Subphenotype- and complication-guided adjunctive fosfomycin versus standard monotherapy in Staphylococcus aureus bacteraemia: pooled analysis of two randomised trials

Background: bacteraemia (SAB) have failed to improve clinical outcomes-likely reflecting the lack of risk-targeted patient selection. The FEN-AUREUS classification enables early risk stratification based on clinical subphenotypes. We aimed 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. Methods: We conducted a post-hoc analysis of individual-level data from two multicentre randomised trials evaluating adjunctive fosfomycin in SAB. Participants were classified according to the FEN-AUREUS framework into phenotypes and risk subphenotypes. Associations between subphenotype, complicated bacteraemia, and 60-day mortality as the primary outcome and 30-day mortality and 8-week treatment success as secondary outcomes were assessed. A DOOR analysis provided an integrated assessment of overall outcomes. This study is registered with ClinicalTrials.gov, NCT07155590. Findings: Among 369 patients (median age 68 years, IQR 56-78; 262/369 [68·8%] male), high-risk subphenotypes were associated with greater 60-day mortality (23·2% versus 6·6%; risk ratio [RR] 3·49, 95% confidence interval [CI] 1·87-6·52; adjusted hazard ratio [aHR] 3·38, 1·69-6·78), regardless of complication status. Combining risk subphenotypes with the IDSA classification showed heterogeneity in response to adjunctive fosfomycin. In patients with low-risk and uncomplicated SAB (n = 107), 60-day mortality was low with both monotherapy and adjunctive fosfomycin (2·1% versus 3·4%; risk difference [RD] -1·3% [95% CI -7·4 to 4·8]; p = 0·68), and treatment success at week 8 exceeded 89%. In the intermediate strata, 60-day mortality was 18·8% with monotherapy versus 7·4% (RD 11·3% [95% CI -5·4 to 28·1]; p = 0·20) with adjunctive fosfomycin in low-risk/complicated SAB (n = 59), and 15·0% versus 22·8% (RD -7·8% [95% CI -19·9 to 4·3]; p = 0·21) in high-risk/uncomplicated SAB (n = 159); week-8 treatment success was 78·1% versus 88·9% and 61·3% versus 54·4%, respectively. By contrast, in high-risk, complicated SAB (n = 44), adjunctive fosfomycin was associated with higher treatment success (25·8% versus 69·2%; RD -43·4% [-72·9 to -14·0]; p = 0·007) and a non-significant reduction in 60-day mortality (45·2% versus 23·1%). DOOR analysis suggested a more favourable overall outcome profile with adjunctive therapy in this subgroup. Interpretation: Integrating early risk subphenotyping with IDSA complication criteria may enable more precise identification of SAB patients who may benefit from intensified therapy, while supporting monotherapy in those at lowest risk. This stratified approach provides a practical framework to refine patient selection for future trials and personalised therapeutic strategies. Funding: Instituto de Salud Carlos III, Madrid, Spain.