Subphenotype- and Complication-guided Adjunctive Fosfomycin Therapy for Staphylococcus Aureus Bacteraemia

Subphenotype- and Complication-guided Adjunctive Fosfomycin Therapy for Staphylococcus Aureus Bacteraemia: Pooled Analysis of Two Randomised Trials

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