title: Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques.
abstract: Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential to shorten therapy for active tuberculosis (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. tuberculosis infection, equal proportions of cynomolgus macaques develop active disease or latent infection and that latently infected animals reactivated upon neutralization of TNF. Using this model we now show that chemoprophylaxis of latently infected cynomolgus macaques with 6 mo of isoniazid (INH) effectively prevented anti-TNF antibody-induced reactivation. Similarly, 2-mo treatment of latent animals with a combination of INH and rifampicin (RIF) was highly effective at preventing reactivation disease in this model. Metronidazole (MTZ), which has activity only against anaerobic, nonreplicating bacteria, was as effective as either of these treatments in preventing reactivation of latent infection. Because hypoxic lesions also occur during active TB, we further showed that addition of MTZ to INH/RIF effectively treated animals with active TB within 2 mo. Healing lesions were associated with distinct changes in cellular pathology, with a shift toward increasingly fibrotic and calcified lesions. Our data in the nonhuman primate model of active and latent TB supports targeting bacteria in hypoxic environments for preventing reactivation of latent infection and possibly shortening the duration of therapy in active TB.
authors: Division of Infectious Diseases, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors: Philana Ling
authors: PL
authors: Lin
authors: Veronique
authors: V
authors: Dartois
authors: Paul J
authors: PJ
authors: Johnston
authors: Christopher
authors: C
authors: Janssen
authors: Laura
authors: L
authors: Via
authors: Michael B
authors: MB
authors: Goodwin
authors: Edwin
authors: E
authors: Klein
authors: Clifton E
authors: CE
authors: Barry
authors: Joanne L
authors: JL
authors: Flynn
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D000995:Antitubercular Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D007371:Interferon-gamma / Q000378:metabolism; D007538:Isoniazid / Q000494:pharmacology; D055985:Latent Tuberculosis / Q000188:drug therapy*; D008252:Macaca fascicularis; D008795:Metronidazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D055502:Secondary Prevention; D014375:Tuberculoma / Q000188:drug therapy; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000981:Antiprotozoal Agents; D000995:Antitubercular Agents; D008795:Metronidazole; D007371:Interferon-gamma; D007538:Isoniazid