Implications of edge cases for antimicrobial susceptibility predictions for rifampin, delamanid, and pretomanid with the WHO Mycobacterium tuberculosis mutation catalog.

Abstract

The WHO mutation catalog is the reference for genotypic antimicrobial susceptibility predictions (ASPs) for Mycobacterium tuberculosis. To increase sensitivity, WHO endorsed additional grading rules to classify mutations with insufficient experimental evidence. For rifampin, this includes any non-silent rpoB mutation in the rifampin resistance-determining region (RRDR). For delamanid and pretomanid, the rules include loss-of-function (LoF) variants in six resistance genes, including fbiC. Here, we describe three edge cases in which these additional grading rules overcalled resistance. The first case was a low-frequency rpoB variant in RRDR caused by a sequencing artifact. The second case inv..