Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Antimicrob Agents Chemother. 2013 Aug;57(8):3903-9. doi: 10.1128/AAC.00753-13. Epub 2013 Jun 3.
Pulmonary lesions from active tuberculosis patients are thought to contain persistent, nonreplicating bacilli that arise from hypoxic stress. Metronidazole, approved for anaerobic infections, has antituberculosis activity against anoxic bacilli in vitro and in some animal models and may target persistent, nonreplicating bacilli. In this double-blind, placebo-controlled trial, pulmonary multidrug-resistant tuberculosis subjects were randomly assigned to receive metronidazole (500 mg thrice daily) or placebo for 8 weeks in addition to an individualized background regimen. Outcomes were measured radiologically (change on high-resolution computed tomography [HRCT]), microbiologically (time to sputum smear and culture conversion), and clinically (status 6 months after stopping therapy). Enrollment was stopped early due to excessive peripheral neuropathies in the metronidazole arm. Among 35 randomized subjects, 31 (15 metronidazole, 16 placebo) were included in the modified intent-to-treat analysis. There were no significant differences by arm in improvement of HRCT lesions from baseline to 2 or 6 months. More subjects in the metronidazole arm converted their sputum smear (P = 0.04) and liquid culture (P = 0.04) to negative at 1 month, but these differences were lost by 2 months. Overall, 81% showed clinical success 6 months after stopping therapy, with no differences by arm. However, 8/16 (50%) of subjects in the metronidazole group and 2/17 (12%) of those in the placebo group developed peripheral neuropathy. Subjects who received metronidazole were 4.3-fold (95% confidence interval [CI], 1.1 to 17.1) more likely to develop peripheral neuropathies than subjects who received placebo. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer term. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens.
活动性肺结核患者的肺部病变被认为含有持续存在的、非复制的细菌，这些细菌是由缺氧应激引起的。甲硝唑已被批准用于治疗厌氧菌感染，它在体外和一些动物模型中对缺氧细菌具有抗结核活性，并且可能针对持续存在的、非复制的细菌。在这项双盲、安慰剂对照试验中，肺部耐多药结核病患者被随机分配接受甲硝唑（每天三次，每次 500 毫克）或安慰剂治疗 8 周，同时接受个体化的背景治疗方案。结果通过影像学（高分辨率计算机断层扫描[HRCT]的变化）、微生物学（痰涂片和培养转换的时间）和临床（停止治疗后 6 个月的状态）进行测量。由于甲硝唑组出现过多的周围神经病，提前停止了入组。在 35 名随机分配的受试者中，有 31 名（15 名接受甲硝唑治疗，16 名接受安慰剂治疗）被纳入修改后的意向治疗分析。两组在基线至 2 个月和 6 个月时 HRCT 病变改善方面没有显著差异。甲硝唑组有更多的受试者在 1 个月时痰涂片（P=0.04）和液体培养（P=0.04）转为阴性，但这些差异在 2 个月时消失。总的来说，81%的患者在停止治疗后 6 个月时临床治愈，两组之间没有差异。然而，甲硝唑组的 16 名受试者中有 8 名（50%）和安慰剂组的 17 名受试者中有 2 名（12%）出现周围神经病。接受甲硝唑治疗的受试者发生周围神经病的可能性是接受安慰剂治疗的受试者的 4.3 倍（95%置信区间[CI]，1.1 至 17.1）。甲硝唑可能增加早期痰涂片和培养转换，但长期使用毒性太大。目前正在临床试验中的新型具有需氧和厌氧活性的硝基咪唑类药物可能会增加未来治疗方案的杀菌效力。
