title: MIC of Delamanid (OPC-67683) against Mycobacterium tuberculosis Clinical Isolates and a Proposed Critical Concentration.
abstract: 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.
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Stinson
authors.affiliation: Public Health Research Institute Tuberculosis Center, New Jersey Medical School-Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kurepina
authors.affiliation: MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Amour
authors.initials: A
authors.lastname: Venter
authors.affiliation: Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawasaki
authors.affiliation: Microbiocon, LLC, Washington, DC, USA.
authors.forename: Juliano
authors.initials: J
authors.lastname: Timm
authors.affiliation: Public Health Research Institute Tuberculosis Center, New Jersey Medical School-Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Shashkina
authors.affiliation: Public Health Research Institute Tuberculosis Center, New Jersey Medical School-Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland, USA.
authors.forename: Yongge
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan lawrence.geiter@otsuka-us.com matsumoto.makoto@otsuka.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland, USA lawrence.geiter@otsuka-us.com matsumoto.makoto@otsuka.jp.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Geiter
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles