A mutation associated with clofazimine and bedaquiline cross-resistance in MDR-TB following bedaquiline treatment

Preliminary Results of Bedaquiline as Salvage Therapy for Patients With Nontuberculous Mycobacterial Lung Disease

“…30,31 Milano et al 30 report that azole resistance in MTB is mediated by the MmpS5-MmpL5 effl ux system, a mutation associated with clofazimine and bedaquiline cross-resistance in MDR-TB following bedaquiline treatment. 30 The mechanisms of bedaquiline resistance in Mab and MAC have not been determined.…”

Bedaquiline: 10 years later, the drug susceptibility testing protocol is still pending

“…The article in this issue of the ERJ [20] has several elements of interest. First, the scientific community was surprised to learn about cross-resistance between clofazimine and bedaquiline, here presented for the first time in a patient in clinical practice.…”

“…In contrast, the Rv0678 gene sequence of the August 2013 isolate revealed a mutation at nucleotide position 2 (GTG→GCG) resulting in the loss of the start codon (replacement of methionine by alanine), suggesting that overexpression of the mmpL5 efflux pump gene due to impaired Rv0678 function is responsible for the observed resistance. Notably, the relapse isolates of the patient did not have any mutations in the atpE gene [20].…”

“…The patient described in a letter in this issue of the European Respiratory Journal (ERJ) indicates that emergence of drug resistance to bedaquiline is an already ongoing threat: SOMOSKOVI et al [20] provide the first non-trial in vivo evidence of acquired resistance due to a mutation in Rv0678, and its association with clofazimine and bedaquiline cross-resistance in an M. tuberculosis isolate from a patient with MDR-TB. In January 2011, a Tibetan refugee was diagnosed with a bilateral and radiologically advanced MDR-TB at the Swiss Reference Center for Mycobacteria (Zurich, Switzerland).…”

Barriers to new drug development in respiratory disease

“…The danger of this is already being seen with the first cases of bedaquiline resistance being reported [7]. What is needed are new compounds developed as part of new combinations to treat all forms of TB.…”