Bedaquiline resistance pattern in clofazimine-resistant clinical isolates of tuberculosis patients

Objectives: Bedaquiline (BDQ) is a potent drug for treating drug-resistant tuberculosis (TB). Here, we analysed the resistance profiles of BDQ in CFZ-resistant clinical isolates and investigated the clinical risk factors of BDQ and CFZ cross/co-resistance.Methods: The AlarmarBlue microplate assay was performed to determine the minimum inhibitory con-centration (MIC) of the CFZ-resistant Mycobacterium tuberculosis (MTB) clinical isolates to CFZ and BDQ. The clinical characteristics of the respective patients were analysed to explore the possible risk factors of BDQ resistance. The drug-resistance-associated genes including Rv0678, Rv1979c, atpE, pepQ and Rv1453 were sequenced and analysed.Results: A total of 72 clinical CFZ-resistant MTB isolates were collected; among these, half were identified as BDQ-resistant. The MIC value of BDQ closely correlated with CFZ (Spearman's q = 0.766, P < 0.005). Among the isolates with a MIC of CFZ & GE;4 mg/L, 92.31% (12/13) were resistant to BDQ. Pre-XDR and exposure to BDQ or CFZ are the major risk factors for concurrent BDQ resistance. Among the 36 cross/co-resistant isolates, 50% (18/36) had mutations in Rv0678, 8.3% (3/36) had mutations in Rv0678 +Rv1453, 5.6% (2/36) had mutations in Rv0678 +Rv1979c, 2.8% (1/36) had mutations in Rv0678 +Rv1979c +Rv1453, 2.8% (1/36) had mutations in atpE +Rv0678 +Rv1453, 2.8% (1/36) had mutations in Rv1979c, and 27.7% (10/36) had no variations in the target genes.Conclusion: Nearly half of the CFZ-resistant isolates were still sensitive to BDQ, whereas this rate dra-matically decreased among patients with pre-XDR TB or those who had been exposed to BDQ or CFZ.& COPY; 2023 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )