Multidrug-Resistant Tuberculosis Not Due to Noncompliance but to Between-Patient Pharmacokinetic Variability
Multidrug-Resistant Tuberculosis Not Due to Noncompliance but to Between-Patient Pharmacokinetic Variability
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DOI：
10.1093/infdis/jir658
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发表时间：
2011-12-15
影响因子：
6.4
通讯作者：
Gumbo, Tawanda
中科院分区：
文献类型：
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作者：
Srivastava, Shashikant;Pasipanodya, Jotam G.;Gumbo, Tawanda
背景据信，不遵守是耐多药结核病（MDR-结核病）出现的近因。与出现MDR-结核病相关的不依从水平尚不清楚。在随机对照试验中，一些患者被随机分配到非依从性组，这是不道德的;因此，应采用其他研究设计。我们进行了中空纤维的杀菌和消毒效果的研究，接种物与0.5%的利福平和异烟肼耐药等基因菌株在一些实验中。标准治疗每天进行一次，持续28-56天，不依从程度在0%到100%之间变化。使用方差分析比较耐药人群的大小。我们还利用计算机辅助临床试验模拟了南非开普敦10 000例结核病患者，探讨了药代动力学变异性对耐多药结核病出现的影响。治疗失败仅发生在不依从性>= 60%的情况下。令人惊讶的是，异烟肼和利福平耐药人群在任何实验中都没有达到>= 1%的比例，并且没有达到更高的比例。然而，临床试验模拟表明，约1%的结核病患者的完美遵守仍然会发展为耐多药结核病，由于药代动力学变异。基于临床前模型的这些数据表明，单是不依从并不是出现MDR-结核病的充分条件。
Background. It is believed that nonadherence is the proximate cause of multidrug-resistant tuberculosis (MDR-tuberculosis) emergence. The level of nonadherence associated with emergence of MDR-tuberculosis is unknown. Performance of a randomized controlled trial in which some patients are randomized to nonadherence would be unethical; therefore, other study designs should be utilized.Methods. We performed hollow fiber studies for both bactericidal and sterilizing effect, with inoculum spiked with 0.5% rifampin- and isoniazid-resistant isogenic strains in some experiments. Standard therapy was administered daily for 28-56 days, with extents of nonadherence varying between 0% and 100%. Sizes of drug-resistant populations were compared using analysis of variance. We also explored the effect of pharmacokinetic variability on MDR-tuberculosis emergence using computer-aided clinical trial simulations of 10 000 Cape Town, South Africa, tuberculosis patients.Results. Therapy failure was only encountered at extents of nonadherence >= 60%. Surprisingly, isoniazid- and rifampin-resistant populations did not achieve >= 1% proportion in any experiment and did not achieve a higher proportion with nonadherence. However, clinical trial simulations demonstrated that approximately 1% of tuberculosis patients with perfect adherence would still develop MDR-tuberculosis due to pharmacokinetic variability alone.Conclusions. These data, based on a preclinical model, demonstrate that nonadherence alone is not a sufficient condition for MDR-tuberculosis emergence.