Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial

What is it about?

Treatment failure occurs in about 25% of patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. We assessed whether cloxacillin plus fosfomycin achieves better treatment success than cloxacillin alone in hospitalized adults with MSSA bacteremia. We conducted a multicenter, open-label, phase III-IV superiority randomized clinical trial. We randomly assigned (1:1) patients to receive 2g/4h of intravenous cloxacillin alone or with 3g/6h of intravenous fosfomycin for the initial seven days. The primary endpoint was treatment success at day 7, a composite endpoint comprising: patient alive, stable or with improved quick-SOFA score, afebrile, and with negative blood cultures, adjudicated by an independent committee blinded to treatment. We randomized 215 patients, 105 received cloxacillin plus fosfomycin and 110 received cloxacillin alone. We analyzed the primary endpoint by intention-to-treat in 214 patients who received at least one day of treatment. Treatment success at day 7 from randomization was achieved in 83 (79.8%) of 104 patients receiving combination treatment versus 82 (74.5%) of 110 patients receiving monotherapy (risk difference 5.3% [95% CI –5.95 to 16.48]). Secondary endpoints, including mortality and adverse events, were similar in the two groups except for persistent bacteremia at day 3, which was less common in the combination arm. In a prespecified interim analysis, the independent committee blinded to treatment allocation recommended stopping recruitment for futility prior to meeting planned randomization of 366 patients. Cloxacillin plus fosfomycin did not achieve better treatment success at day 7 of therapy than cloxacillin alone in MSSA bacteremia. Further trials should consider the intrinsic heterogeneity of the infection by using a more personalized approach.

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Why is it important?

We found that cloxacillin plus fosfomycin did not achieve better treatment success at day 7 of therapy than cloxacillin alone in hospitalized adult patients with MSSA bacteremia.

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