{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:48:20Z","timestamp":1792712900506,"version":"4.5.0"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"35","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,8,28]]},"abstract":"<jats:p>\n                    Targeting\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    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\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1121497109","type":"journal-article","created":{"date-parts":[[2012,7,24]],"date-time":"2012-07-24T00:48:19Z","timestamp":1343090899000},"page":"14188-14193","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":116,"title":["Metronidazole prevents reactivation of latent\n                    <i>Mycobacterium tuberculosis<\/i>\n                    infection in macaques"],"prefix":"10.1073","volume":"109","author":[{"given":"Philana Ling","family":"Lin","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, Children\u2019s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Dartois","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Novartis Institute for Tropical Diseases, Singapore;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Janssen","sequence":"additional","affiliation":[{"name":"Division of Laboratory Animal Research, University of Pittsburgh, Pittsburgh, PA 15261; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Via","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Goodwin","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin","family":"Klein","sequence":"additional","affiliation":[{"name":"Division of Laboratory Animal Research, University of Pittsburgh, Pittsburgh, PA 15261; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Clifton E.","family":"Barry","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JoAnne L.","family":"Flynn","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,7,23]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2236"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsa031667"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/421499"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2007.1138"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200904-0536OC"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00079310"},{"key":"e_1_3_3_7_2","first-page":"CD001363","article-title":"Isoniazid for preventing tuberculosis in non-HIV infected persons","author":"Smieja MJ","year":"2000","unstructured":"MJ Smieja, CA Marchetti, DJ Cook, FM Smaill, Isoniazid for preventing tuberculosis in non-HIV infected persons. 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