Rifamycin-, macrolide-, and ethambutol-free combinations to treat Mycobacterium avium complex lung disease

OBJECTIVE Poor sustained sputum culture conversion with guidelines-based therapy for Mycobacterium avium complex lung disease highlights the need for new and improved multidrug combinations. DESIGN We tested eight drugs by performing minimum inhibitory concentration (MIC) experiments with the ATCC#700898 strain and 49 clinical isolates, followed by single and multidrug combination studies. RESULTS MIC₉₀ of rifabutin, rifampin, azithromycin, and ethambutol were 4, 16, 256, and 128 mg/L, respectively. Among other drugs, MIC₉₀ (mg/L) in lowest to highest rank order were for bedaquiline (0.25), tedizolid (16), tebipenem (64), and minocycline (128). As monotherapy, none of the drugs had better MAC kill compared to rifampin. While minocycline alone killed 1.76 ± 0.33 log₁₀ CFU/mL MAC, replacement of rifabutin in the standard therapy resulted in 6.27 ± 0.28 log₁₀ CFU/mL MAC kill, showing minocycline's synergistic effect with azithromycin and ethambutol. An example of a macrolide-rifamycin-ethambutol-free oral regimen, the azithromycin-minocycline-tedizolid combination killed 4.35 ± 0.42 log₁₀ CFU/mL MAC. The tebipenem-tedizolid-minocycline combination killed 4.82 ± 0.42 log₁₀ CFU/mL; however, addition of bedaquiline resulted in a lower kill of 2.71 ± 0.22 log₁₀ CFU/mL, suggesting a likely antagonism. CONCLUSION We tested eight different drugs to identify several rifamycin-, macrolide-, and ethambutol-free oral multidrug combinations. The minocycline-based regimens warrant further preclinical and clinical testing. .