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Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms
Amita Sekar1,2, Dmitry Gil1,2, Peyton Tierney1
1Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, USA.
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 Staphylococcus aureus and Staphylococcus 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 (6 h) and established (24 h) biofilms were grown on 316L stainless steel plates and the synergistic biofilm eradication activity was determined and characterized using adherent bacteria count, minimum biofilm eradication concentration (MBEC) measurement for GS, visualization by live/dead imaging, scanning electron microscopy, gene expression of biofilm-associated genes, and bacterial membrane fluidity assessment.
Results:
Gentamicin-ketorolac (GS-KT) 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.
Insights
Combining gentamicin with ketorolac shows synergistic antibacterial effects against Staphylococci biofilms. This combination enhances antibiotic efficacy by overcoming biofilm resistance and altering bacterial physiology, offering new strategies for treating implant-associated infections.
Area of Science:
- Microbiology
- Pharmacology
- Biomedical Engineering
Background:
- Antibiotic resistance is a growing threat to microbial infection treatment.
- Synergistic antibacterial action with antibiotics can be achieved using other therapeutics.
- Investigating synergy between gentamicin and ketorolac addresses antibiotic resistance challenges.
Purpose of the Study:
- To investigate the antibacterial synergy between gentamicin and ketorolac.
- To assess their combined effects on biofilm growth dynamics and acquired resistance.
- To elucidate the mechanism of synergy in staphylococcal biofilms.
Main Methods:
- Used control and clinical strains of Staphylococcus aureus and Staphylococcus epidermidis.
- Determined synergistic action against planktonic staphylococci using fractional inhibitory concentration assay.
- Evaluated synergistic biofilm eradication activity using various techniques including live/dead imaging and gene expression analysis.
Main Results:
- Gentamicin-ketorolac combination showed synergistic antibacterial action against planktonic staphylococci.
- Biofilm maturity increased gentamicin resistance, but ketorolac enhanced antibiofilm activity.
- Synergy involves interference with biofilm morphology and bacterial stress response.
Conclusions:
- The gentamicin-ketorolac combination has significant potential for treating orthopaedic infections.
- Results support further investigation into non-antibiotic drug synergy for antimicrobial effects.
- This approach could impact local administration strategies for implant-associated infections.
