MIC of Delamanid (OPC-67683) against Mycobacterium tuberculosis Clinical Isolates and a Proposed Critical Concentration

The increasing global burden of multidrug-resistant tuberculosis (MDR-TB) requires reliable drug susceptibility testing that accurately characterizes susceptibility and resistance of pathogenic bacteria to effectively treat patients with this deadly disease. Delamanid is an anti-TB agent first appro...

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Published in:Antimicrobial agents and chemotherapy 2016-06, Vol.60 (6), p.3316-3322
Main Authors: Stinson, Kelly, Kurepina, Natalia, Venter, Amour, Fujiwara, Mamoru, Kawasaki, Masanori, Timm, Juliano, Shashkina, Elena, Kreiswirth, Barry N, Liu, Yongge, Matsumoto, Makoto, Geiter, Lawrence
Format: Article
Language:English
Subjects:
Antitubercular Agents
Antitubercular Agents - pharmacology
Drug Resistance, Multiple, Bacterial
Humans
Microbial Sensitivity Tests
Mycobacterium tuberculosis
Mycobacterium tuberculosis - drug effects
Nitroimidazoles
Nitroimidazoles - pharmacology
Oxazoles
Oxazoles - pharmacology
Susceptibility
Tuberculosis, Pulmonary - drug therapy
Tuberculosis, Pulmonary - microbiology
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Summary:The increasing global burden of multidrug-resistant tuberculosis (MDR-TB) requires reliable drug susceptibility testing that accurately characterizes susceptibility and resistance of pathogenic bacteria to effectively treat patients with this deadly disease. Delamanid is an anti-TB agent first approved in the European Union in 2014 for the treatment of pulmonary MDR-TB in adults. Using the agar proportion method, delamanid MIC was determined for 460 isolates: 316 from patients enrolled in a phase 2 global clinical trial, 76 from two phase 2 early bactericidal activity trials conducted in South Africa, and 68 isolates obtained outside clinical trials (45 from Japanese patients and 23 from South African patients). With the exception of two isolates, MICs ranged from 0.001 to 0.05 μg/ml, resulting in an MIC50 of 0.004 μg/ml and an MIC90 of 0.012 μg/ml. Various degrees of resistance to other anti-TB drugs did not affect the distribution of MICs, nor did origin of isolates from regions/countries other than South Africa. A critical concentration/breakpoint of 0.2 μg/ml can be used to define susceptible and resistant isolates based on the distribution of MICs and available pharmacokinetic data. Thus, clinical isolates from delamanid-naive patients with tuberculosis have a very low MIC for delamanid and baseline resistance is rare, demonstrating the potential potency of delamanid and supporting its use in an optimized background treatment regimen for MDR-TB.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.03014-15