Emergence of bedaquiline, pretomanid and linezolid resistance after implementation of new drug-resistant tuberculosis regimens in South Africa

PROJECT SUMMARY Drug-resistant (DR) tuberculosis (TB) threatens to derail the progress made in global control of TB and HIV. Of the nearly 500,000 new cases of multidrug-resistant (MDR) TB worldwide annually, only half are cured and those with extensively drug-resistant (XDR) TB have even poorer outcomes. New and repurposed drugs for TB have revolutionized MDR/XDR TB treatment, resulting in improved cure rates and shorter, fully-oral regimens. Bedaquiline (Bdq) and pretomanid (Pa) are medications from the first novel TB drug classes created since 1968. Combined with a repurposed medication, linezolid (Lzd), these new drugs have provided substantial improvements in survival and cure rates. The emergence of widespread Bdq, Pa or Lzd resistance could undermine these drugs’ potential. The natural history of drug resistance is conceptualized as evolving from sporadic drug-resistant mutants with low-level resistance soon after the drug is introduced, to a few highly adapted transmissible strains that spread resistance across a population in a mature DR TB epidemic. As seen in MDR/XDR TB, population-level drug resistance appears only after widespread transmission of drug-resistant strains occurs, rather than through isolated instances of acquired resistance on TB treatment. In the proposed study, we will examine the emergence of Bdq, Pa, and Lzd resistance in South Africa as treatment with these new drugs is expanded to all drug-resistant TB cases. In Aim 1, we will prospectively characterize changes in resistance-conferring mutations for Bdq, Pa and Lzd using whole genome sequencing (WGS) on isolates from patients in three provinces. In Aim 2, we will examine minimum inhibitory concentrations (MIC) to assess for meaningful shifts in the level of resistance to Bdq, Pa, and Lzd over the course of the study. In Aim 3, we will use WGS, prior treatment exposure, and geospatial analysis to identify increased transmissibility and geographic spread of Bdq, Pa, and Lzd resistance. The proposed study will provide essential information that can inform the development of new rapid diagnostic assays for these critical new TB drugs. Further, our phenotypic analyses will inform decisions on whether it is necessary to add drugs to existing treatment regimens or increase the dose of a specific medication. Finally, our analyses of genetic clonality and geographic spread will provide early warning signs to TB control programs about the potential for widespread transmitted resistance. South Africa serves as a bellwether for the emergence and spread of DR TB. It is a high-burden country that is leading the global scale up of new treatment regimens containing Bdq, Lzd, and now Pa, for all drug-resistant patients. The proposed study is optimally timed to prospectively study the emergence, evolution and dispersal of drug resistance to Bdq, Pa and Lzd as they are being scaled up for the DR TB treatment worldwide.