Combination antibiotic therapy in Staphylococcus aureus endocarditis: evidence, controversies, and future directions

Staphylococcus aureus is now the leading cause of infective endocarditis (IE) worldwide and is associated with high mortality and frequent complications. Combination antimicrobial therapy has long been proposed to enhance bactericidal activity, improve biofilm penetration, and limit resistance; however, its true clinical value remains uncertain. This narrative review examines the experimental and clinical evidence for combination regimens in Staphylococcus aureus infective endocarditis (S. aureus IE). We searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Library through September 2025 for randomised trials, comparative observational studies, major guidelines, and key experimental reports. Evidence is synthesised across methicillin-susceptible and methicillin-resistant strains, and across native and prosthetic valve disease. We summarise the biological rationale, potential benefits, and stewardship impact of combination therapy. We also highlight the practical implications for when to consider, avoid, or de-escalate combination therapy, and outline priorities for future research. We find that evidence for combination therapy in S. aureus endocarditis remains limited and largely observational. Adjunctive rifampin and aminoglycosides have not shown consistent clinical benefit and are associated with increased toxicity. Beta-lactam combinations with vancomycin or daptomycin may reduce the bacteremia duration, but this has not translated into improved survival. Emerging regimens, particularly daptomycin combined with ceftaroline show promise in persistent bacteremia, although evidence remains observational. Overall, current data do not support routine use of combination therapy and favour a selective, case-based approach. High-quality multicentre studies integrating microbiological, pharmacodynamic, and clinical endpoints are urgently needed to define optimal combination strategies.