Mutant prevention concentration and phenotypic and molecular basis of fluoroquinolone resistance in clinical isolates and in vitro-selected mutants of Escherichia coli from dogs

被引:19
作者
Gebru, Elias [1 ]
Damte, Dereje [1 ]
Choi, Myung-Jin [1 ]
Lee, Seung-Jin [1 ]
Kim, Young-Hoan [2 ]
Park, Seung Chun [1 ]
机构
[1] Kyungpook Natl Univ, Coll Vet Med, Lab Appl Pharmacokinet & Pharmacodynam, Taegu 702701, South Korea
[2] Gyeongbuk Vet Serv Lab, Taegu 702210, South Korea
关键词
E; coli; Fluoroquinolones; MPC; Resistance; Dynamic models; DNA GYRASE; DYNAMIC-MODEL; COMPARATIVE PHARMACODYNAMICS; TOPOISOMERASE MUTATIONS; CIPROFLOXACIN; LEVOFLOXACIN; ENROFLOXACIN; MOXIFLOXACIN; BREAKPOINTS; MECHANISMS;
D O I
10.1016/j.vetmic.2011.07.033
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The antibacterial activity, selection of Escherichia coli (E. coli) mutants and mechanisms of fluoroquinolone resistance were investigated by integrating the minimum inhibitory concentration (MIC), mutant prevention concentration (MPC) and in vitro dynamic model approaches. Difloxacin and orbifloxacin, for which the above information has been scarce, were used. A range of area under curve over a 24 h interval (AUC(24 h))/MIC ratios and selected E. coli strains were investigated using the dynamic models. Continuous incubation for three days in the presence of difloxacin or orbifloxacin resulted in losses in E. coli susceptibility. An AUC(24 h)/MIC (AUC(24 h)/MPC)-dependent fluoroquinolone activity and selection of E. con mutants was confirmed. Maximum losses in susceptibility occurred at AUC(24 h)/MIC ratios of 54 (orbifloxacin) and 57.3 (difloxacin). AUC(24 h)/MIC ratios of 169.8 (orbifloxacin) and 199.5 (difloxacin) were estimated to be protective against the selection of E. coli mutants, and the corresponding ratios based on AUC(24 h)/MPC predictions were 34 (orbifloxacin) and 36.3 (difloxacin). When integrating our in vitro data with pharmacokinetic data in dogs, the conventional clinical doses of both drugs were found to be inadequate to attain the above protective values for 90% of the mutant subpopulation (AUC(24 h)/MPC90). Both target mutations, esp. at codon 83 (Ser to Leu) of gyrA, and overexpression of efflux pumps contributed to resistance development, with mutants also showing decreased susceptibility to enrofloxacin and marbofloxacin. Additional studies would determine the role of mutations found outside the QRDR, at codon 24 of gyrA, and at codon 116 of parC, and establish the significance of these observations in vivo. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:384 / 394
页数:11
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