Wallis R S, Patil S, Cheon S H, Edmonds K, Phillips M, Perkins M D, Joloba M, Namale A, Johnson J L, Teixeira L, Dietze R, Siddiqi S, Mugerwa R D, Eisenach K, Ellner J J
Case Western Reserve University, Cleveland Ohio, USA.
Antimicrob Agents Chemother. 1999 Nov;43(11):2600-6. doi: 10.1128/AAC.43.11.2600.
Although Mycobacterium tuberculosis is eradicated rapidly during therapy in some patients with pulmonary tuberculosis, it can persist for many months in others. This study examined the relationship between mycobacterial drug tolerance (delayed killing in vitro), persistence, and relapse. It was performed with 39 fully drug-susceptible isolates from a prospective trial of standard short-course antituberculous therapy with sputum smear-positive, human immunodeficiency virus-uninfected subjects with pulmonary tuberculosis in Brazil and Uganda. The rate of killing in vitro was determined by monitoring the growth index (GI) in BACTEC 12B medium after addition of drug to established cultures and was measured as the number of days required for 99% sterilization. Drugs differed significantly in bactericidal activity, in the following order from greatest to least, rifampin > isoniazid-ethambutol > ethambutol (P < 0.001). Isolates from subjects who had relapses (n = 2) or in whom persistence was prolonged (n = 1) were significantly more tolerant of isoniazid-ethambutol and rifampin than isolates from other subjects (P < 0.01). More generally, the duration of persistence during therapy was predicted by strain tolerance to isoniazid and rifampin (P = 0.012 and 0.026, respectively). Tolerance to isoniazid-ethambutol and tolerance to rifampin were highly correlated (P < 0.001). Tolerant isolates did not differ from others with respect to the MIC of isoniazid; the rate of killing of a tolerant isolate by isoniazid-ethambutol was not increased at higher drug concentrations. These observations suggest that tolerance may not be due to drug-specific mechanisms. Tolerance was of the phenotypic type, although increased tolerance appeared to emerge after prolonged drug exposure in vivo. This study suggests that drug tolerance may be an important determinant of the outcome of therapy for tuberculosis.
尽管在一些肺结核患者的治疗过程中结核分枝杆菌能迅速被清除，但在其他患者体内它可能会持续存在数月。本研究探讨了分枝杆菌耐药性（体外延迟杀灭）、持续性和复发之间的关系。研究使用了39株完全药物敏感的分离株，这些分离株来自巴西和乌干达对痰涂片阳性、未感染人类免疫缺陷病毒的肺结核患者进行标准短程抗结核治疗的前瞻性试验。体外杀菌率通过在已建立的培养物中添加药物后监测BACTEC 12B培养基中的生长指数（GI）来确定，并以达到99%杀菌所需的天数来衡量。药物的杀菌活性差异显著，从最强到最弱依次为：利福平＞异烟肼-乙胺丁醇＞乙胺丁醇（P＜0.001）。复发患者（n = 2）或持续性延长患者（n = 1）的分离株对异烟肼-乙胺丁醇和利福平的耐受性明显高于其他患者的分离株（P＜0.01）。更普遍地说，治疗期间的持续时间可通过菌株对异烟肼和利福平的耐受性来预测（分别为P = 0.012和0.026）。对异烟肼-乙胺丁醇的耐受性和对利福平的耐受性高度相关（P＜0.001）。耐受性分离株与其他分离株在异烟肼的最低抑菌浓度方面没有差异；在较高药物浓度下，异烟肼-乙胺丁醇对耐受性分离株的杀灭率并未增加。这些观察结果表明，耐受性可能不是由药物特异性机制引起的。耐受性属于表型类型，尽管在体内长时间接触药物后似乎会出现耐受性增加。本研究表明，药物耐受性可能是结核病治疗结果的一个重要决定因素。
