{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:35:19Z","timestamp":1768520119928,"version":"3.49.0"},"posted":{"date-parts":[[2024,12,11]]},"group-title":"Microbiology","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T00:00:00Z","timestamp":1733875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,12,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  <jats:italic>Mycobacterium avium<\/jats:italic>\n                  , a leading non-tuberculous mycobacterium (NTM) pathogen, causes chronic pulmonary infections, particularly in individuals with underlying lung conditions or immunosuppression. Current treatments involve prolonged multi-drug regimens with poor outcomes and significant side effects, highlighting the urgent need for improved therapies. Using a BALB\/c mouse model of chronic\n                  <jats:italic>M. avium<\/jats:italic>\n                  pulmonary disease, we evaluated the efficacy of individual antibiotics\u2014 clarithromycin, clofazimine, and rifabutin\u2014and combination regimens including clarithromycin+bedaquiline and clarithromycin+clofazimine+bedaquiline. Clarithromycin demonstrated potent bactericidal activity, reducing lung bacterial burden by 2.2 log\n                  <jats:sub>10<\/jats:sub>\n                  CFU, while clofazimine transitioned from bacteriostatic to bactericidal, achieving a 1.7 log\n                  <jats:sub>10<\/jats:sub>\n                  CFU reduction. Rifabutin was bacteriostatic against\n                  <jats:italic>M. avium<\/jats:italic>\n                  MAC 101 but ineffective against MAC 104. The triple-drug regimen of clarithromycin+clofazimine+bedaquiline was the most effective, achieving a 3.3 log\n                  <jats:sub>10<\/jats:sub>\n                  CFU reduction in bacterial load, with 98% clearance within the first week and continued efficacy over eight weeks. Gross pathology confirmed these results, with granulomatous lesions observed only in untreated or rifabutin-treated mice. Combination therapy demonstrated enhanced efficacy compared to monotherapy. The findings underscore the potential of oral clarithromycin+clofazimine+bedaquiline or clarithromycin+clofazimine regimen as a promising therapeutic strategy for\n                  <jats:italic>M. avium<\/jats:italic>\n                  pulmonary disease.\n                <\/jats:p>","DOI":"10.1101\/2024.12.11.627976","type":"posted-content","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T22:51:53Z","timestamp":1734043913000},"source":"Crossref","is-referenced-by-count":2,"title":["Regimen comprising clarithromycin, clofazimine and bedaquiline is more efficacious than monotherapy in a mouse model of chronic\n                  <i>Mycobacterium avium<\/i>\n                  lung infection"],"prefix":"10.64898","author":[{"given":"Binayak","family":"Rimal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth A.","family":"Howe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chandra","family":"Panthi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2214-0114","authenticated-orcid":false,"given":"Gyanu","family":"Lamichhane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024121223001413000_2024.12.11.627976v1.1","doi-asserted-by":"crossref","first-page":"102267","DOI":"10.1016\/j.tube.2022.102267","article-title":"Nontuberculous mycobacteria in the environment","volume":"137","year":"2022","journal-title":"Tuberculosis"},{"key":"2024121223001413000_2024.12.11.627976v1.2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1651491"},{"key":"2024121223001413000_2024.12.11.627976v1.3","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1080\/17476348.2021.1987891","article-title":"Nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex - disease burden, unmet needs, and advances in treatment developments","volume":"15","year":"2021","journal-title":"Expert Rev Respir Med"},{"key":"2024121223001413000_2024.12.11.627976v1.4","doi-asserted-by":"crossref","unstructured":"Zo S , Choe J , Kim DH , Kim S-Y , Jhun BW . 