Monotherapy vs. combination therapy for Enterococcus faecalis bacteraemia: a target trial emulation

Objectives Optimal treatment for Enterococcus faecalis bloodstream infection (EF-BSI) remains a topic of debate. We aim to evaluate the effectiveness of combination therapy compared with monotherapy in patients with EF-BSI and no endocarditis. Methods This was a target trial emulation based on a prospective, multicentre, international dataset collected in 24 international centres from January 2019 to December 2024. We included all adult patients with monomicrobial EF-BSI with negative echocardiography within 7 days from BSI onset. Exclusion criteria were diagnosis of endocarditis, not receiving or completed the therapy at randomization. Primary endpoint was clinical failure defined as a composite of death, relapse of EF-BSI, and diagnosis of endocarditis, at 90 days. Results Overall, 373 patients were eligible for inclusion, 267 of whom (71%) received monotherapy, mainly ampicillin (174 of 267, 65%); most prescribed combination regimens were ampicillin with either ceftriaxone or gentamicin (80 of 106, 75%). The composite clinical failure was met by 114 of 373 (31%) patients. The outcomes among patients who received monotherapy or combination treatment were 75 of 267 (28%) versus 39 of 106 (36%); p 0.185, leading to an overall risk difference in favour of monotherapy of 2% (95% CI, −10% to 15%). Sepsis or septic shock at the time of presentation was the only independent variables associated with clinical failure, after performing a weighted univariable and multivariable Cox regression model (adjusted hazard ratio, 0.85; 95% CI, 0.52–1.39). Conclusions With the limitation of our sample size and observational design, we were not able to observe a better outcome associated with combination treatment for EF-BSI. If confirmed, these results would promote therapeutic simplification according to antimicrobial stewardship principles.