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bioRxiv · 10.1101/2024.12.11.627976

Regimen comprising clarithromycin, clofazimine and bedaquiline is more efficacious than monotherapy in a mouse model of chronic Mycobacterium avium lung infection

Rimal, B.·Howe, R. A.·Panthi, C. M.·Lamichhane, G.
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Abstract

Mycobacterium avium, 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 M. avium pulmonary disease, we evaluated the efficacy of individual antibiotics-- clarithromycin, clofazimine, and rifabutin--and combination regimens including clarithromycin+bedaquiline and clarithromycin+clofazimine+bedaquiline. Clarithromycin demonstrated potent bactericidal activity, reducing lung bacterial burden by 2.2 log10 CFU, while clofazimine transitioned from bacteriostatic to bactericidal, achieving a 1.7 log10 CFU reduction. Rifabutin was bacteriostatic against M. avium MAC 101 but ineffective against MAC 104. The triple-drug regimen of clarithromycin+clofazimine+bedaquiline was the most effective, achieving a 3.3 log10 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 M. avium pulmonary disease.

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Rimal, B., Howe, R. A., Panthi, C. M., Lamichhane, G.. 2024-12-11. Regimen comprising clarithromycin, clofazimine and bedaquiline is more efficacious than monotherapy in a mouse model of chronic Mycobacterium avium lung infection. https://doi.org/10.1101/2024.12.11.627976

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