Estimating the relative contribution of transmission to bedaquiline resistance burden in tuberculosis. A transmission threshold model.

Bedaquiline (BDQ) is a cornerstone antibiotic for treating multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB). Resistance to BDQ (BDQR) can arise through three mechanisms: spontaneous mutation, acquisition during treatment, or transmission of a resistant strain. We developed a transmission threshold model to estimate the contribution of each mechanism to BDQR burden in MDR/RR-TB We integrated four data sources: (i) novel estimates of spontaneous resistance probability; (ii) updated estimates of acquired resistance during treatment probability; (iii) a systematic review of country-level BDQR prevalence in MDR/RR-TB (BR-MDR/RR-TB); and (iv) WHO MDR/RR-TB notification and treatment data. We estimated the proportion of BR-MDR/RR-TB attributable to transmission, using transmission threshold values defined as the ratio of BDQR observed in prevalence studies to expectations from spontaneous and acquired mechanisms alone. Analyses were conducted across hypothetical BDQR prevalence and treatment coverage scenarios, as well as country-specific data. We estimated spontaneous resistance among all MDR/RR-TB at 0.073% (95% CrI: 0.062-0.085%) and acquired resistance among MDR/RR-TB patients receiving BDQ at 3.6% (95% CrI: 2.8-4.4%). BDQR prevalence among MDR/RR-TB varied between 0-20% across 18 countries between 2015-2024. Scenario modelling suggested that spontaneous and acquired resistance alone could not account for BDQR prevalence among MDR/RR-TB above 1.9% in settings where [≤]50% of MDR/RR-TB patients had received BDQ in the previous year-- suggesting possible transmission. In Brazil, China, Mozambique, and South Africa, threshold values and associated uncertainty were consistent with BR-MDR/RR-TB transmission since 2020. Other countries had threshold values consistent with resistance primarily arising spontaneously or through acquisition. Determining country- and year-specific threshold values may help guide decisions on when to prioritise protecting a new antibiotic by preventing resistance acquisition versus when ongoing transmission requires interventions focused on interrupting transmission.