Efficacy and safety of metronidazole for pulmonary multidrug-resistant
tuberculosis.
Author(s): Carroll MW(1), Jeon D, Mountz JM, Lee JD, Jeong YJ, Zia N, Lee M, Lee J, Via LE,
Lee S, Eum SY, Lee SJ, Goldfeder LC, Cai Y, Jin B, Kim Y, Oh T, Chen RY, Dodd LE,
Gu W, Dartois V, Park SK, Kim CT, Barry CE 3rd, Cho SN.
Affiliation(s): Author information:
(1)Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases,
National Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, Maryland, USA.
Publication date & source: 2013, Antimicrob Agents Chemother. , 57(8):3903-9
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.
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