{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:07:52Z","timestamp":1791526072676,"version":"4.3.4"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Completion of preventive therapy is a major bottleneck in global tuberculosis control. Long-acting injectable drug formulations would shorten therapy administration and may thereby improve completion rates. Recently, a long-acting formulation of bedaquiline demonstrated antituberculosis activity for up to 12 weeks after injection in a validated mouse model of preventive therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The objectives of this study were to 1) determine the total duration of activity after an injection of long-acting bedaquiline and 2) evaluate the activity of regimens comprised of long-acting bedaquiline plus short (2\u20134 wk) oral companion courses of bedaquiline, with or without rifapentine, using the validated mouse model of tuberculosis preventive therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>After the establishment of a stable Mycobacterium tuberculosislung infection in bacillus Calmette-Gu\u00e9rin (BCG)-immunized BALB\/c mice, treatment was initiated with 1 of 12 randomly assigned regimens. In addition to positive and negative controls, six regimens included one or two injections of long-acting bedaquiline (alone or with oral bedaquiline with or without rifapentine), and four comparator regimens consisted of oral agents only. Lung bacterial burden was measured monthly for up to 28 weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>One injection of long-acting bedaquiline at 160 mg\/kg exerted antituberculosis activity for 12 weeks. Compared with the positive control (daily isoniazid-rifapentine for 4 wk), six regimens had equivalent bactericidal activity (including two all-oral comparator regimens), and two regimens had superior sterilizing activity: one injection with 2 weeks of oral bedaquiline and high-dose rifapentine; and two injections with 4 weeks of oral bedaquiline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Long-acting injectable bedaquiline has significant potential for shortening tuberculosis preventive therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202012-4541oc","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T11:32:08Z","timestamp":1640259128000},"page":"570-579","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":24,"title":["Efficacy of Long-Acting Bedaquiline Regimens in a Mouse Model of Tuberculosis Preventive Therapy"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5622-1721","authenticated-orcid":false,"given":"Amit","family":"Kaushik","sequence":"first","affiliation":[{"name":"Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9359-9144","authenticated-orcid":false,"given":"Nicole C.","family":"Ammerman","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rokeya","family":"Tasneen","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Lachau-Durand","sequence":"additional","affiliation":[{"name":"Janssen R&D, Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Andries","sequence":"additional","affiliation":[{"name":"Janssen R&D, Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1440-9889","authenticated-orcid":false,"given":"Eric","family":"Nuermberger","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,3,1]]},"reference":[{"key":"2026022021035746500_bib1","volume-title":"WHO operational handbook on tuberculosis. Module 1: prevention\u2013tuberculosis preventive treatment.","author":"World Health Organization","year":"2020"},{"key":"2026022021035746500_bib2","volume-title":"The END TB strategy.","author":"World Health Organization","year":"2015"},{"key":"2026022021035746500_bib3","doi-asserted-by":"crossref","first-page":"125","DOI":"10.5588\/ijtld.17.0486","article-title":"Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges","volume":"22","author":"Swindells","year":"2018","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026022021035746500_bib4","doi-asserted-by":"crossref","first-page":"937","DOI":"10.5588\/ijtld.17.0515","article-title":"Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study","volume":"22","author":"Rajoli","year":"2018","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026022021035746500_bib5","doi-asserted-by":"crossref","first-page":"e00007","DOI":"10.1128\/AAC.00007-19","article-title":"Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection","volume":"63","author":"Kaushik","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2026022021035746500_bib6","volume-title":"WHO consolidated guidelines on drug-resistant tuberculosis treatment.","author":"World Health Organization","year":"2019"},{"key":"2026022021035746500_bib7","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1164\/rccm.200905-0795OC","article-title":"Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection","volume":"180","author":"Zhang","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026022021035746500_bib8","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1164\/rccm.201103-0397OC","article-title":"Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection","volume":"184","author":"Zhang","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026022021035746500_bib9","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1093\/jac\/dku504","article-title":"Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug","volume":"70","author":"Svensson","year":"2015","journal-title":"J Antimicrob Chemother"},{"key":"2026022021035746500_bib10","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1128\/AAC.04171-14","article-title":"Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects","volume":"59","author":"Winter","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2026022021035746500_bib11","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1164\/rccm.201912-2489OC","article-title":"Rifapentine population pharmacokinetics and dosing recommendations for latent