Staphylococcus aureus bacteraemia (SAB) is a major global cause of sepsis-related mortality. Randomised trials of adjunctive antibiotics, including fosfomycin, have not shown consistent benefit, possibly due to inclusion of unselected SAB populations. The FEN-AUREUS classification enables early risk stratification based on clinical subphenotypes. The investigators aim to validate this framework in a pooled trial cohort and assess whether combining subphenotypes with IDSA-defined complicated SAB could identify patients most likely to benefit from adjunctive fosfomycin. The investigators will conduct a post-hoc analysis of individual-level data from two multicentre randomised trials-BACSARM and SAFO-evaluating fosfomycin in SAB. Participants will be classified using FEN-AUREUS into source phenotypes (A, B and C) and risk subphenotypes (1 = low-risk, 2 = high-risk). Associations between subphenotype, treatment arm, and outcomes (30/60-day mortality, 8-week treatment success) will be assessed using multivariable models. Monte Carlo simulations will explore power by subgroup. FEN-AUREUS subphenotypes combined with complication status have the potential to identify patients with SAB that could likely benefit form combination therapy with fosfomycin.

Inclusion criteria for the present study: all patients included in the BACSAFO cohort, composed of all patients included in the intention-to-treat populations of the BACSARM and SAFO randomised clinical trials (RCT).

Inclusion criteria for the BACSARM and SAFO RCTs:

• > or = 18 years old
• Monomicrobial Staphylococcus aureus bacteraemia
• Evidence of active infection

Common exclusion criteria for the BACSARM and SAFO RCTs:

• 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

Particular exclusion criteria for the BACSARM RCT:

• Diagnosis of MRSA pneumonia
• Prior history of eosinophilic pneumonia
• Use of additional antibiotic therapy with microbiological activity against MRSA

Particular exclusion criteria for the SAFO RCT:

• Prior history of myasthenia gravis
• Acute SARS-CoV2 infection

The BACSAFO cohort pools individual participant data from two multicentre, randomised, superiority trials evaluating adjunctive fosfomycin for the treatment of SAB: BACSARM and SAFO. The BACSARM trial included 155 adult patients with methicillin-resistant (MRSA), randomised 1:1 to receive either daptomycin alone or daptomycin plus fosfomycin. The SAFO trial enrolled 214 adult patients with methicillin-susceptible (MSSA) bacteraemia, randomised to cloxacillin alone or cloxacillin plus fosfomycin.

Raw anonymised data relating to primary and secondary outcomes and safety may be shared upon request with researchers who provide a methodologically reasonable proposal. Requests for data should be sent to the corresponding author (JC). Interested researchers must obtain the approval of the Bellvitge University Hospital Ethics Committee.