title: Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis.
abstract: 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.
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Carroll
authors.forename: Doosoo
authors.initials: D
authors.lastname: Jeon
authors.forename: James M
authors.initials: JM
authors.lastname: Mountz
authors.forename: Jong Doo
authors.initials: JD
authors.lastname: Lee
authors.forename: Yeon Joo
authors.initials: YJ
authors.lastname: Jeong
authors.forename: Nadeem
authors.initials: N
authors.lastname: Zia
authors.forename: Myungsun
authors.initials: M
authors.lastname: Lee
authors.forename: Jongseok
authors.initials: J
authors.lastname: Lee
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Eum
authors.forename: Sung-Joong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Goldfeder
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.forename: Boyoung
authors.initials: B
authors.lastname: Jin
authors.forename: Youngran
authors.initials: Y
authors.lastname: Kim
authors.forename: Taegwon
authors.initials: T
authors.lastname: Oh
authors.forename: Ray Y
authors.initials: RY
authors.lastname: Chen
authors.forename: Lori E
authors.initials: LE
authors.lastname: Dodd
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Gu
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.forename: Seung-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Cheon Tae
authors.initials: CT
authors.lastname: Kim
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D016001:Confidence Intervals; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D012720:Severity of Illness Index; D013183:Sputum / Q000382:microbiology; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D008795:Metronidazole