Defining bedaquiline susceptibility, resistance, cross-resistance and associated genetic determinants : a retrospective cohort study

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dc.contributor.author Ismail, Nazir Ahmed
dc.contributor.author Omar, Shaheed V.
dc.contributor.author Joseph, Lavania
dc.contributor.author Govender, Netricia
dc.contributor.author Blows, Linsay
dc.contributor.author Ismail, Farzanah
dc.contributor.author Koornhof, Hendrik
dc.contributor.author Dreyer, Andries W
dc.contributor.author Kaniga, Kone
dc.contributor.author Ndjeka, Norbert
dc.date.accessioned 2019-10-11T08:12:10Z
dc.date.available 2019-10-11T08:12:10Z
dc.date.issued 2018-02
dc.description.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 brothmicrodilution (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 ≤0.125 μg/ml and 0.25 μg/ml using BMD and ≤1 μg/ml and 2 μg/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. en_ZA
dc.description.department Medical Microbiology en_ZA
dc.description.librarian am2019 en_ZA
dc.description.sponsorship Janssen Pharmaceuticals en_ZA
dc.description.uri http://www.journals.elsevier.com/ebiomedicine en_ZA
dc.identifier.citation Ismail, N.A., Omar, S.V., Joseph, L. et al. 2018, 'Defining bedaquiline susceptibility, resistance, cross-resistance and associated genetic determinants : a retrospective cohort study', EBioMedicine, vol. 28, pp. 136-142. en_ZA
dc.identifier.issn 2352-3964 (online)
dc.identifier.other 10.1016/j.ebiom.2018.01.005
dc.identifier.uri http://hdl.handle.net/2263/71794
dc.language.iso en en_ZA
dc.publisher Elsevier en_ZA
dc.rights © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license. en_ZA
dc.subject Mutation en_ZA
dc.subject Tuberculosis (TB) en_ZA
dc.subject Bedaquiline (BDQ) en_ZA
dc.subject Multi-drug resistant tuberculosis (MDR-TB) en_ZA
dc.subject Cut-off value (ECV) en_ZA
dc.subject Resistance associated variant (RAV) en_ZA
dc.subject Clofazimine (CFZ) en_ZA
dc.subject Minimal inhibitory concentrations (MIC) en_ZA
dc.title Defining bedaquiline susceptibility, resistance, cross-resistance and associated genetic determinants : a retrospective cohort study en_ZA
dc.type Article en_ZA


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