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Comparative mutant prevention concentration and mechanism of resistance to veterinary fluoroquinolones in
Elias Gebru Awji1, Dereje Damte Tassew, Joong-Su Lee
1College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, South Korea.
Background:
The problem of antibacterial drug resistance is increasing worldwide, in part due to the therapeutic concentrations currently used based on the minimal inhibitory concentration (MIC) as a measure of potency are often the very concentrations required to selectively enrich the resistant mutant portion of the population. A mutant prevention concentration (MPC)-based dosing strategy is suggested to improve the therapeutic outcome based on the MIC.
Objective:
Our aim was to investigate the MPC and mechanism of resistance to various fluoroquinolones using recent Staphylococcus pseudintermedius isolates from canine pyoderma.
Methods:
The broth microdilution method for MIC and a series of agar plates containing different concentrations of fluoroquinolones were inoculated with ∼10(10) colony-forming units of the bacterial culture for MPC were used. PCR was used to identify mutation in the resistant isolates.
Results:
The rank order of potency based on MIC and MPC was ciprofloxacin = enrofloxacin ≥ marbofloxacin > difloxacin ≥ orbifloxacin. Integrating our data with reported pharmacokinetic data at the recommended dose ranges revealed that only high doses of ciprofloxacin, enrofloxacin and marbofloxacin could achieve a maximal plasma concentration (C(max)) greater than the MPC of 90% of isolates (C(max)/MPC(90)). The overall rank of potency against S. pseudintermedius, based on C(max)/MIC, C(max)/MPC, the area under concentration-time curve (AUC)/MIC and AUC/MPC values, was in decreasing order: enrofloxacin > ciprofloxacin ≥ marbofloxacin ≥ orbifloxacin = difloxacin. Sequencing of the quinolone resistant determining region of gyrA, gyrB, grlA and grlB of resistant strains showed a base-pair substitution in both gyrA and gyrB that resulted in Ser-84 to Leu and Ser-80 to Arg amino acid changes, respectively.
Conclusions And Clinical Importance:
High doses of ciprofloxacin, enrofloxacin and marbofloxacin could minimize the selection of resistant mutants, whereas the possibility of selecting mutants with the conventional doses of difloxacin and orbifloxacin, and low clinical doses of all fluoroquinolones, seems high.
Insights
Antibacterial drug resistance is a growing global concern. Using mutant prevention concentration (MPC) dosing for fluoroquinolones in canine pyoderma can minimize resistant bacterial growth.
Area of Science:
- Veterinary Microbiology
- Antimicrobial Resistance
- Pharmacodynamics
Background:
- Antibacterial drug resistance is a significant global health challenge.
- Current dosing strategies based on minimal inhibitory concentration (MIC) may inadvertently promote resistance.
- Mutant prevention concentration (MPC) offers a potential alternative for optimizing antimicrobial therapy.
Purpose of the Study:
- To evaluate the mutant prevention concentration (MPC) of various fluoroquinolones against Staphylococcus pseudintermedius.
- To investigate the genetic mechanisms of fluoroquinolone resistance in canine pyoderma isolates.
- To compare the efficacy of different fluoroquinolones using both MIC and MPC values.
Main Methods:
- Broth microdilution for MIC determination and agar-based methods for MPC determination.
- Inoculation with high bacterial loads (∼10(10) CFU) to assess mutant prevention.
- Polymerase Chain Reaction (PCR) sequencing of resistance-determining regions (gyrA, gyrB, grlA, grlB) in resistant isolates.
Main Results:
- Fluoroquinolone potency ranking varied between MIC and MPC values.
- High doses of ciprofloxacin, enrofloxacin, and marbofloxacin achieved plasma concentrations exceeding the MPC for most isolates.
- Specific mutations in gyrA and gyrB genes correlated with fluoroquinolone resistance.
Conclusions:
- High-dose fluoroquinolones (ciprofloxacin, enrofloxacin, marbofloxacin) may reduce the selection of resistant mutants.
- Conventional doses of difloxacin and orbifloxacin, and low clinical doses of all tested fluoroquinolones, pose a higher risk for selecting resistant mutants.
- MPC-based dosing strategies warrant consideration for optimizing fluoroquinolone therapy in canine pyoderma.
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