Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance, 2nd ed
Overview
Of the more than 10 million people estimated to have fallen ill with tuberculosis (TB) in 2022, just over 400 000 people developed TB resistant to rifampicin (RIF), and 1.3 million people developed TB resistant isoniazid (INH). Drug resistance must be detected rapidly and accurately to initiate appropriate and effective treatment.
Detection of RIF resistance has improved significantly with the introduction of rapid molecular diagnostic tools that require less complex infrastructure and are simpler to perform than conventional culture-based methods. Resistance mechanisms to INH and fluoroquinolones are also well understood, and molecular tools are commercially available for detecting mutations associated with resistance to these drugs. Recent developments in targeted next-generation sequencing assays for detection of drug-resistance represent an important step forward. A major obstacle to the development and utility of sequence-based technologies and next-generation molecular diagnostics to detect resistance to a larger spectrum of anti-TB medicines has been the lack of a standardized, comprehensive catalogue of mutations.
In response to this issue the WHO developed a catalogue of mutations and their association with phenotypic drug resistance in 2021. The catalogue provides a reference standard for the interpretation of mutations conferring resistance to 13 anti-TB medicines. This 2023 update includes the analysis of over 52 000 isolates with matched data on whole genome sequencing and phenotypic drug susceptibility testing from 67 countries for the 13 medicines. It lists more than 30 000 variants, their frequency and association with resistance and susceptibility and includes methods used, mutations identified and summaries of important findings for each drug. The additional isolates included in this update resulted in 86 variants associated with bedaquiline resistance (up from zero in the previous catalogue), eight variants associated with linezolid resistance (up from one in the previous catalogue) and 24 variants associated with resistance to delamanid (up from one in the previous catalogue).
Tuberculosis laboratories around the world can use the catalogue as a support in the interpretation of genome sequencing results. The catalogue can also guide the development of new molecular drug susceptibility tests, including targeted next-generation sequencing.
The full catalogue in Excel format can be downloaded here.