tuberculosis infection","volume":"202","author":"Hibma","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"2026022021035746500_bib12","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1055\/s-0028-1085705","article-title":"Using animal models to develop new treatments for tuberculosis","volume":"29","author":"Nuermberger","year":"2008","journal-title":"Semin Respir Crit Care Med"},{"key":"2026022021035746500_bib13","doi-asserted-by":"crossref","first-page":"tbtb-2017","DOI":"10.1128\/microbiolspec.TBTB2-0034-2017","article-title":"Preclinical efficacy testing of new drug candidates","volume":"5","author":"Nuermberger","year":"2017","journal-title":"Microbiol Spectr"},{"key":"2026022021035746500_bib14","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1056\/NEJMoa1806808","article-title":"One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis","volume":"380","author":"Swindells","year":"2019","journal-title":"N Engl J Med"},{"key":"2026022021035746500_bib15","doi-asserted-by":"crossref","first-page":"4178","DOI":"10.1128\/AAC.00830-09","article-title":"Paradoxical effect of isoniazid on the activity of rifampin-pyrazinamide combination in a mouse model of tuberculosis","volume":"53","author":"Almeida","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"2026022021035746500_bib16","doi-asserted-by":"crossref","first-page":"4331","DOI":"10.1128\/AAC.00912-12","article-title":"Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis","volume":"56","author":"Rosenthal","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"2026022021035746500_bib17","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1128\/AAC.00720-11","article-title":"Pharmacokinetics and pharmacodynamics of TMC207 and its N-desmethyl metabolite in a murine model of tuberculosis","volume":"56","author":"Rouan","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"2026022021035746500_bib18","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.7164\/antibiotics.37.1066","article-title":"Pharmacokinetics of rifapentine, a new long lasting rifamycin, in the rat, the mouse and the rabbit","volume":"37","author":"Assandri","year":"1984","journal-title":"J Antibiot (Tokyo)"},{"key":"2026022021035746500_bib19","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1128\/AAC.00177-16","article-title":"Clofazimine contributes sustained antimicrobial activity after treatment cessation in a mouse model of tuberculosis chemotherapy","volume":"60","author":"Swanson","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"key":"2026022021035746500_bib20","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1208\/s12248-019-0341-y","article-title":"Guidance for rifampin and midazolam dosing protocols to study intestinal and hepatic cytochrome P450 (CYP) 3A4 induction and de-induction","volume":"21","author":"Kapetas","year":"2019","journal-title":"AAPS J"},{"key":"2026022021035746500_bib21","author":"Vermeulen"},{"key":"2026022021035746500_bib22","doi-asserted-by":"crossref","first-page":"5485","DOI":"10.1128\/AAC.05293-11","article-title":"Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis","volume":"55","author":"Tasneen","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2026022021035746500_bib23","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1084\/jem.104.5.737","article-title":"Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique: I. The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy","volume":"104","author":"McCune","year":"1956","journal-title":"J Exp Med"},{"key":"2026022021035746500_bib24","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1084\/jem.104.5.763","article-title":"The fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique: II. The conversion of tuberculous infection to the latent state by the administration of pyrazinamide and a companion drug","volume":"104","author":"McCune","year":"1956","journal-title":"J Exp Med"},{"key":"2026022021035746500_bib25","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1084\/jem.123.3.445","article-title":"Microbial persistence: I. The capacity of tubercle bacilli to survive sterilization in mouse tissues","volume":"123","author":"McCune","year":"1966","journal-title":"J Exp Med"},{"key":"2026022021035746500_bib26","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1084\/jem.123.3.469","article-title":"Microbial persistence: II. Characteristics of the sterile state of tubercle bacilli","volume":"123","author":"McCune","year":"1966","journal-title":"J Exp Med"},{"key":"2026022021035746500_bib27","first-page":"625","article-title":"La dur\u00e9e optimale de l\u2019antibioth\u00e9rapie par l\u2019association isoniazide + rifampicine dans la tuberculose exp\u00e9rimentale de la souris. Etude de la phase post-th\u00e9rapeutique. Epreuve de la cortisone","volume":"3","author":"Grumbach","year":"1975","journal-title":"Rev Fr Mal Respir"},{"key":"2026022021035746500_bib28","doi-asserted-by":"crossref","first-page":"S35","DOI":"10.1111\/j.1753-4887.1995.tb01514.x","article-title":"Mechanisms underlying the increased susceptibility of aged mice to tuberculosis","volume":"53","author":"Orme","year":"1995","journal-title":"Nutr Rev"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/205\/5\/570\/67008742\/ajrccm_205_5_570.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/205\/5\/570\/67008742\/ajrccm_205_5_570.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T02:04:09Z","timestamp":1771639449000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/205\/5\/570\/8492040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,1]]},"references-count":28,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3,1]]},"published-print":{"date-parts":[[2022,3,1]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.202012-4541oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,3]]},"published":{"date-parts":[[2022,3,1]]},"assertion":[{"value":"2020-12-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}