174 Chapter 8 The present Following the non-inferiority trial in 2006, the U.S. guideline included daptomycin as first-choice therapy, comparable to vancomycin, for MRSAB in 2011 [10,19]. Although daptomycin monotherapy was shown to be non-inferior to vancomycin for treatment of MRSAB, the possibility of treatment-emergent resistance and treatment failure has become apparent over time [132,133]. Therefore, it is often recommended to add a second antibiotic agent to daptomycin (e.g., trimethoprim-sulfamethoxazole) with the goal of preventing daptomycin resistance from emerging, especially if source control is not achieved [10]. In Europe and the UK, the only first-choice agent in the guidelines remains vancomycin [134,135]. However, when the MIC is 2 µg/mL or higher, vancomycin is believed to be less effective, and alternative treatment options should be considered. Multiple mono- or combination therapy options for the treatment of MRSAB have been studied in the last decade. One promising concept was the combination of vancomycin or daptomycin with an anti-staphylococcal beta-lactams (ASBLs) such as nafcillin or flucloxacillin. This clinical approach was based on exciting in vitro data demonstrating the synergy with both vancomycin and daptomycin when an ASBL was added. The CAMERA2 trial addressed this question by randomizing MRSAB patients to receive either standard therapy (daptomycin or vancomycin) or standard therapy with the addition of an ASBL. While the proportion of patients with persistent S. aureus bacteremia at day five was significantly lower in the combination therapy group, all-cause mortality was not significantly different and combination therapy was associated with a significantly increased rate of acute kidney injury [136]. However, whether this is true for all beta-lactams and for all patient categories has not yet been clarified [137]. The DASH trial, which enrolled only MSSA bacteremia patients, demonstrated that the addition of daptomycin to anti-staphylococcal beta-lactam did not reduce the duration of bacteremia, 90-day mortality, or rate of recurrence [138]. Ceftaroline is a fifth-generation cephalosporin with robust activity against MRSA due to its unique ability to bind with high affinity to PBP-2a [139]. It is FDA approved for the treatment of community-acquired pneumonia and acute bacterial skin and skin structure infections (including those with concurrent bacteremia) but is frequently used off-label, either alone or in combination with another antibiotic, as a treatment for MRSAB. The combination of daptomycin and ceftaroline, especially when initiated early in the disease course, is possibly associated with reduced in-hospital mortality compared to monotherapy with vancomycin or daptomycin [140–142]. Although we are lacking high-quality data to support such an approach, ceftaroline is commonly used in clinical practice in combination with vancomycin or daptomycin to treat persistent MRSAB [143,144]. There are several observational studies showing expedited bacterial clearance when deployed as a salvage therapy in refractory
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