Refined understanding of the impact of the Mycobacterium tuberculosis complex diversity on the intrinsic susceptibility to pretomanid

Abstract

This study confirmed that the Mycobacterium tuberculosis complex lineage 1, responsible for 28% of global tuberculosis cases, is less susceptible to pretomanid (Pa). It also refined the understanding of the intrinsic susceptibilities of lineages 5 and 6, most frequent in West Africa, and lineages 8 and 9. Regulators must review whether these in vitro differences affect the clinical efficacy of the WHO-recommended BPaL(M) regimen and set breakpoints for antimicrobial susceptibility testing accordingly. Notably, regulators should provide detailed justifications for their decisions to facilitate public scrutiny.

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

“…In our view, the approach by Nimmo et al to systematically date the emergence of mutations in resistance genes should be extended to other novel antimicrobials and be carried out routinely as part of WHO surveillance studies (e.g. for pretomanid, for which lineage effects exist and to which intrinsic resistance is known to have emerged repeatedly [ 10 ]). Older mutations could be prioritised for characterisation to assess whether and how they affect the susceptibility to those agents, thereby improving clinical development and facilitating the development of phenotypic and genotypic AST assays.…”