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

• Published in: Journal of medical microbiology Vol. 60; no. 10; pp. 1512 - 1522
• Main Authors: GEBRU, Elias, CHOI, Myung-Jin, LEE, Seung-Jin, DAMTE, Dereje, SEUNG CHUN PARK
• Format: Journal Article
• Language: English
• Published: Reading Society for General Microbiology 01.10.2011
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Bacteriology; Biological and medical sciences; Clinical isolates; Codons; Data processing; DNA topoisomerase IV; DNA, Bacterial - chemistry; DNA, Bacterial - genetics; Dog Diseases - microbiology; Dogs; Drug Resistance, Bacterial; Drugs; Enrofloxacin; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli - isolation & purification; Escherichia coli Infections - microbiology; Escherichia coli Infections - veterinary; Female; Fluoroquinolones; Fluoroquinolones - pharmacology; Fundamental and applied biological sciences. Psychology; Infectious diseases; Leucine; Male; Medical sciences; Microbial Sensitivity Tests; Microbiology; Minimum inhibitory concentration; Miscellaneous; Molecular Sequence Data; Mutation; Pharmacokinetics; Resistant mutant; Selection, Genetic; Sequence Analysis, DNA; Serine; Time Factors; Origin; Fissipedia; Carnivora; Marbofloxacin; Escherichia coli; Enrofloxacin; Mechanism; Prevention; Resistance; Fluoroquinolone derivatives; Vertebrata; Mammalia; Bacteria; Mutation; Antibacterial agent; Veterinary; Dog; Clinical isolate; Quinolone derivatives; Enterobacteriaceae
• ISSN: 0022-2615; 1473-5644
• DOI: 10.1099/jmm.0.028654-0

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 in vitro dynamic model approaches using Escherichia coli isolates from diseased dogs. Using the dynamic models, selected E. coli strains and enrofloxacin and marbofloxacin at a range of simulated area under concentration-time curve over a 24 h interval (AUC(24 h))/MIC ratios were investigated. Our results indicated increasing losses in susceptibility of E. coli upon continuous exposure to enrofloxacin and marbofloxacin in vitro. This effect was transferable to other fluoroquinolones, as well as to structurally unrelated drugs. Our results also confirmed an AUC(24 h)/MIC (AUC(24 h)/MPC)-dependent antibacterial activity and selection of resistant E. coli mutants, in which maximum losses in fluoroquinolone susceptibility occurred at simulated AUC(24 h)/MIC ratios of 40-60. AUC(24 h)/MPC ratios of 39 (enrofloxacin) and 32 (marbofloxacin) were considered protective against the selection of resistant mutants of E. coli. 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 E. coli. Target mutations, especially at codon 83 (serine to leucine) of gyrA, and overexpression of efflux pumps contributed to resistance development in both clinically resistant and in vitro-selected mutants of E. coli. We also report here a previously undescribed mutation at codon 116 of parC in two laboratory-derived resistant mutants of E. coli. 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.