We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs.

This survey provides the first representative data for Pakistan on its MDR-TB burden. The Xpert assay had nearly 100% specificity, even in a low MDR-TB prevalence setting. The use of this assay greatly simplifies survey logistics, making it a feasible option for survey implementation, especially in resource-constrained settings.

We discuss the possible reasons for the decrease in resistance rates in TB, putative drivers of resistance other than volume of FQ consumption, and the possible impact of the National Tuberculosis Programme and drug regulatory activities.

Bedaquiline is a novel anti-tuberculosis drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) recommended by the World Health Organization (WHO) [1] and recently upgraded to the group A classification of TB drugs as one of the three key drugs, along with linezolid and fluoroquinolones, to be included in all MDR-TB treatment regimens. Based on this grouping of second-line drugs, extensively drug-resistant tuberculosis (XDR-TB) is redefined as MDR- or rifampicin-resistant-TB that is resistant to a fluoroquinolone and to either bedaquiline or linezolid or both. Moreover, bedaquiline, in combination with pretomanid and linezolid, is a part of BPaL regimen recommended for treating adult pulmonary TB patients having pre-XDR-TB or MDR-TB which is either non-responsive or intolerant to recommended standard treatment [2]. However, globally emerging resistance to bedaquiline threatens the effectiveness of novel treatment regimens for drug-resistant TB.

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