Mutant-prevention concentration and mechanism of resistance in clinical isolates and enrofloxacin/marbofloxacin-selected mutants of of canine origin Free

Abstract

The antibacterial activity and selection of resistant bacteria, along with mechanisms of fluoroquinolone resistance, were investigated by integrating the static [MIC or mutant-prevention concentration (MPC)] and dynamic model approaches using isolates from diseased dogs. Using the dynamic models, selected strains and enrofloxacin and marbofloxacin at a range of simulated area under concentration–time curve over a 24 h interval (AUC)/MIC ratios were investigated. Our results indicated increasing losses in susceptibility of upon continuous exposure to enrofloxacin and marbofloxacin . This effect was transferable to other fluoroquinolones, as well as to structurally unrelated drugs. Our results also confirmed an AUC/MIC (AUC/MPC)-dependent antibacterial activity and selection of resistant mutants, in which maximum losses in fluoroquinolone susceptibility occurred at simulated AUC/MIC ratios of 40–60. AUC/MPC ratios of 39 (enrofloxacin) and 32 (marbofloxacin) were considered protective against the selection of resistant mutants of . Integrating our MIC and MPC data with published pharmacokinetic information in dogs revealed a better effect of the conventional dosing regimen of marbofloxacin than that of enrofloxacin in restricting the selection of resistant mutants of Target mutations, especially at codon 83 (serine to leucine) of , and overexpression of efflux pumps contributed to resistance development in both clinically resistant and -selected mutants of . We also report here a previously undescribed mutation at codon 116 of in two laboratory-derived resistant mutants of . Additional studies would determine the exact role of this mutation in fluoroquinolone susceptibility, as well as establish the importance of our findings in the clinical setting.

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2011-10-01
2024-03-28
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