National genomic survey of drug-resistance and multi-jurisdictional clusters of Mycobacterium tuberculosis in Australia 2015–2023

Background Tuberculosis is a global public health priority. In Australia, genomic analysis of Mycobacterium tuberculosis ( Mtb ) occurs at state or territory level, thus multijurisdictional genomics of Mtb remains poorly understood. We present the first national assessment of Mtb using nine years of genomic data from all Australian jurisdictions, as a part of the Australian Pathogen Genomics program. Methods Our national Mtb sequence dataset spanned 2015–2023 and represented culture-confirmed cases. AusTrakka was optimised to allow secure, national contribution of Mtb genomes and metadata. Drug resistance was determined using tbtamr , and genomic clusters were identified via hierarchical single linkage clustering (5 SNPs) from pairwise SNP distances. Criteria were established to identify clusters of national public health significance. Findings We analysed 6616 Mtb sequences, representing 59% of notified cases nationwide. Lineages 1–4 were detected, with lineage 2 the most prevalent and drug resistant. At the 5-SNP threshold, 373 genomic (17% of sequences) clusters were identified, with 48 (13%) clusters identified as nationally significant. Critically, 31 genomic clusters spanned multiple jurisdictions and persisted for >5 years. Genomic analysis inferred low rates of Mtb drug resistance in Australia. Interpretation This first-of-a-kind study on genomic diversity of Mtb in Australia highlighted the benefits of national aggregation and analysis of Mtb sequencing data. It identified multi-jurisdictional clusters which, on average, persisted longer than clusters within jurisdictions. We also established the framework and infrastructure for implementing national coordination, detection, and surveillance of priority clusters to enhance tuberculosis control in Australia. Funding Australian National Health and Medical Research Council, Medical Research Futures Fund (FSPGN00049).