Mutant selection window hypothesis updated
Mutant selection window hypothesis updated
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DOI：
10.1086/511642
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发表时间：
2007-03-01
影响因子：
11.8
通讯作者：
Zhao, Xilin
中科院分区：
文献类型：
--
作者：
Drlica, Karl;Zhao, Xilin
突变选择窗口假说认为，对于每种抗菌剂-病原体组合，存在一个抗菌剂浓度范围，在该范围内，单步耐药突变体会发生选择性扩增。这一假设提出了一种抗突变剂量策略，该策略与选择窗口的上边界有关：突变预防浓度。描述了突变预防浓度（用琼脂平板测量的静态参数）与限制突变体在体外和动物体内扩增的波动药物浓度之间的相关性。当逐步获得耐药性时，突变体选择窗口增加，使得抑制每个连续突变体的难度越来越大。对于以药物浓度依赖的方式杀死耐药突变体的药物，建议使用24小时药物浓度曲线下的面积除以突变体预防浓度的值作为设计抗突变体给药方案的指标。一个临床实例强调了这种方案的必要性，在该实例中，获得耐药性的同时发生了清除易感细菌细胞的情况。这些数据支持使用突变体选择窗口来优化抗菌药物给药方案。
The mutant selection window hypothesis postulates that, for each antimicrobial-pathogen combination, an antimicrobial concentration range exists in which selective amplification of single-step, drug-resistant mutants occurs. This hypothesis suggests an antimutant dosing strategy that is keyed to the upper boundary of the selection window: the mutant prevention concentration. Correlations are described between the mutant prevention concentration - a static parameter that is measured with agar plates - and fluctuating drug concentrations that restrict mutant amplification in vitro and in animals. When drug resistance is acquired stepwise, the mutant selection window increases, making the suppression of each successive mutant increasingly more difficult. For agents that kill drug-resistant mutants in a drug concentration - dependent manner, the use of the area under the 24-h time - drug concentration curve value divided by the value of the mutant prevention concentration is suggested as an index for designing antimutant dosing regimens. The need for such regimens is emphasized by a clinical example in which acquisition of drug resistance occurs concurrently with eradication of susceptible bacterial cells. These data support using the mutant selection window to optimize antimicrobial dosing regimens.