Transmission of bedaquiline-resistant Mycobacterium tuberculosis in KwaZulu-Natal, South Africa.

RATIONALE: Bedaquiline is a critical component of new drug-resistant tuberculosis (TB) treatment regimens. Emergence of bedaquiline-resistant Mycobacterium tuberculosis (Mtb) threatens to undermine already limited treatment options. Understanding the evolution and transmission of bedaquiline-resistant strains is a high priority for TB control.

OBJECTIVES: We evaluated the prevalence, strain genetic diversity, and transmission of bedaquiline resistance among people with drug-resistant TB.

METHODS: We conducted a prospective study of all patients diagnosed with TB resistant to a fluoroquinolone or a second-line injectable drug in KwaZulu-Natal province, South Africa, between 2018 and 2022. We utilized whole genome sequencing (WGS), SNP-based clustering, and Bayesian reconstruction of transmission trees to examine the genomic characteristics and transmission networks of bedaquiline-resistant Mtb strains.

MEASUREMENTS AND MAIN RESULTS: We enrolled 843 of 1070 eligible individuals and obtained WGS for 632 participants. Of the sequenced isolates, 14% (n = 89) were genotypically bedaquiline-resistant, 67% (n = 60) of which were in clusters of recently transmitted infections. Resistance was present across all Mtb lineages and across strains with different resistance profiles to other TB drugs. We observed no differences in lineage distribution, bedaquiline resistance-associated mutations, or drug resistance profiles between clustered and nonclustered isolates. Transmission inference and geographic reconstruction of transmission networks indicate considerable unsampled cases within transmission networks.

CONCLUSIONS: Bedaquiline resistance was common in this cohort of individuals with highly drug-resistant TB. Most bedaquiline-resistant infections were attributable to recent transmission, involving Mtb strains with diverse genetic backgrounds and a variety of causative mutations. The diversity and transmissibility of bedaquiline-resistant Mtb signal a growing public health threat.