results. A meta-analysis that included patients with infections at varied sites suggested that there was increased mortality among patients with MRSA bacteremia when the vancomycin MIC was ≥2 mcg/mL (by E-test; odds ratio [OR] 1.72, 95% CI 1.34-2.21); increased mortality was not observed in cases with vancomycin test MIC ≤1.5 mcg/mL. A subsequent meta-analysis that included 38 studies and that was limited to S. aureus bacteremias found no difference in mortality based on vancomycin MIC. The different results may reflect differences in the studies selected for analysis, the types of infections included, or the number of studies included in the analysis.
Other studies have not found a direct correlation between vancomycin MIC and outcome with vancomycin therapy. In one report, investigators observed comparable outcomes among patients infected with high vancomycin MIC S. aureus isolates and patients infected with lower vancomycin MIC isolates. In addition, one group found that infections due to high vancomycin MIC S. aureus paradoxically had a better clinical outcome. On the other hand, higher vancomycin MIC has been associated with worse outcomes despite treatment with other active anti-staphylococcal agents and even with methicillin-susceptible S. aureus. Thus, it is likely that multiple factors, including the characteristics and comorbidities of the infected patient and perhaps virulence determinants associated with the staphylococcal isolate contribute to the associations between vancomycin and outcome.
Adjustments to antimicrobial therapy for patients with MRSA bacteremia should be based primarily on clinical response. Clinical guidelines have defined persistent bacteremia and treatment failure as lasting ≥7 days, though others favor use of alternative treatment approaches within 3 to 4 days of persistent bacteremia. Persistent bacteremia may be due to a retained prosthetic device, a persistent collection, or an endovascular source of infection that requires surgery. Careful evaluation for persistent foci of infection should be performed.
If antibiotic failure seems the most likely explanation for insufficient clinical response to vancomycin and if the MIC approaches the limit of the susceptible range (ie, 2 mcg/mL), vancomycin should be discontinued and therapy switched to an alternative agent .
Daptomycin, a bactericidal agent, is favored as an appropriate alternative to vancomycin for treatment of MRSA bacteremia. Retrospective studies of patients with MRSA and high vancomycin MIC (>1 mcg/mL) have noted lower mortality and lower rates of persistent bacteremia. Emergence of daptomycin resistance in the setting of S. aureus bacteremia has been described.
Linezolid is bacteriostatic, and toxicity limits prolonged use, although it may be effective for salvage treatment. Given reports of failure of both agents during extended therapy, careful monitoring for relapsed infection as well as adverse drug effects is critical.
High-dose trimethoprim-sulfamethoxazole did not achieve noninferiority to vancomycin for treatment of severe MRSA infection in a large trial and should not be used for treatment of severe staphylococcal infection.
Clinical data do not support the practice of combination therapy (such as vancomycin plus gentamicin or rifampin) to improve clinical outcomes for MRSA bacteremia in the absence of a prosthetic device. Short-course, low-dose gentamicin combined with vancomycin for MRSA bacteremia and native valve infective endocarditis (IE) has been associated with an increased risk of nephrotoxicity. In one randomized trial of 42 patients with MRSA endocarditis treated with vancomycin alone or in combination with rifampin, the duration of bacteremia was longer with combination therapy group than in the vancomycin monotherapy group (nine versus seven days). The use of rifampin combination therapy in a study of native valve S. aureus IE did not improve outcomes but was associated with hepatic adverse effects, drug interactions, and emergence of resistance.
MRSA bacteremia may persist in the setting of poor source control, pharmacokinetic limitations, or medical comorbidities. Potential salvage measures include increasing the drug dosage (eg, for daptomycin), switching to an alternative antibiotic agent, or using combination therapy. The optimal salvage regimen for persistent MRSA bacteremia is uncertain; further study is needed. One case series including patients whose isolates demonstrated diminished daptomycin susceptibility noted success with the combination of daptomycin and a beta-lactam agent for the treatment of patients with persistent MRSA bacteremia. Another reported noted enhanced bactericidal activity in vitro with combination therapy using daptomycin and ceftaroline.
Treatment of osteomyelitis consists of debridement and antimicrobial therapy.
Vancomycin or daptomycin are the antibiotics of choice for treatment of osteomyelitis due to MRSA. Failure rates of up to 46 percent have been reported with vancomycin therapy and, compared with beta-lactam therapy, patients with S. aureus osteomyelitis treated with vancomycin had a twofold higher recurrence rate. The addition of rifampin is discussed in detail separately.
Daptomycin (6 mg/kg/day) is an acceptable alternative agent to vancomycin. A retrospective, observational study including adults with osteomyelitis treated with daptomycin noted clinical improvement in 90 percent of cases.
In the setting of insufficient debridement or persistently elevated inflammatory markers, some favor treatment with oral consolidative therapy after a course of parenteral therapy. Regimens include trimethoprim-sulfamethoxazole (4 mg/kg/dose of the trimethoprim component) in combination with rifampin 600 mg once daily, linezolid (600 mg by mouth [PO] or intravenously [IV] twice daily), or clindamycin (600 mg PO or IV three times daily) .