<i>In Vitro</i> Activity of Bedaquiline against Nontuberculous Mycobacteria in China

Abstract

The main goal of our study was to evaluate the <i>in vitro</i> bedaquiline susceptibility of six prevalent species of pathogenic nontuberculous mycobacteria (NTM) in China. In addition, we investigated the potential molecular mechanisms contributing to bedaquiline resistance in the different NTM species. Among slowly growing mycobacteria (SGM), bedaquiline exhibited the highest activity against <i>Mycobacterium avium</i>; the MIC₅₀ and MIC₉₀ values were 0.03 and 16 mg/liter, respectively. Among rapidly growing mycobacteria (RGM), <i>Mycobacterium abscessus</i> subsp. <i>abscessus</i> (<i>M. abscessu</i>s) and <i>Mycobacterium abscessus</i> subsp. <i>massiliense</i> (<i>M. massiliense</i>) seemed more susceptible to bedaquiline than <i>Mycobacterium fortuitum</i>, with MIC₅₀ and MIC₉₀ values of 0.13 and >16 mg/liter, respectively, for both species. On the basis of bimodal distributions of bedaquiline MICs, we proposed the following epidemiological cutoff (ECOFF) values: 1.0 mg/liter for SGM and 2.0 mg/liter for RGM. Among <i>M. avium</i>, <i>Mycobacterium intracellulare</i>, <i>Mycobacterium kansasii</i>, <i>M. abscessus</i>, <i>M. massiliense</i>, and <i>M. fortuitum</i> isolates, 14 (29.8%), 41 (27.2%), 33 (39.3%), 44 (20.2%), 42 (25.8%), and 7 (31.8%), respectively, were resistant to bedaquiline. No significant differences in the proportions of bedaquiline resistance among these species were observed (<i>P</i> > 0.05). Genetic mutations were observed in 74 isolates (10.8%), with all nucleotide substitutions being synonymous. In conclusion, our data demonstrate that bedaquiline shows moderate <i>in vitro</i> activity against NTM species. Using the proposed ECOFF values, we could distinguish between bedaquiline-resistant and -susceptible strains with the broth dilution method. In addition, no nonsynonymous mutations in the <i>atpE</i> gene that conferred bedaquiline resistance in all six NTM species were identified.