Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms.

Autor:	Sekar A; Harris Orthopaedic Laboratory, Massachusetts General Hospital; Boston, U.S.A.; Department of Orthopaedic Surgery, Harvard Medical School, Harvard University; Boston, U.S.A., Gil D; Harris Orthopaedic Laboratory, Massachusetts General Hospital; Boston, U.S.A.; Department of Orthopaedic Surgery, Harvard Medical School, Harvard University; Boston, U.S.A., Tierney PA; Harris Orthopaedic Laboratory, Massachusetts General Hospital; Boston, U.S.A., McCanne M; Harris Orthopaedic Laboratory, Massachusetts General Hospital; Boston, U.S.A., Daesety V; Harris Orthopaedic Laboratory, Massachusetts General Hospital; Boston, U.S.A., Trendafilova D; Harris Orthopaedic Laboratory, Massachusetts General Hospital; Boston, U.S.A., Muratoglu OK; Harris Orthopaedic Laboratory, Massachusetts General Hospital; Boston, U.S.A.; Department of Orthopaedic Surgery, Harvard Medical School, Harvard University; Boston, U.S.A., Oral E; Harris Orthopaedic Laboratory, Massachusetts General Hospital; Boston, U.S.A.; Department of Orthopaedic Surgery, Harvard Medical School, Harvard University; Boston, U.S.A.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Oct 26. Date of Electronic Publication: 2023 Oct 26.
DOI:	10.21203/rs.3.rs-3471646/v1
Abstrakt:	Background: While antibiotics remain our primary tools against microbial infection, increasing antibiotic resistance (inherent and acquired) is a major detriment to their efficacy. A practical approach to maintaining or reversing the efficacy of antibiotics is the use of other commonly used therapeutics, which show synergistic antibacterial action with antibiotics. Here, we investigated the extent of antibacterial synergy between the antibiotic gentamicin and the anti-inflammatory ketorolac regarding the dynamics of biofilm growth, the rate of acquired resistance, and the possible mechanism of synergy. Methods: Control (ATCC 12600, ATCC 35984) and clinical strains (L1101, L1116) of S. aureus and S. epidermidis with varying antibiotic susceptibility profiles were used in this study to simulate implant-material associated low-risk and high-risk biofilms in vitro . The synergistic action of gentamicin sulfate (GS) and ketorolac tromethamine (KT), against planktonic staphylococcal strains were determined using the fractional inhibitory concentration measurement assay. Nascent (6hr) and established (24hr) biofilms were grown on 316 stainless steel plates and the synergistic biofilm eradication activity was determined and characterized using adherent bacteria count, MBEC measurement for GS, gene expression of biofilm-associated genes, visualization by live/dead imaging, scanning electron microscopy, and bacterial membrane fluidity assessment. Results: Gentamicin-ketorolac combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both 'low-risk' and 'high-risk' biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin-ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties. Conclusion: The results of this study have a significant impact on the local administration of antibiotics and other therapeutic agents commonly used in the prevention and treatment of orthopaedic infections. Further, these results warrant the study of synergy for the concurrent or sequential administration of non-antibiotic drugs for antimicrobial effect. Competing Interests: Declarations Competing interests: O.K.M. declares the following disclosures: Royalties - Corin, Mako, Iconacy, Renovis, Arthrex, ConforMIS, Meril Healthcare, Exactech, Cambridge Polymer Group; Stake/Equity-Cambridge Polymer Group, Orthopedic Technology Group, Alchimist. E.O. declares the disclosures: Royalties-Corin, Iconacy, Renovis, Arthrex, ConforMIS, Meril Healthcare, Exactech; Paid consultant – WL Gore & Assoc; Editorial Board – JBMR; Officer/Committee-SFB, ISTA. None of these are in direct conflict with the study. Authors declare that they have no competing interests.
Databáze:	MEDLINE
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