Restricting the selection of antibiotic-resistant mutant bacteria: Measurement and potential use of the mutant selection window
Restricting the selection of antibiotic-resistant mutant bacteria: Measurement and potential use of the mutant selection window
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DOI：
10.1086/338571
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发表时间：
2002-02-15
影响因子：
6.4
通讯作者：
Drlica, K
中科院分区：
文献类型：
--
作者：
Zhao, XL;Drlica, K
耐药突变菌的选择被认为发生在一个药物浓度范围内（突变选择窗口），该范围从易感细胞的最低抑制浓度（MIC）延伸到最不易感的单步细菌突变体的MIC（突变预防浓度[MPC]）。利用大肠杆菌和金黄色葡萄球菌估计妥布霉素、氯霉素、利福平、青霉素、万古霉素和几种氟喹诺酮类药物的MPCs。对报告的血清药物水平的比较表明，在单药治疗期间，新的氟喹诺酮类药物最不可能增加耐药突变菌群。这些数据部分解释了在医疗实践中耐药突变菌种群的选择性富集。通过结构修饰，缩小了氟喹诺酮类药物的突变体选择窗口范围（MPC:MIC），为抗生素的改良指明了新的方向。利用金黄色葡萄球菌确定利福平和托布霉素联合使用的突变体选择窗口和MPC，作为单独不能阻断突变菌群富集的化合物联合治疗的指导。
The selection of antibiotic-resistant mutant bacteria is proposed to occur in a drug concentration range (the mutant selection window) that extends from the minimum inhibitory concentration (MIC) of susceptible cells to the MIC of the least susceptible, single-step bacterial mutants (the mutant prevention concentration [MPC]). MPCs were estimated for tobramycin, chloramphenicol, rifampicin, penicillin, vancomycin, and several fluoroquinolones by use of Escherichia coli and Staphylococcus aureus. Comparisons among reported serum drug levels indicate that new fluoroquinolones are the least likely to enrich populations of resistant mutant bacteria during monotherapy. These data partly explain the selective enrichment of populations of resistant mutant bacteria in medical practice. The mutant selection window range (MPC:MIC) was narrowed for fluoroquinolones by structure modification, pointing to a new direction in antibiotic refinement. The mutant selection window and the MPC were determined for combinations of rifampicin and tobramycin, using S. aureus, as a guide for combination therapy with compounds that alone cannot block enrichment of mutant bacterial populations.