The Efficacy of Cefazolin and Ertapenem combination treatment for Persistent MSSA Bacteraemia: A ten-year multicentre retrospective cohort study.

Objectives Persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is associated with significant morbidity and mortality. Cefazolin-ertapenem combination therapy has demonstrated synergistic activity in preclinical models and small case series, but comparative clinical evidence is lacking. Methods We conducted a multicentre retrospective review of all patients aged >18 years with persistent MSSA bacteraemia at two Queensland tertiary hospitals between January 2014 and December 2024. The primary outcome was time to blood culture sterilisation, compared between patients who commenced cefazolin-ertapenem combination therapy prior to first negative blood culture and a matched cohort of non-combination-treated patients. Secondary outcomes included 90-day all-cause mortality, 90-day relapse, development of multi-resistant organisms, Clostridioides difficile infection, and adverse drug events. Results A total of 288 episodes of persistent MSSA bacteraemia in 283 patients were identified. Twenty-six patients received cefazolin-ertapenem combination therapy. Among the 14 patients who commenced combination therapy prior to first negative blood culture, median time to sterilisation was 1 day (IQR 1 - 2), compared with 2 days (IQR 1 - 3) in the matched non-combination group. Cox regression in the matched cohort (n=114) demonstrated an increased rate of blood culture clearance with combination therapy (HR 1.8; 95% CI 1.2 - 2.7; P =0.004). In the full cohort, ninety-day mortality (20.0% vs 23.0%, P=0.73) and relapse rates (11.5% vs 8.3%, P =0.57) did not differ significantly between groups. Conclusions Cefazolin-ertapenem combination therapy was associated with accelerated blood culture sterilisation in persistent MSSA bacteraemia. Prospective randomised evaluation is warranted.