Emergence of Rv0678 (mmpR5) mutations mediating resistance to bedaquiline and clofazimine in a liver transplant recipient with rifampicin-susceptible tuberculosis: A case report

Bedaquiline (Bdq) is a cornerstone therapeutic agent for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB), particularly in short-course regimens, and is currently under investigation for potential use in drug-susceptible tuberculosis. However, the emergence of Bdq-resistant TB strains has garnered global concern due to their profound impact on clinical treatment outcomes. Herein, we present the first documented case of a liver transplant recipient with rifampicin-susceptible pulmonary tuberculosis who developed concurrent resistance to both Bdq and clofazimine (Cfz). To mitigate hepatotoxicity and minimize drug-drug interactions, the patient's treatment was transitioned from a rifampicin-based regimen to a Bdq-containing regimen, co-administered with cycloserine (Cs), Cfz, and contezolid (Cte). Initial clinical responses were favorable, characterized by sputum culture conversion and radiographic improvement. However, at the four-month follow-up, sputum cultures reverted to positive, and pulmonary lesions demonstrated radiological progression. Whole-genome sequencing (WGS) analysis identified mutations in the Rv0678 gene (c.137dupG, c.144dupC, and c.58dupG), which were absent in pre-Bdq treatment isolates and are known to confer resistance to both Bdq and Cfz. Phenotypic drug susceptibility testing (DST) further confirmed susceptibility to Bdq and Cfz before Bdq exposure and resistance to both drugs after Bdq treatment. This case highlights the critical need for potent combination regimens during Bdq treatment, particularly among immunocompromised patients.