Tuberculosis resistance acquisition in space and time: an analysis of globally diverse M. tuberculosis whole genome sequences

BackgroundMycobacterium tuberculosis (MTB) whole genome sequencing data can provide insights into temporal and geographic trends in resistance acquisition and inform public health interventions.\n\nMethodsWe curated a set of clinical MTB isolates with high quality sequencing and culture-based drug susceptibility data spanning four lineages and more than 20 countries. We constructed geographic and lineage specific MTB phylogenies and used Bayesian molecular dating to infer the most-recent-common-susceptible-ancestor age for 4,869 instances of resistance to 10 drugs.\n\nFindingsOf 8,550 isolates curated, 6,099 from 15 countries met criteria for molecular dating. The number of independent resistance acquisition events was lower than the number of resistant isolates across all countries, suggesting ongoing transmission of drug resistance. Ancestral age distributions supported the presence of old resistance, [≥]20 years prior, in the majority of countries. A consistent order of resistance acquisition was observed globally starting with resistance to isoniazid, but resistance ancestral age varied by country. We found a direct correlation between country wealth and resistance age (R2= 0.47, P-value= 0.014). Amplification of fluoroquinolone and second-line injectable resistance among multidrug-resistant isolates is estimated to have occurred very recently (median ancestral age 4.7 years IQR 1.9-9.8 prior to sample collection). We found the sensitivity of commercial molecular diagnostics for second-line resistance to vary significantly by country (P-value 20 years).\n\nCountries with lower gross wealth indices were found to have more recent resistance acquisition to the drug rifampicin. Based on the resistance patterns identified in our study we estimate that commercial diagnostic tests vary considerably in sensitivity for second-line resistance diagnosis by country.\n\nImplications of all available evidenceThe longevity of resistant MTB in many parts of the world emphasizes its fitness for transmission and its continued threat to public health. The association between country wealth and recent resistance acquisition emphasizes the need for continued investment in TB care delivery and surveillance programs. Geographically relevant diagnostics that take into account a countrys unique distribution of resistance are necessary.