Oral Presentation Australian Society for Microbiology Annual Scientific Meeting 2023

Genomic markers of drug resistance in Mycobacterium tuberculosis populations with minority variants  (93853)

Xiaomei Zhang 1 2 , Connie Lam 2 3 , Elena Martinez 2 4 , Eby Sim 2 3 , Taryn Crighton 4 5 , Ben Marais 1 2 , Vitali Sintchenko 1 2 3 4
  1. Centre for Research Excellence in Tuberculosis (TB-CRE), Centenary Institute, Sydney, NEW SOUTH WALES, Australia
  2. Sydney Infectious Diseases Institute (Sydney ID), The University of Sydney, Sydney, New South Wales, Australia
  3. Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Western Sydney Local Health District, Sydney, New South Wales, Australia
  4. Centre for Infectious Diseases and Microbiology-Laboratory Services, Westmead Hospital, Western Sydney Local Health District, Sydney, New South Wales, Australia
  5. NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, NSW Health Pathology , Sydney, New South Wales, Australia

Minority variants of Mycobacterium tuberculosis harbouring mutations conferring resistance can become dominant populations during tuberculosis (TB) treatment, leading to treatment failure. Our understanding of  drug resistant within-host sub-populations and the frequency of resistance conferring mutations in minority variants remains limited.

M. tuberculosis sequences recovered from liquid cultures of culture-confirmed TB cases notified between January 2017 and December 2021 in New South Wales, Australia were examined. Potential drug resistance conferring minority variants were identified using LoFreq, and mixed populations of different M. tuberculosis strains (>=100 SNPs apart) were examined using QuantTB.

A total of 1831 routinely sequenced M. tuberculosis strains were included in the analysis. Drug resistance conferring minority variants were detected in 3.5% (65/1831) of sequenced cultures; 84.6% (55/65) had majority strains that were drug susceptible and 15.4% (10/65) had majority strains that were drug resistant. Minority variants with high confidence drug resistance conferring mutations were 1.5 times more common when the majority strains were drug resistant. Mixed M. tuberculosis strain populations were documented in 10.0% (183/1831) of specimens. Minority variants with high confidence drug resistance conferring mutations were more frequently detected in mixed M. tuberculosis strain populations (2.7%, 5/183) than in single strain populations (0.6%, 10/1648; p=0.01)  .

Drug resistant minority variants require careful monitoring in settings that implement routine M. tuberculosis sequencing. The frequency with which drug resistant minority variants are detected is influenced by selective culture methods and culture-independent sequencing should provide a more accurate picture.