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Meta-Analysis
. 2025 Aug 6;69(8):e0119924.
doi: 10.1128/aac.01199-24. Epub 2025 Jun 17.

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

Madeline Mellett  1 , Alexander Lawandi  2   3   4 , Chelsea Caya  5 , Todd C Lee  3 , Ahmed Babiker  6   7 , Jesse Papenburg  8 , Cedric P Yansouni  3   4   9 , Matthew P Cheng  3   4   5
Affiliations
Meta-Analysis

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

Madeline Mellett et al. Antimicrob Agents Chemother. .

Abstract

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.

Keywords: Staphylococcus aureus; antimicrobial combinations; synergy.

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Conflict of interest statement

M.P.C. reports research support from the Canadian Institutes of Health Research and is supported by the Fonds de Recherche du Québec—Santé, research contracts from Cidara Therapeutics, Scynexis, and Amplyx Pharmaceuticals, honoraria from AstraZeneca, Takeda, Merck, and Pfizer, three pending patents (methods for detecting tissue damage, graft-versus-host disease, and infections using cell-free DNA profiling, methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA, and rapid identification of antimicrobial resistance and other microbial phenotypes using highly-multiplexed fluorescence in situ hybridization), stock options as a member of the scientific advisory board for GEn1E Lifesciences and Nomic Bio, and equity as co-founder of Kanvas Biosciences. J.P. reports grants from MedImmune and Merck, personal fees from Enanta, all outside the submitted work. A.B. has served on a clinical advisory board for Beckman Coulter and received consulting fees from Merck outside the submitted work. C.P.Y. reports being on an Independent Data Monitoring Committee (IDMC) for Medicago Inc. until 2021 outside the scope of the submitted work. The other authors have no conflict of interest to report.

Figures

Fig 1
Fig 1
Flow diagram of included studies evaluating antibiotic synergy for S. aureus.
Fig 2
Fig 2
Top five synergistic combinations for MRSA. (A) Fosfomycin and carbapenems. (B) Fosfomycin and oxazolidinones. (C) Cephalosporins and fosfomycin. (D) Carbapenems and lipoglycopeptides. (E) Fosfomycin and lipopeptides.
Fig 3
Fig 3
Top five synergistic combinations for MSSA. (A) Carbapenems and glycopeptides. (B) Fosfomycin and oxazolidinones. (C) Aminoglycosides and cephalosporins. (D) β-Lactams and cephalosporins. (E) Aminoglycosides and lipoglycopeptides.
See this image and copyright information in PMC

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