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Background We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. Methods A randomized (1:1) phase III superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg of daptomycin intravenously per kilogram daily plus 2 g of fosfomycin intravenously every six hours, or 10 mg of daptomycin intravenously per kilogram daily. Primary endpoint was treatment success six weeks after the end of therapy. Results Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at six weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs. 42.0%; relative risk: 1.29, 95%CI 0.93 to 1.8, p=0.135). At six weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs. 9 patients, p=0.003) and lower complicated bacteremia (16.2% vs. 32.1%; p=0.022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in four of 81 patients (4.9%) receiving daptomycin alone (p=0.018). Conclusion Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events.

This randomized clinical trial investigates noninferiority of fosfomycin vs ceftriaxone or meropenem in achieving clinical and microbiological cure among patients with urinary tract infections due to multidrug-resistant Escherichia coli .