Adjunctive Fosfomycin for the Treatment of Staphylococcus aureus Bacteremia: A Pooled Post-hoc Analysis of Individual Participant Data from Two Randomized Trials.

Background: The role of adjunctive fosfomycin in Staphylococcus aureus bacteremia (SAB) remains uncertain.

Methods: We performed a post-hoc pooled analysis of individual participant data from the multicenter BACSARM and SAFO randomized controlled trials, which assessed fosfomycin combined with daptomycin or cloxacillin versus monotherapy for methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) SAB. The primary outcome was treatment success at 8 weeks, defined as the patient being alive, without signs of relapse, and showing resolution of fever and improvement in clinical signs and symptoms of infection. Secondary outcomes included persistent bacteremia at days 3 and 7, all-cause mortality at days 14, 30, and 60, and adverse events leading to treatment discontinuation. Bayesian and frequentist methods were used to estimate treatment effects, with the primary Bayesian analysis using a minimally informative prior centred on no treatment effect. This study is registered with ClinicalTrials.gov, NCT06695832.

Results: The intention-to-treat population comprised 369 participants, of whom 178 received fosfomycin combination therapy and 191 received monotherapy. The primary Bayesian analysis showed a 91.8% posterior probability that fosfomycin improves treatment success at 8 weeks (median relative risk [RR] 1.10, 95% credibility interval [Crl] 0.97-1.26) with sensitivity analyses (using pessimistic, sceptical, and optimistic priors) yielding probabilities between 75.8% and 97.2%. Fosfomycin was associated with a significant reduction in persistent bacteremia at day 3 (median RR 0.19, 95% CrI 0.07-0.41) and day 7 (median RR 0.22, 95% CrI 0.03-0.84). The adjusted frequentist analysis demonstrated an association between fosfomycin combination therapy and treatment success at 8 weeks (RR 1.04, 95% CI 1.02-1.06; p<0.001). Combination therapy was associated with a higher risk of adverse events (RR 2.03, 95% CI 1.13-3.63; p=0.017).

Conclusions: Adjunctive fosfomycin may improve early bacterial clearance and treatment success in SAB but at the cost of increased toxicity.