Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
J Antimicrob Chemother. 2012 Nov;67(11):2700-6. doi: 10.1093/jac/dks280. Epub 2012 Jul 18.
To test the mutant selection window (MSW) hypothesis with Staphylococcus aureus exposed to vancomycin in an animal model and to compare in vivo and in vitro exposures that restrict the enrichment of resistant mutants.
Local infection with S. aureus was established in rabbits, and the infected animals were treated with various doses of twice-daily vancomycin (half-life 6 h) for 3 consecutive days to provide antibiotic concentrations below the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC. Changes in susceptibility and the numbers of surviving organisms were monitored daily on agar plates containing 2× and 4× MIC of vancomycin.
S. aureus lost vancomycin susceptibility when drug concentrations at the site of infection fluctuated between the lower and upper boundaries of the MSW, defined in vitro as the MIC(99) and the MPC, respectively. Both boundaries were determined in vitro, before starting animal studies. The value at which resistant mutants are not enriched in vivo was estimated as an AUC(24)/MPC value of ∼15 h, where AUC(24) is the area under the drug concentration time curve in a 24 h interval. The estimated anti-mutant AUC/MIC ratio in vivo was ≥200 h.
These findings support the MSW hypothesis and the anti-mutant AUC/MIC ratio estimated in vivo is consistent with that reported in in vitro studies. Keeping vancomycin concentrations above the MPC or AUC(24)/MPC >15 h is a straightforward way to restrict the acquisition of resistance.
通过动物模型检测金黄色葡萄球菌暴露于万古霉素时的突变选择窗（MSW）假说，并比较限制耐药突变体富集的体内和体外暴露情况。
在兔中建立金黄色葡萄球菌局部感染，并用不同剂量的每日两次万古霉素（半衰期 6 小时）连续治疗 3 天，以提供低于 MIC、MIC 与突变预防浓度（MPC）之间以及高于 MPC 的抗生素浓度。每天在含有 2×和 4×MIC 万古霉素的琼脂平板上监测敏感性变化和存活菌数。
当感染部位的药物浓度在 MSW 的下限和上限之间波动时，即体外分别定义为 MIC（99）和 MPC，金黄色葡萄球菌失去了对万古霉素的敏感性。这两个边界都是在开始动物研究之前在体外确定的。在体内不富集耐药突变体的估计值为 AUC（24）/MPC 值约为 15 小时，其中 AUC（24）是 24 小时间隔内药物浓度时间曲线下的面积。体内估计的抗突变 AUC/MIC 比值为≥200 小时。
这些发现支持 MSW 假说，体内估计的抗突变 AUC/MIC 比值与体外研究报告的一致。使万古霉素浓度保持在 MPC 以上或 AUC（24）/MPC＞15 小时是限制获得耐药性的一种简单方法。
