LAUSR

Criteria to definephenotypic resistance to bedaquiline (BDQ) are not variants were all found among susceptible isolates. All CFZ susceptible well determined and uncertainties around the genetic basis of resistance and cross resistance with clofazimine (CFZ) for this novel drug continue (Keller et al., 2015; Villellas et al., 2017; Xu et al., 2017). It is essential that susceptibility criteria for Mycobacterium tuberculosis (MTB) isolates towards new and repurposed drugs are established, given their increasing relevance in the new WHO treatment recommendations (Borisov et al., 2017; Falzon et al., 2017). The study reported by Ismail and colleagues in EBioMedicine addresses this important topic (Ismail et al., 2018). The study was performed in the Republic of South Africa, a country with a high burden of drug resistant tuberculosis (TB) and a major prescriber of BDQ with approximately 7420 of the 12,194 courses dispensed worldwide (Country Updates (Internet), 2017). This study presents an important retrospective analysis of South African TB isolates intended to inform the interpretive criteria for BDQ drug susceptibility testing (DST) by using various methodologies to determine BDQ epidemiological cutoff values and assessing the role of putative resistance-associated variants. The investigators analysed 391 strains (from 378 BDQ naïve and 13 BDQ-exposed patients) by determining Minimum Inhibitory Concentration (MIC) on Middlebrook 7H9 broth microdilution and MGIT 960 liquid culture and defining susceptibility, resistance and intermediate levels of resistance (the latter not currently accepted for mycobacteria). All but one isolate had whole genome sequencing (WGS) performed. Microbiological failures among BDQ exposed patients occurred in those with a nonsusceptible BDQMIC, an Rv0678mutation and ≤2 active drug classes. Cross-resistance between CFZ and BDQ was complete for patient isolates with Rv0678 mutants and defined resistant to BDQ. On the other hand, Rv0678 mutations were not found to be the dominant cause of CFZ resistance, and only 1/3 of CFZ intermediate/resistant strains were also BDQ-resistant. Also, Rv1979 mutations were reported to be associated with only ≤1% intermediate BDQ resistance and pepQ