{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:14:54Z","timestamp":1784546094936,"version":"3.55.0"},"reference-count":26,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2016,7,22]],"date-time":"2016-07-22T00:00:00Z","timestamp":1469145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,8,1]],"date-time":"2016-08-01T00:00:00Z","timestamp":1470009600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"European Union's Seventh Framework Programme","award":["115337"],"award-info":[{"award-number":["115337"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Currently, the most effective tuberculosis control method involves case finding and 6 months of chemotherapy. There is a need to improve our understanding about drug interactions, combination activities, and the ability to remove persistent bacteria using the current regimens, particularly in relation to relapse. We aimed to investigate the therapeutic effects of three main components, rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA), in current drug regimens using a modified version of the Cornell mouse model. We evaluated the posttreatment levels of persistent\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>\n            in the organs of mice using culture filtrate derived from\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            strain H37Rv. When RMP was combined with INH, PZA, or INH-PZA, significant additive activities were observed compared to each of the single-drug treatments. However, the combination of INH and PZA showed a less significant additive effect than either of the drugs used on their own. Apparent culture negativity of mouse organs was achieved at 14 weeks of treatment with RMP-INH, RMP-PZA, and RMP-INH-PZA, but not with INH-PZA, when conventional tests, namely, culture on solid agar and in liquid broth, indicated that the organs were negative for bacteria. The relapse rates for RMP-containing regimens were not significantly different from a 100% relapse rate at the numbers of mice examined in this study. In parallel, we examined the organs for the presence of culture filtrate-dependent persistent bacilli after 14 weeks of treatment. Culture filtrate treatment of the organs revealed persistent\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            . Modeling of mycobacterial elimination rates and evaluation of culture filtrate-dependent organisms showed promise as surrogate methods for efficient factorial evaluation of drug combinations in tuberculosis in mouse models and should be further evaluated against relapse. The presence of culture filtrate-dependent persistent\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            is the likely cause of disease relapse in this modified Cornell mouse model.\n          <\/jats:p>","DOI":"10.1128\/aac.02548-15","type":"journal-article","created":{"date-parts":[[2016,5,24]],"date-time":"2016-05-24T16:26:28Z","timestamp":1464107188000},"page":"4778-4785","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Investigation of Elimination Rate, Persistent Subpopulation Removal, and Relapse Rates of Mycobacterium tuberculosis by Using Combinations of First-Line Drugs in a Modified Cornell Mouse Model"],"prefix":"10.1128","volume":"60","author":[{"given":"Yanmin","family":"Hu","sequence":"first","affiliation":[{"name":"Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Pertinez","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Ortega-Muro","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Research and Development, Diseases of Developing World, Tres Cantos, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Alameda-Martin","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Research and Development, Diseases of Developing World, Tres Cantos, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjun","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Schipani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraint","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Coates","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","first-page":"237","article-title":"WHO global tuberculosis control report 2010. Summary","volume":"18","author":"WHO","year":"2010","unstructured":"WHO. 2010. WHO global tuberculosis control report 2010. Summary. Cent Eur J Public Health 18:237.","journal-title":"Cent Eur J Public Health"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0205-187"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.3.552"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.3.548"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00830-09"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.00641"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200905-0661OC"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.104.5.763"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.104.5.737"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.182.22.6358-6365.2000"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2014.11.002"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.6.2061-2068.2004"},{"key":"e_1_3_3_14_2","first-page":"R665","article-title":"Multiexponential, multicompartmental, and noncompartmental modeling. 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Bull Int Union Tuberc 53:5\u201312.","journal-title":"Bull Int Union Tuberc"},{"key":"e_1_3_3_22_2","first-page":"1100","article-title":"Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis","author":"East African\/British Medical Research Council","year":"1974","unstructured":"East African\/British Medical Research Council. 1974. Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet ii:1100\u20131106.","journal-title":"Lancet"},{"key":"e_1_3_3_23_2","first-page":"1079","article-title":"Controlled clinical trial of short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis","author":"East African\/British Medical Research Council","year":"1972","unstructured":"East African\/British Medical Research Council. 1972. Controlled clinical trial of short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet i:1079\u20131085.","journal-title":"Lancet"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-3879(75)90020-3"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00934-10"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/172.6.1550"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00595-10"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02548-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02548-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:57:59Z","timestamp":1645477079000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02548-15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8]]},"references-count":26,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,8]]}},"alternative-id":["10.1128\/AAC.02548-15"],"URL":"https:\/\/doi.org\/10.1128\/aac.02548-15","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8]]},"assertion":[{"value":"2015-10-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-05-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-07-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}