Marked increases in case rates of drug-resistant tuberculosis and nontuberculous mycobacterial infections have brought renewed urgency to the development of new treatment regimens for mycobacterial infections. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of drug-susceptible tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial therapy. In vitro measures of drug activity predict the potency of a drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a drug or the activity of drug combinations. In vitro measures of drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of drug activity but still do not predict sterilizing activity. In contrast, animal models of tuberculosis have predicted relative drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.

译文

耐药结核病和非结核分枝杆菌感染的病例率显着增加,为开发新的分枝杆菌感染治疗方案带来了新的紧迫性。临床前数据,例如药物活性和药代动力学的体外测量,用于设计新的治疗方案。这篇综述调查了有关药物敏感结核病治疗的广泛已发表的临床经验,以评估这些临床前措施在预测抗细菌治疗临床结果中的应用。药物活性的体外测量可以预测药物的效力,以防止对其他抗细菌药物的耐药性出现,但不能预测药物的灭菌活性或药物组合的活性。药物活性的体外测量无法可靠地预测生物体应被认为具有抗性的水平。药物在组织中的渗透和对细胞内杆菌的活性的测定适度增加了药物活性的体外测量的预测值,但仍不能预测灭菌活性。相反,结核病的动物模型已经预测了相对的药物效力 (包括灭菌活性),多药疗法的功效以及所需的治疗持续时间。尽管药代动力学参数表明每天需要多次剂量,但所有一线抗结核药物在每周两次的情况下均具有活性。很难预测具有休眠能力的细胞内病原体的治疗效果。需要更好的体外模型,尤其是可以预测灭菌活性的模型。

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