Abstract
BackgroundBedaquiline (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). MethodsA 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. FindingsA 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. InterpretationCriteria 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.
Highlights
Drug-resistant tuberculosis (TB) has been declared a public health “crisis” by the World Health Organization (WHO, 2014), demanding drastic action
Phenotypic BDQ Minimal inhibitory concentrations (MIC) testing was performed for all 378 clinical isolates using the Middlebrook 7H10 agar dilution (M10A), broth microdilution (BMD) and MGIT methods
The introduction of BDQ, a new class of anti-mycobacterial agent introduced after several decades, has been welcomed with great
Summary
Drug-resistant tuberculosis (TB) has been declared a public health “crisis” by the World Health Organization (WHO, 2014), demanding drastic action. Bedaquiline (BDQ), a novel class of anti-mycobacterial drug inhibiting mycobacterial adenosine triphosphate synthase (Preiss et al, 2015; Koul et al, 2007), was approved by the United States (US) Food and Drug Administration (FDA) in 2012 for the treatment of multi-drug resistant (MDR-) TB (Cox and Laessig, 2014), as part of combination therapy Introduction of this novel agent to MDR-TB management has been a major advancement, reducing time to sputum culture conversion and improving patient outcomes (Ndjeka et al, 2015; Guglielmetti et al, 2015; Udwadia et al, 2014; Diacon et al, 2009, 2014). Cross- resistance between BDQ and CFZ is an emerging concern but in this study was primarily among those with an Rv0678 mutation
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