Laboratory of Pharmacokinetics and Pharmacodynamics, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea.
J Med Microbiol. 2011 Oct;60(Pt 10):1512-1522. doi: 10.1099/jmm.0.028654-0. Epub 2011 May 19.
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.
采用整合静态 [最小抑菌浓度（MIC）或突变预防浓度（MPC）] 和体外动态模型方法，对来自患病犬的大肠杆菌分离株进行了抗菌活性和耐药菌选择以及氟喹诺酮类耐药机制的研究。使用动态模型，研究了选定的大肠杆菌菌株以及恩诺沙星和马波沙星在模拟的 24 小时间隔下浓度时间曲线下面积（AUC（24 h））/MIC 比值范围内的情况。我们的研究结果表明，大肠杆菌对恩诺沙星和马波沙星的体外连续暴露导致其敏感性逐渐下降。这种影响可转移至其他氟喹诺酮类药物，以及结构上无关的药物。我们的结果还证实了 AUC（24 h）/MIC（AUC（24 h）/MPC）依赖性抗菌活性和耐药大肠杆菌突变体的选择，其中氟喹诺酮类药物敏感性的最大损失发生在模拟 AUC（24 h）/MIC 比值为 40-60 时。AUC（24 h）/MPC 比值为 39（恩诺沙星）和 32（马波沙星）被认为可防止大肠杆菌耐药突变体的选择。将我们的 MIC 和 MPC 数据与犬科动物的已发表药代动力学信息相结合，揭示了马波沙星常规剂量方案比恩诺沙星更能有效限制大肠杆菌耐药突变体的选择。靶基因突变，尤其是在 gyrA 密码子 83（丝氨酸变为亮氨酸）和外排泵的过度表达，导致大肠杆菌临床耐药株和体外选择的耐药株耐药性的发展。我们还报告了两个实验室衍生的大肠杆菌耐药突变株中 parC 密码子 116 以前未描述的突变。进一步的研究将确定该突变在氟喹诺酮类药物敏感性中的确切作用，并确定我们在临床环境中的发现的重要性。
