In vivo validation of the mutant selection window hypothesis with moxifloxacin in a murine model of tuberculosis
In vivo validation of the mutant selection window hypothesis with moxifloxacin in a murine model of tuberculosis
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DOI：
10.1128/aac.01123-07
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发表时间：
2007-12-01
影响因子：
4.9
通讯作者：
Grosset, Jacques
中科院分区：
文献类型：
--
作者：
Almeida, Deepak;Nuermberger, Eric;Grosset, Jacques
联合治疗是预防结核病（TB）治疗期间出现耐药性的最有效策略。另一种策略，尽管是理论上的，是限制药物浓度落在MIC和突变体预防浓度（MPC）之间的"突变体选择窗口"（MSW）中的时间。高于MPC的药物浓度防止体外抗性突变体的选择性扩增，即使是单一药物暴露。MSW的概念已经在体外而不是体内使用氟喹诺酮类药物对结核分枝杆菌进行了验证。使用小鼠模型，其中血清氟沙星（MXF）浓度保持在MPC以上，我们测试了这种策略是否可以防止选择MXF耐药突变体。在用M.在肺结核中，当平均肺log（10）CFU计数为7.9 +/-0.2时，小鼠或者不接受治疗，或者在饮食中接受0.25%的MXF以接近常规人类剂量，或者接受1.5%的MXF以维持血清浓度高于MPC（8 μ g/ml）。给药56天后，0.25%和1.5%的MXF给药小鼠的肺CFU计数分别为3.5 +/- 0.8和0.9 +/- 0.6。在给予0.25% MXF的小鼠中，在第28天选择了MXF耐药突变体，并在第56天在16%（3/19）的试验小鼠中检测到。在给予1.5%MXF的小鼠中未检测到MXF抗性突变体的选择。我们的结论是，保持MXF的血清浓度高于MPC防止MXF耐药突变体的选择。虽然MXF在临床上无法实现这一目标，但可能使用具有更有效活性和/或改善药代动力学的新氟喹诺酮类药物。
Combination therapy is the most effective strategy to prevent emergence of resistance during tuberculosis (TB) treatment. Another strategy, albeit theoretical, is to limit the time that drug concentrations fall in the '' mutant selection window '' (MSW) between the MIC and the mutant prevention concentration (MPC). Drug concentrations above the MPC prevent selective amplification of resistant mutants in vitro even with a single drug exposure. The MSW concept has been validated using fluoroquinolones against Mycobacterium tuberculosis in vitro but not in vivo. Using a mouse model in which serum moxifloxacin (MXF) concentrations were maintained above the MPC, we tested whether this strategy prevents selection of MXF-resistant mutants. Beginning 2 weeks after aerosol infection with M. tuberculosis, when the mean lung log(10) CFU count was 7.9 +/- 0.2, mice received either no treatment or MXF in the diet at 0.25% to approximate the conventional human dose or 1.5% to maintain serum concentrations above the MPC (8 mu g/ml). After 56 days of treatment, lung CFU counts were 3.5 +/- 0.8 and 0.9 +/- 0.6 in 0.25% and 1.5% of the MXF-treated mice, respectively. In mice given 0.25% MXF, MXF-resistant mutants were selected by day 28 and detected in 16% (3/19) of mice tested on day 56. No selection of MXF-resistant mutants was detected in mice given 1.5% MXF. We conclude that maintaining serum concentrations of MXF above the MPC prevents selection of MXF-resistant mutants. Although this target cannot be achieved clinically with MXF, it might be possible with new fluoroquinolones with more potent activity and/or improved pharmacokinetics.