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

Objectives: Optimal treatment for E. faecalis bloodstream infection (EF-BSI) remains a topic of debate. We aim to evaluate the effectiveness of combination therapy compared to monotherapy in patients with EF-BSI and no endocarditis. Methods: This was a target trial emulation based on a prospective, multicenter, international dataset collected in 24 international centers 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, of whom 267/373 (71%) received monotherapy, mainly ampicillin (174/267, 65%); most prescribed combination regimens were ampicillin with either ceftriaxone or gentamicin (80/106, 75%). The composite clinical failure was met by 114/373 (31%) patients. The outcomes among patients that received monotherapy or combination treatment were [75/267 (28%) versus 39/106 (36%); p=0.185] leading to an overall risk difference in favor of monotherapy of 2% (95%CI -10% to 15%). Sepsis or septic shock at the time of presentation was the only independent variables associated to clinical failure, after performing a weighted uni and multi-variable Cox regression model [aHR=0.85, 95%CI=0.52-1.39]. Conclusion: 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.