Transmission is a key driver of extensively drug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant (XDR) TB are threatening global TB control. The World Health Organization has recently endorsed new regimens for the treatment of MDR-TB that rely on the new and repurposed drugs bedaquiline, pretomanid and linezolid with or without moxifloxacin (BPaL(M)). As BPaL(M) is being rolled-out, resistance to these new drugs is already emerging, leading to acquired XDR-TB. Importantly, instances of transmitted XDR-TB have been reported. The spread of highly drug-resistant M. tuberculosis (MTB) strains pose at risk novel TB treatments that took decades to develop. In this study, we analyzed 6,926 MTB genomes from a 13-year nationwide study in Georgia, a known geographical hotspot of MDR-TB, together with more than 80,000 MTB genomes from public sources to estimate the relative contribution of transmission to the burden of XDR-TB. We show that XDR-TB is already geographically widespread, occurring in at least 27 countries across four continents. Moreover, we estimated that a quarter of the XDR-TB cases identified are likely the consequence of transmission. Our findings call for urgent improvements in the global diagnostic capacity, infection control, and surveillance of XDR-TB.