2024. Long-term clinical course of Mycobacterium avium complex pulmonary disease patients with treatment failure. Antimicrob Agents Chemother 68.","DOI":"10.1128\/aac.01055-24"},{"key":"2024121223001413000_2024.12.11.627976v1.5","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/cid\/ciaa241","article-title":"Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS\/ERS\/ESCMID\/IDSA Clinical Practice Guideline","volume":"71","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2024121223001413000_2024.12.11.627976v1.6","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.ccm.2023.06.009","article-title":"Treatment of Mycobacterium avium Complex Pulmonary Disease: When Should I Treat and What Therapy Should I Start?","volume":"44","year":"2023","journal-title":"Clin Chest Med"},{"key":"2024121223001413000_2024.12.11.627976v1.7","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ccm.2021.11.007","article-title":"Nontuberculous Mycobacteria","volume":"43","year":"2022","journal-title":"Clin Chest Med Diagnosis Treat"},{"key":"2024121223001413000_2024.12.11.627976v1.8","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2016-209729"},{"key":"2024121223001413000_2024.12.11.627976v1.9","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1513\/AnnalsATS.202008-925OC","article-title":"Amikacin Liposome Inhalation Suspension for Mycobacterium avium Complex Lung Disease: A 12-Month Open-Label Extension Clinical Trial","volume":"18","year":"2021","journal-title":"Ann Am Thorac Soc"},{"key":"2024121223001413000_2024.12.11.627976v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2019.08.010"},{"key":"2024121223001413000_2024.12.11.627976v1.11","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04841-14"},{"key":"2024121223001413000_2024.12.11.627976v1.12","doi-asserted-by":"crossref","unstructured":"Lanoix J-P , Joseph C , Peltier F , Castelain S , Andr\u00e9jak C. 2020. Synergistic Activity of Clofazimine and Clarithromycin in an Aerosol Mouse Model of Mycobacterium avium Infection. Antimicrob Agents Chemother 64.","DOI":"10.1128\/AAC.02349-19"},{"key":"2024121223001413000_2024.12.11.627976v1.13","doi-asserted-by":"crossref","first-page":"e0311167","DOI":"10.1371\/journal.pone.0311167","article-title":"Efficacy of mefloquine and its enantiomers in a murine model of Mycobacterium avium infection","volume":"19","year":"2024","journal-title":"PLoS One"},{"key":"2024121223001413000_2024.12.11.627976v1.14","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/20.5.1186"},{"key":"2024121223001413000_2024.12.11.627976v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.09.031"},{"key":"2024121223001413000_2024.12.11.627976v1.16","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.11.2521"},{"key":"2024121223001413000_2024.12.11.627976v1.17","doi-asserted-by":"crossref","first-page":"20631","DOI":"10.1038\/s41598-023-48001-y","article-title":"Intracellular and in vivo activities of oxazolidinone drugs against Mycobacterium avium complex infection","volume":"13","year":"2023","journal-title":"Sci Rep"},{"key":"2024121223001413000_2024.12.11.627976v1.18","doi-asserted-by":"crossref","first-page":"1115530","DOI":"10.3389\/fcimb.2023.1115530","article-title":"Efficacy of PBTZ169 and pretomanid against Mycobacterium avium, Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum in BALB\/c mice models","volume":"13","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"key":"2024121223001413000_2024.12.11.627976v1.19","first-page":"475","article-title":"Triple-Antibiotic Combination Exerts Effective Activity against Mycobacterium avium subsp","volume":"13","year":"2024","journal-title":"hominissuis Biofilm and Airway Infection in an In Vivo Murine Model. Antibiotics"},{"key":"2024121223001413000_2024.12.11.627976v1.20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199309163291202"},{"key":"2024121223001413000_2024.12.11.627976v1.21","doi-asserted-by":"publisher","DOI":"10.1086\/514748"},{"key":"2024121223001413000_2024.12.11.627976v1.22","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkw417"},{"key":"2024121223001413000_2024.12.11.627976v1.23","first-page":"102268","article-title":"Clofazimine as a comparator for preclinical efficacy evaluations of experimental therapeutics against pulmonary M","volume":"137","year":"2022","journal-title":"abscessus infection in mice. Tuberculosis"},{"key":"2024121223001413000_2024.12.11.627976v1.24","unstructured":"Larsen M. 2000. Some Common Methods in Mycobacterial Genetics, p. 313\u2013320. In Hatfull, GF , Jacobs, W. R. J (eds.), Molecular Genetics of Mycobacteria. American Society for Microbiology, Washington DC."},{"key":"2024121223001413000_2024.12.11.627976v1.25","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00766-06"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.12.11.627976","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:38:51Z","timestamp":1768462731000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.12.11.627976"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,11]]},"references-count":25,"URL":"https:\/\/doi.org\/10.1101\/2024.12.11.627976","relation":{},"subject":[],"published":{"date-parts":[[2024,12,11]]},"subtype":"preprint"}}