Combination therapy with cefazolin or nafcillin with ertapenem for methicillin-susceptible Staphylococcus aureus endocarditis

Objectives In-hospital mortality rates for patients with methicillin-susceptible Staphylococcus aureus (MSSA) infectious endocarditis (IE) remain very high and approach 40%. Limited data have suggested that combination antibiotic therapy with cefazolin or nafcillin/oxacillin with ertapenem may expedite blood culture clearance and improve clinical outcomes. We evaluated outcomes of patients with MSSA IE receiving combination antimicrobial therapy as directed by a multidisciplinary team. Methods This was a single-centre retrospective study of patients with definite MSSA IE treated with combination therapy identified from an institutional registry between 7 September 2021 and 15 August 2025. Clinical and outcomes data were recorded by study investigators. Results A total of 52 patients with definite MSSA IE who received combination therapy with cefazolin or nafcillin with ertapenem were identified. Median age was 37 years (33–45), and 51.9% were male. Sixty-nine percent had recent injection drug use, and 63.2% were admitted to intensive care. Seventy-five percent received cefazolin with ertapenem, and 25% received nafcillin and ertapenem. Median duration of bacteraemia before combination therapy was 3 days (2–5), median total duration of bacteraemia was 5 days (4–7), and median duration of combination therapy was also 5 days (3–6). In-hospital mortality was 5.8%, and 90-day mortality was 19.2% with no relapsed infections at 90 days. Conclusions Using a structured approach, guided by a multidisciplinary endocarditis team, patients with MSSA IE were treated with combination therapy with low in-hospital mortality and short durations of ertapenem utilization. Randomized controlled trial data are needed to determine the efficacy of combination treatment compared to monotherapy.