To demonstrate that the combination of daptomycin and fosfomycin is superior to daptomycin alone in the treatment of methicillin resistant Staphylococcus aureus (MRSA) bacteremia.

The mortality associated to MRSA bacteremia remains higher than 30% of episodes despite the availability of new antibiotics. Objective: To demonstrate that the combination of daptomycin and fosfomycin is superior to daptomycin alone in the treatment of methicillin resistant Staphylococcus aureus (MRSA) bacteremia. Design: Randomized, open-label and multicenter study. Intervention: Patients with MRSA bacteremia will be randomized (1:1) in Group 1: daptomycin 10mg/Kg/24h intravenous (iv) and Group 2: daptomycin 10 mg/kg/24 iv plus fosfomycin and 2g/6h iv. Duration of therapy will be 10-14 days for uncomplicated bacteremia and up to 42 days for complicated bacteremia. Follow up: There will be a clinical and microbiological evaluation at baseline, during treatment and at week 6 after the end of therapy (test of cure visit, TOC). Complicated bacteremia was considered if: a) persistence of a positive blood culture at 72-96 h from the start of antibiotic, b) evidence of spread of infection (metastatic infection) c) infection involving a non-removable device in less than 4 days. Sample size: Assuming 60% cure rate with daptomycin and a 20% difference in cure rates between both groups, we estimated that 103 patients will be needed for each group (α:0.05, ß: 0.2). Main endpoint: clinical and microbiological response at the TOC visit. Treatment success was defined as the resolution of clinical signs and symptoms and negative blood culture. Treatment failure was defined if any of the following situations: a) lack of clinical response at 72 h or more after initiation of the study therapy b) persistent bacteremia (positive blood culture on day 7 after randomization), c) withdrawal of treatment due to adverse effects or for any other reason based on clinical judgment. d) relapse of MRSA bacteremia before the TOC visit e) death for any reason before the TOC visit. Secondary endpoints: evaluation in both groups of clinical and microbiological response at end of therapy (EOT visit); mortality at EOT and TOC visit; persistent MRSA bacteremia; recurrence of MRSA bacteremia (positive blood culture when previous ones were negative); emergence of daptomycin or fosfomycin resistance and severe adverse effects.

Inclusion Criteria:

• Patients with at least 1 positive blood culture to MRSA within 72h up to randomization
• Adult patients, equal or older than 18 years old
• Signed informed consent
• Mandatory use of contraception methods for fertile women during the study period and for 6 months after stopping antibiotic therapy

Exclusion Criteria:

• Polymicrobial bacteremia
• Pneumonia associated to the bacteremia
• Severe clinical status with expected survival of less than 24 hours
• Allergy to daptomycin or fosfomycin
• A positive pregnancy test at the time of inclusion
• Any clinical condition that requires additional antibiotic therapy with microbiological activity against MRSA
• Patient already included in another clinical trial
• Prior history of eosinophilic pneumonia