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Susceptibility of Staphylococcus aureus to Anti-Inflammatory Drugs with a Focus on the Combinatory Effect of
Onyedika Emmanuel Okpala1, Johana Rondevaldova1, Hayford Osei-Owusu1
1Department of Crop Sciences and Agroforestry, Faculty of Tropical AgriSciences, Czech University of Life Sciences Prague, Kamycka 129, Suchdol, 165 00 Prague, Czech Republic.
Abstract:
Musculoskeletal infections (MIs) are among the most difficult-to-treat staphylococcal diseases due to antibiotic resistance. This has encouraged the development of innovative strategies, such as combination therapy, to combat MI. The aim of this study was to investigate the in vitro antistaphylococcal activity of anti-inflammatory drugs and the combined antimicrobial effect of celecoxib and oxacillin. The minimum inhibitory concentrations (MICs) of 17 anti-inflammatory drugs against standard strains and clinical isolates of S. aureus, including methicillin-resistant strains (MRSAs), were determined using the broth microdilution method. The fractional inhibitory concentration indices (FICIs) were evaluated using checkerboard assays. Celecoxib produced the most potent antistaphylococcal effect against all tested strains (MICs ranging from 32 to 64 mg/L), followed by that of diacerein against MRSA3 and MRSA ATCC 33592 (MIC 64 mg/L). Several synergistic effects were observed against the tested S. aureus strains, including MRSA (FICI ranging from 0.087 to 0.471). The strongest synergistic interaction (FICI 0.087) was against MRSA ATCC 33592 at a celecoxib concentration of 2 mg/L, with a 19-fold oxacillin MIC reduction (from 512 to 26.888 mg/L). This is the first report on the combined antistaphylococcal effect of celecoxib and oxacillin. These findings suggest celecoxib and its combination with oxacillin as perspective agents for research focused on the development of novel therapies for MI caused by S. aureus. This study further indicates that celecoxib could resensitize certain MRSA strains, in some cases, to be susceptible to β-lactams (e.g., oxacillin) that were not previously tested. It is essential to mention that the in vitro concentrations of anti-inflammatory drugs are higher than those typically obtained in patients. Therefore, an alternative option for its administration could be the use of a drug delivery system for the controlled slow release from an implant at the infection site.
Insights
Celecoxib shows potent activity against Staphylococcus aureus, including resistant strains. Combining celecoxib with oxacillin demonstrates synergistic effects, offering a potential new strategy for treating difficult musculoskeletal infections.
Area of Science:
- Pharmacology and Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Musculoskeletal infections (MIs) caused by Staphylococcus aureus are challenging due to increasing antibiotic resistance.
- Innovative therapeutic strategies, including combination therapy, are crucial for overcoming treatment difficulties.
- Anti-inflammatory drugs are being explored for their potential antimicrobial properties.
Purpose of the Study:
- To evaluate the in vitro antistaphylococcal activity of various anti-inflammatory drugs.
- To investigate the combined antimicrobial effect of celecoxib and oxacillin against Staphylococcus aureus.
- To explore the potential of celecoxib in resensitizing methicillin-resistant Staphylococcus aureus (MRSA) to beta-lactams.
Main Methods:
- Determined Minimum Inhibitory Concentrations (MICs) of 17 anti-inflammatory drugs against standard and clinical strains of S. aureus, including MRSAs, using broth microdilution.
- Evaluated fractional inhibitory concentration indices (FICIs) via checkerboard assays to assess drug synergy.
- Tested combination effects of celecoxib and oxacillin on MRSA strains.
Main Results:
- Celecoxib exhibited the most potent antistaphylococcal activity (MICs 32-64 mg/L) against all tested strains.
- Significant synergistic effects were observed with celecoxib and oxacillin combinations (FICI 0.087-0.471), notably reducing oxacillin MIC by 19-fold against MRSA ATCC 33592.
- Celecoxib demonstrated potential to resensitize certain MRSA strains to oxacillin.
Conclusions:
- Celecoxib and its combination with oxacillin represent promising agents for novel therapies against S. aureus musculoskeletal infections.
- The findings suggest celecoxib could overcome resistance mechanisms, making MRSA susceptible to beta-lactams like oxacillin.
- Controlled drug delivery systems may be necessary to achieve effective in vitro concentrations at infection sites.
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