Antibiotic synergy against Staphylococcus aureus: a systematic review and meta-analysis

Antimicrobial combinations have been extensively evaluated in vitro to identify synergistic combinations for clinical use. Despite the available literature, no studies comprehensively summarize the findings for antimicrobial combinations against Staphylococcus aureus. We performed a systematic review to identify synergistic combinations that may be beneficial for clinical use against S. aureus. The PubMed, Cochrane, and Web of Science databases were queried from inception to February 2024 for studies of in vitro assays evaluating two antimicrobials in combination against isolates of S. aureus. Studies were included if they used common methods to determine synergy including time-kill assays, checkerboard assays, or the combined gradient diffusion method. The proportion of isolates for which synergy was identified was compared for different antimicrobial combinations. Two hundred sixty-five studies were included for analysis. One hundred forty-two studies evaluated synergy against methicillin-resistant S. aureus (MRSA), 31 against methicillin-susceptible S. aureus (MSSA), and 92 assessed synergy against both MRSA and MSSA, or did not define the methicillin susceptibility profile of the isolates studied. Time-kill assays (n = 176) and checkerboard assays (n = 158) were the most frequently used methods, with few studies evaluating synergy using the combined gradient diffusion method (n = 13). The proportion of synergy varied based on the antimicrobial combination and isolate being evaluated. Antimicrobial synergy has been extensively studied for S. aureus, with combinations of glycopeptides and cephalosporins being studied most frequently. Future evaluations of synergy for S. aureus should focus on antimicrobial combinations with strong rationales and robust potential for clinical use.