Efficacy and Safety of Metronidazole for Pulmonary Multidrug-Resistant Tuberculosis
Myungsun Lee ; Matthew W. Carroll ; Jongseok Lee ; Sang-Nae Cho ; Clifton E. Barry III ; Cheon Tae Kim ; Seung-Kyu Park ; Veronique Dartois ; Wenjuan Gu ; Lori E. Dodd ; Ray Y. Chen ; Taegwon Oh ; Youngran Kim ; Boyoung Jin ; Ying Cai ; Lisa C. Goldfeder ; Sung-Joong Lee ; Seok-Yong Eum ; Soyoung Lee ; Laura E. Via ; Nadeem Zia ; Yeon Joo Jeong ; Jong Doo Lee ; James M. Mountz ; Doosoo Jeon
Antimicrobial Agents and Chemotherapy, Vol.57(8) : 3903~3909, 2013
Antimicrobial Agents and Chemotherapy
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.