We Are Underprepared for Bedaquiline Resistance: A Call for Clinical and Programmatic Readiness

Bedaquiline has transformed the treatment of multidrug-resistant tuberculosis (MDR-TB). However, bedaquiline resistance now threatens these gains. Emerging surveillance data demonstrate both baseline and acquired resistance across high-burden settings, with bedaquiline-resistant disease associated with poor clinical outcomes, high mortality, and growing evidence of transmission. In this Perspective, we examine the converging factors driving this trend, including bedaquiline's unique pharmacokinetic properties and limitations of current drug-susceptibility testing (DST) approaches. We describe critical gaps in phenotypic and genotypic DST, including delayed detection, diagnostic gray zones, and heteroresistance, which undermine timely clinical decision-making. We highlight the need to evaluate bedaquiline-sparing regimens alongside strengthened resistance surveillance, development of composite DST standards, and adoption of rapid molecular tools such as targeted next-generation sequencing. We emphasize the importance of equitable access to effective companion drugs and robust, person-centered treatment support. Coordinated action across clinical, programmatic, and research domains is essential to preserve bedaquiline's efficacy and future TB treatments.