title: A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testing.
abstract: The aim of this study was to establish standardized drug susceptibility testing (DST) methodologies and reference MIC quality control (QC) ranges for bedaquiline, a diarylquinoline antimycobacterial, used in the treatment of adults with multidrug-resistant tuberculosis. Two tier-2 QC reproducibility studies of bedaquiline DST were conducted in eight laboratories using Clinical Laboratory and Standards Institute (CLSI) guidelines. Agar dilution and broth microdilution methods were evaluated. Mycobacterium tuberculosis H37Rv was used as the QC reference strain. Bedaquiline MIC frequency, mode, and geometric mean were calculated. When resulting data occurred outside predefined CLSI criteria, the entire laboratory data set was excluded. For the agar dilution MIC, a 4-dilution QC range (0.015 to 0.12 μg/ml) centered around the geometric mean included 95.8% (7H10 agar dilution; 204/213 observations with one data set excluded) or 95.9% (7H11 agar dilution; 232/242) of bedaquiline MICs. For the 7H9 broth microdilution MIC, a 3-dilution QC range (0.015 to 0.06 μg/ml) centered around the mode included 98.1% (207/211, with one data set excluded) of bedaquiline MICs. Microbiological equivalence was demonstrated for bedaquiline MICs determined using 7H10 agar and 7H11 agar but not for bedaquiline MICs determined using 7H9 broth and 7H10 agar or 7H9 broth and 7H11 agar. Bedaquiline DST methodologies and MIC QC ranges against the H37Rv M. tuberculosis reference strain have been established: 0.015 to 0.12 μg/ml for the 7H10 and 7H11 agar dilution MICs and 0.015 to 0.06 μg/ml for the 7H9 broth microdilution MIC. These methodologies and QC ranges will be submitted to CLSI and EUCAST to inform future research and provide guidance for routine clinical bedaquiline DST in laboratories worldwide.
authors.affiliation: Janssen Research & Development, LLC, Titusville, New Jersey, USA kkaniga@its.jnj.com.
authors.forename: Koné
authors.initials: K
authors.lastname: Kaniga
authors.affiliation: IRCCS, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Cirillo
authors.affiliation: TB Supranational Reference Laboratory, The Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
authors.affiliation: National TB Reference Laboratory, Center for Tuberculosis, National Institute of Communicable Diseases, Johannesburg, South Africa.|Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa.
authors.forename: Nazir A
authors.initials: NA
authors.lastname: Ismail
authors.affiliation: University of Massachusetts Medical School, Massachusetts Supranational TB Reference Laboratory, Boston, Massachusetts, USA.
authors.forename: Devinder
authors.initials: D
authors.lastname: Kaur
authors.affiliation: Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Nacer
authors.initials: N
authors.lastname: Lounis
authors.affiliation: Reference Laboratory, Division of TB Elimination, United States Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Beverly
authors.initials: B
authors.lastname: Metchock
authors.affiliation: Department of Medical Microbiology, Center of Laboratory Medicine, Luzerner Kantonsspital LUKS, Luzern, Switzerland.
authors.forename: Gaby E
authors.initials: GE
authors.lastname: Pfyffer
authors.affiliation: TASK Applied Science, SA MRC Centre for TB Research, DST/NRF Center of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Amour
authors.initials: A
authors.lastname: Venter
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D064687:Diarylquinolines / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods* / Q000592:standards*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011786:Quality Control; D015203:Reproducibility of Results
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline