Primary Clofazimine and Bedaquiline Resistance among Isolates from Patients with Multidrug-Resistant Tuberculosis

Abstract

Clofazimine has been repurposed for the treatment of tuberculosis, especially for multidrug-resistant tuberculosis (MDR-TB). To test the susceptibility to clofazimine of Mycobacterium tuberculosis clinical isolates, MICs of clofazimine were determined using the microplate alamarBlue assay (MABA) method for 80 drug-resistant isolates and 10 drug-susceptible isolates for comparison. For five clofazimine-resistant strains isolated from previously treated pre-extensively drug-resistant TB (pre-XDR-TB) and XDR-TB patients without prior exposure to clofazimine or bedaquiline, clofazimine MICs were ≥1.2 μg/ml. Four isolates with cross-resistance to bedaquiline had Rv0678 mutations. The other isolate with no resistance to bedaquiline had an Rv1979c mutation. This study adds to a recent study showing that 6.3% of MDR-TB patients without prior clofazimine or bedaquiline exposure harbored isolates with Rv0678 mutations, which raises concern that preexisting resistance to these drugs may be associated with prior TB treatment. Furthermore, we propose a tentative breakpoint of 1.2 μg/ml for clofazimine resistance using the MABA method. More-widespread surveillance and individualized testing for clofazimine and bedaquiline resistance, together with assessment of their clinical usage, especially among previously treated and MDR-TB patients, are warranted.

Keywords: Mycobacterium tuberculosis; Rv0678; bedaquiline; clofazimine; resistance.

FIG 1

Distribution of clofazimine MICs determined by the MABA method for 90 M. tuberculosis clinical isolates.

FIG 2

Phylogenetic analysis of M. tuberculosis isolates. The tree was constructed by TreeBeST using the PhyML method, set to 1,000 bootstrap resamplings.