The efficacy of a regimen comprising clarithromycin, clofazimine, and bedaquiline in a mouse model of chronic <i>Mycobacterium avium</i> lung infection

<i>Mycobacterium avium,</i> a leading nontuberculous mycobacterium (NTM) pathogen, causes chronic pulmonary infections, particularly in individuals with underlying lung conditions or immunosuppression. Current treatments involve prolonged multidrug regimens with poor outcomes and significant side effects, highlighting the urgent need for improved therapies. Using a BALB/c mouse model of chronic <i>M. avium</i> 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 <i>M. avium</i> 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 8 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 <i>M. avium</i> pulmonary disease.