Staphylococcus aureus bacteraemia is a frequent and life-threatening infection, despite current standard antibiotic monotherapy. This study aims to clarify the role of fosfomycin as an adjunctive therapy for improving outcomes in patients with this serious infection. Two clinical trials suggested that adjunctive fosfomycin therapy might offer a clinical benefit in certain cases, but the results are inconclusive. We aim to analyse pooled data from these trials in order to identify subgroups of patients that might benefit most from this therapy.

Background. Improving outcomes in patients with methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus bacteraemia (SAB) is a critical healthcare goal. Two recent randomised clinical trials (RCTs), the BACSARM trial and the SAFO trial, assessed the efficacy of fosfomycin as an adjunctive therapy for MRSA and MSSA SAB respectively. Although neither trial demonstrated statistically significant differences in their primary endpoints of treatment success and reduced mortality respectively, both studies observed lower rates of persistent bacteraemia in the fosfomycin groups.

Methods. We will perform a post-hoc analysis of pooled individual patient data from the BACSARM and SAFO trials, which will be referred to as the BACSAFO study. The primary exposure of interest is fosfomycin adjunctive therapy, and the primary outcome will be treatment success at 8 weeks, defined as the patient being alive, without signs of relapse, and showing improvement in clinical signs and symptoms. We will use both Bayesian and frequentist methodologies: the Bayesian analysis will use a hierarchical Bayesian log-binomial model, while the frequentist analysis will apply a hierarchical log-binomial model. In addition, we will investigate whether adjunctive fosfomycin is particularly beneficial in specific patient subgroups (created according to age, methicillin resistance, place of acquisition, and complicated bacteraemia status).

Discussion. The BACSAFO study aims to clarify the role of fosfomycin as an adjunctive therapy for improving outcomes in SAB patients. Although previous trials have not demonstrated significant differences in the primary endpoints, the significant reductions in rates of persistent bacteraemia observed suggest that fosfomycin might offer a clinical benefit in certain cases. By analysing pooled data and attempting to identify subgroups that might benefit most, this study has the potential to refine treatment strategies and inform trial design and planning for future RCTs investigating combination antibiotic therapies for SAB.

Inclusion Criteria:

• All patients included in the BACSARM and SAFO clinical trials.

Exclusion Criteria:

• For both trials: polymicrobial bacteraemia, severe clinical status with expected survival < 24 hours, severe liver disease with Child-Pugh score class C, diagnosis of prosthetic infective endocarditis, allergy or known resistance to study drugs, pregnancy at the time of inclusion, inclusion in another clinical trial.
• For the BACSARM trial: diagnosis of MRSA pneumonia, prior history of eosinophilic pneumonia, use of additional antibiotic therapy with microbiological activity against MRSA.
• For the SAFO trial: prior history of myasthenia gravis, acute SARS-CoV2 infection.

In the BACSARM trial, 155 adult patients with MRSA bacteraemia were randomised 1:1 to receive daptomycin in combination with fosfomycin or daptomycin alone. In the SAFO trial, 214 adult patients with MSSA bacteraemia were randomised 1:1 to receive cloxacillin in combination with fosfomycin or cloxacillin alone. As this is a pooled analysis of all SAB, all patients included in the intention-to-treat analysis of the BACSARM and SAFO trials will be included in the present study, regardless of their susceptibility to methicillin.

Individual data cannot be shared because of privacy restrictions. Raw anonymised data relating to primary and secondary outcomes and safety can be shared upon request to researchers who provide a methodologically reasonable proposal. The request for data can be sent to the corresponding author (J.C.). A period of 18 months after publication of the main study results should elapse before requests are made, so as to allow authors to publish substudies. Interested researchers must obtain the approval of the Bellvitge University Hospital Ethics Committee.

A period of 18 months after publication of the main study results should elapse before requests are made.

Researchers who request to BACSAFO principal investigators providing a methodologically reasonable proposal. Interested researchers must obtain the approval of the Bellvitge University Hospital Ethics Committee.