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. 2018 Feb:28:136-142.
doi: 10.1016/j.ebiom.2018.01.005. Epub 2018 Jan 9.

Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study

Nazir A Ismail  1 , Shaheed V Omar  2 , Lavania Joseph  2 , Netricia Govender  2 , Linsay Blows  2 , Farzana Ismail  3 , Hendrik Koornhof  2 , Andries W Dreyer  2 , Koné Kaniga  4 , Norbert Ndjeka  5
Affiliations

Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study

Nazir A Ismail et al. EBioMedicine. 2018 Feb.

Abstract

Background: Bedaquiline (BDQ) is a novel agent approved for use in combination treatment of multi-drug resistant tuberculosis (MDR-TB). We sought to determine BDQ epidemiological cut-off values (ECVs), define and assess interpretive criteria against putative resistance associated variants (RAVs), microbiological outcomes and cross resistance with clofazimine (CFZ).

Methods: A retrospective cohort study was conducted. Minimal inhibitory concentrations (MIC) to BDQ were determined using 7H9 broth microdilution (BMD) and MGIT960. RAVs were genetically characterised using whole genome sequencing. BDQ ECVs were determined using ECOFFinder and compared with 6-month culture conversion status and CFZ MICs.

Findings: A total of 391 isolates were analysed. Susceptible and intermediate categories were determined to have MICs of ≤0.125μg/ml and 0.25μg/ml using BMD and ≤1μg/ml and 2μg/ml using MGIT960 respectively. Microbiological failures occurred among BDQ exposed patients with a non-susceptible BDQ MIC, an Rv0678 mutation and ≤2 active drug classes. The Rv0678 RAVs were not the dominant mechanism of CFZ resistance and cross resistance was limited to isolates with an Rv0678 mutation.

Interpretation: Criteria for BDQ susceptibility are defined and will facilitate improved early detection of resistance. Cross- resistance between BDQ and CFZ is an emerging concern but in this study was primarily among those with an Rv0678 mutation.

Keywords: Bedaquiline; Clofazimine; Mic; Mutation; Tuberculosis.

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Figures

Fig. 1
Fig. 1
a: Wild-type ECV estimation using iterative non-linear regression on expanding subsets for BDQ on BMD (N = 378). b: Histogram of BDQ BMD MIC distribution (μg/ml), N = 378.
Fig. 2
Fig. 2
a: Wild-type ECV estimation using iterative non-linear regression on expanding subsets for BDQ on MGIT (N = 378). b: Histogram of BDQ MGIT MIC distribution (μg/ml), N = 378.
Fig. 3
Fig. 3
Cross tabulation of BDQ and CFZ MICs (N = 391). Numbers in red are Rv0678 RAVs from BDQ exposed patient isolates while the numbers in green are Rv0678 RAVs from BDQ naïve patients. Numbers in black are wild type for Rv0678 and BDQ naïve. Green line: ECV 95%, Red line: ECV 99.9%.
See this image and copyright information in PMC

Comment in

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