Metronidazole prevents reactivation of latentMycobacterium tuberculosisinfection in macaques

• DOI: 10.1073/pnas.1121497109
• Publication Date: 2012-07-24T04:48:19Z
• Authors: Philana Ling Lin; Veronique Dartois; Paul J. Johnston; Christopher Janssen; Laura Via; Michael B. Goodwin; Edwin Klein; Clifton E. Barry; JoAnne L. Flynn
• Keywords: Dose-Response Relationship, Drug; Antiprotozoal Agents; Antitubercular Agents; Mycobacterium tuberculosis; 3. Good health; Disease Models, Animal; Interferon-gamma; Macaca fascicularis; Latent Tuberculosis; Metronidazole; Isoniazid; Secondary Prevention; Animals; Drug Therapy, Combination; Tuberculoma; Drug Monitoring; Tuberculosis, Pulmonary

Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential shorten therapy for active (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. infection, equal proportions cynomolgus macaques develop disease or infection latently infected animals reactivated neutralization TNF. Using this model we now show chemoprophylaxis with 6 mo isoniazid (INH) effectively prevented anti-TNF antibody-induced reactivation. Similarly, 2-mo treatment a combination INH rifampicin (RIF) was highly effective at preventing model. Metronidazole (MTZ), which activity only against anaerobic, nonreplicating bacteria, either these treatments Because hypoxic lesions also occur during TB, further showed addition MTZ INH/RIF treated TB within 2 mo. Healing were associated distinct changes cellular pathology, shift toward increasingly fibrotic calcified lesions. Our data nonhuman primate supports targeting bacteria environments possibly shortening duration TB.