Bedaquiline-Resistant Tuberculosis Associated with <i>Rv0678</i> Mutations

To the Editor: Bedaquiline is used to treat drugresistant tuberculosis. 1 Programmatic use of bedaquiline in South Africa began in 2015 and by March 2020 accounted for just over half of global use. Resistance to bedaquiline was initially reported to be due to target-based mutations in the gene atpE encoding subunit C of the ATP synthase complex. 2 However, non-target-based mutations in the mmpR (Rv0678) gene encoding the MmpS5-MmpL5 efflux pump repressor are increasingly associated with bedaquiline resistance, although some have shown hypersusceptibility. 3 We describe mutations associated with phenotypic resistance to bedaquiline in surveillance isolates identified in South Africa among patients beginning or not responding clinically and microbiologically to a bedaquiline-based regimen. Ethics approval was obtained from the University of Witwatersrand Human Research Ethic Committee. Bedaquiline testing was performed at the World Health Organization supranational tuberculosis reference laboratory in Johannesburg, which is accredited according to the International Organization for Standardization 15189 standards. Bedaquiline phenotypic drug susceptibility was evaluated with the use of previously described methods and criteria for interpretation. 4 Sanger sequencing or whole-genome sequencing, with a mutation-frequency cutoff set at 5%, was used to identify phenotypically resistant isolates as previously described. 5 Between 2015 and 2019, a total of 199 of 3005 isolates (7%) were identified as bedaquilineresistant and were sequenced successfully. More than a quarter of the isolates (52 of 199 [26%]) were from patients who did not have a response to treatment. Whole-genome sequencing was performed on the majority of isolates (130 of 199 [65%]), and all were found to harbor an Rv0678