Isoniazid bactericidal activity and resistance emergence: Integrating pharmacodynamics and pharmacogenomics to predict efficacy in different ethnic populations
Isoniazid bactericidal activity and resistance emergence: Integrating pharmacodynamics and pharmacogenomics to predict efficacy in different ethnic populations
复制标题
DOI：
10.1128/aac.00185-07
复制
发表时间：
2007-07-01
影响因子：
4.9
通讯作者：
Drusano, George L.
中科院分区：
文献类型：
--
作者：
Gumbo, Tawanda;Louie, Arnold;Drusano, George L.
异烟肼作为联合抗结核治疗的一部分给药，负责该方案的大部分早期杀菌活性（EBA）。然而，结核分枝杆菌对异烟肼耐药性的出现是一个主要问题。我们研究了异烟肼暴露与M。结核菌杀灭，以及耐药性的出现，在我们的体外结核病药效学模型中。由于单核苷酸多态性的N-乙酰转移酶-2基因导致两种不同的清除异烟肼从患者血清中，我们模拟了异烟肼的浓度-时间曲线中遇到的慢和快乙酰化。单药治疗期间的微生物杀灭和耐药性的出现均与0 - 24 h异烟肼浓度-时间曲线下面积（AUC（0 - 24））与异烟肼MIC的比值相关。突变体选择窗口时间假说被否定。接下来，我们利用异烟肼AUC（0 - 24）/MIC比值与微生物杀灭之间的体外关系、异烟肼清除率在具有不同百分比的慢乙酰化剂和快乙酰化剂的人群中的分布以及异烟肼敏感M.在Monte Carlo模拟中，使用结核病临床分离株来计算类似于用300 mg异烟肼治疗的10，000名患者的预期EBA。对于快速乙酰化比例和异烟肼MIC较高的患者人群，标准剂量的平均EBA与0.3 log（10）CFU/ml/天相似，因此是次优的。我们的方法，利用临床前药效学和遗传确定的血清清除率的多峰分布，是一种临床前工具，可以预测不同剂量的新的抗结核药物的EBAs。
Isoniazid, administered as part of combination antituberculosis therapy, is responsible for most of the early bactericidal activity (EBA) of the regimen. However, the emergence of Mycobacterium tuberculosis resistance to isoniazid is a major problem. We examined the relationship between isoniazid exposure and M. tuberculosis microbial kill, as well as the emergence of resistance, in our in vitro pharmacodynamic model of tuberculosis. Since single-nucleotide polymorphisms of the N-acetyltransferase-2 gene lead to two different clearances of isoniazid from serum in patients, we simulated the isoniazid concentration-time profiles encountered in both slow and fast acetylators. Both microbial kill and the emergence of resistance during monotherapy were associated with the ratio of the area under the isoniazid concentration-time curve from 0 to 24 h (AUC(0-24)) to the isoniazid MIC. The time in mutant selection window hypothesis was rejected. Next, we utilized the in vitro relationship between the isoniazid AUC(0-24)/MIC ratio and microbial kill, the distributions of isoniazid clearance in populations with different percentages of slow and fast acetylators, and the distribution of isoniazid MICs for isonazid-susceptible M. tuberculosis clinical isolates in Monte Carlo simulations to calculate the EBA expected for similar to 10,000 patients treated with 300 mg of isoniazid. For those patient populations in which the proportion of fast acetylators and the isoniazid MICs were high, the average EBA of the standard dose was similar to 0.3 log(10) CFU/ml/day and was thus suboptimal. Our approach, which utilizes preclinical pharmacodynamics and the genetically determined multimodal distributions of serum clearances, is a preclinical tool that may be able to predict the EBAs of various doses of new antituberculosis drugs.