Rifamycin-, macrolide-, and ethambutol-free combinations to treat <i>Mycobacterium avium</i> complex lung disease

&lt;sec&gt;&lt;title&gt;OBJECTIVE&lt;/title&gt;Poor sustained sputum culture conversion with guidelines-based therapy for Mycobacterium avium complex lung disease highlights the need for new and improved multidrug combinations.&lt;/sec&gt;&lt;sec&gt;&lt;title&gt;DESIGN&lt;/title&gt;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.&lt;/sec&gt;&lt;sec&gt;&lt;title&gt;RESULTS&lt;/title&gt;MIC 90 of rifabutin, rifampin, azithromycin, and ethambutol were 4, 16, 256, and 128 mg/L, respectively. Among other drugs, MIC 90 (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 log 10 CFU/mL MAC, replacement of rifabutin in the standard therapy resulted in 6.27 ± 0.28 log 10 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 log 10 CFU/mL MAC. The tebipenem–tedizolid–minocycline combination killed 4.82 ± 0.42 log 10 CFU/mL; however, addition of bedaquiline resulted in a lower kill of 2.71 ± 0.22 log 10 CFU/mL, suggesting a likely antagonism.&lt;/sec&gt;&lt;sec&gt;&lt;title&gt;CONCLUSION&lt;/title&gt;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.&lt;/sec&gt;