The exceptions that prove the rule—a historical view of bedaquiline susceptibility

Abstract

In the accompanying study, Nimmo and colleagues estimated the dates of emergence of mutations in mmpR5 (Rv0678), the most important resistance gene to the anti-tuberculosis drug bedaquiline, in over 3500 geographically diverse Mycobacterium tuberculosis genomes. This provided important insights to improve the design and analysis of clinical trials, as well as the World Health Organization catalogue of resistance mutations, the global reference for interpreting genotypic antimicrobial susceptibility testing results.

A composite reference standard is needed for bedaquiline antimicrobial susceptibility testing forMycobacterium tuberculosiscomplex

“…atpE resistance mutations are rarer than those in mmpR5 ) and the relative MIC increases were chosen for illustrative purposes given that the different mechanisms have never been tested in the same study using the same method under controlled conditions ( e.g. with an on-scale quality control (QC) strain in every batch and with sufficiently low antibiotic concentrations to obtain untruncated MICs for all distributions [ 3 , 13 , 15 , 17 ]). Most atpE resistance mutations confer large MIC increases (>16-fold), meaning that these mutations test reliably as resistant [ 3 , 13 ].…”

“…The misclassification of those mutants as susceptible could be minimised by setting an area of technical uncertainty (ATU) that corresponds to the CB S/R . By contrast, some mutations in resistance genes do not affect the phenotype and the C-11A mmpR5 promoter mutation correlates with a borderline hyper-susceptible phenotype [ 17 ]. Such neutral and modest hyper-susceptible mutations are not distinguished in the World Health Organization (WHO) mutation catalogue and would be classified as group 4/5 “not associated with resistance (interim)” [ 3 ].…”

“…Lastly, LoF mutations in either subunit of the mmpL5 - mmpS5 efflux pump should result in a more marked hyper-susceptible phenotype that must be considered for genotypic AST ( i.e. group 1/2 mmpR5 mutations cannot confer bedaquiline resistance if genetically linked to a LoF mutation in either subunit, but WHO did not endorse epistasis for mmpS5 as the available dataset lacked clinical mmpS5 mutants [ 3 , 17 ]). pepQ mutations likely confer similar MIC increases to mmpR5 but appear to be much rarer and are not affected by LoF mutations in mmpL5 - mmpS5 [ 3 ].…”

“…We acknowledge that genotypic AST can yield systematic false-resistant results. For example, WHO endorsed an additional grading rule whereby any frameshift in mmpR5 should be interpreted as a group 2 mutation, but one frameshift at codon 141 may not confer resistance [ 3 , 17 ]. To demonstrate such exceptions definitively requires multiple replicates of high-quality MICs and careful analysis of other confounders, which is beyond the capacity of most laboratories (once proven, such exceptions should be incorporated in the WHO catalogue).…”