Bedaquiline Drug Resistance Emergence Assessment in Multidrug-Resistant Tuberculosis (MDR-TB): a 5-Year Prospective Surveillance Study of Bedaquiline and Other Second-Line Drug Susceptibility Testing in MDR-TB Isolates.
Koné Kaniga, Rumina Hasan, Ruwen Jou, Edita Vasiliauskienė, Charoen Chuchottaworn, Nazir Ismail, Beverly Metchock, Skaidrius Miliauskas, Nguyen Viet Nhung, Camilla Rodrigues, Soyoun Shin, Hulya Simsek, Saijai Smithtikarn, Anh Le Thi Ngoc, Jirakan Boonyasopun, Mubin Kazi, Seungmo Kim, Phalin Kamolwat, Greta Musteikiene, Catherine Ann Sacopon, Sabira Tahseen, Laima Vasiliauskaitė, Mei-Hua Wu, Shaheed Vally Omar
Author Information
Koné Kaniga: Johnson & Johnson Global Public Health, Titusville, New Jersey, USA. ORCID
Rumina Hasan: Department of Pathology and Laboratory Medicine, Aga Khan Universitygrid.7147.5, Karachi, Pakistan.
Ruwen Jou: Tuberculosis Research Center, Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan. ORCID
Edita Vasiliauskienė: Institute of Biomedical Sciences, Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
Charoen Chuchottaworn: Department of Medical Services, Ministry of Public Health, Bangkok, Thailand.
Nazir Ismail: Center for Tuberculosis, National and WHO Supranational TB Reference Laboratory, National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa.
Beverly Metchock: Reference Laboratory, Division of TB Elimination, United States Centers for Disease Control and Preventiongrid.416738.f, Atlanta, Georgia, USA.
Skaidrius Miliauskas: Department of Pulmonology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Nguyen Viet Nhung: Vietnam Integrated Center for TB and Respirology Research, National Lung Hospital, Hanoi, Vietnam.
Camilla Rodrigues: Department of Microbiology, P. D. Hinduja Hospital and Medical Research Centre, Mumbai, India.
Soyoun Shin: The Korean Institute of Tuberculosis, Cheongju-si, Republic of Korea.
Hulya Simsek: National Tuberculosis Reference Laboratory, Public Health Institution of Turkey, Ankara, Turkey.
Saijai Smithtikarn: Division of Tuberculosis, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
Anh Le Thi Ngoc: Vietnam Integrated Center for TB and Respirology Research, National Lung Hospital, Hanoi, Vietnam.
Jirakan Boonyasopun: Mycobacteriology Laboratory, Microbiology Unit, Central Chest Institute of Thailand, Department of Medical Services, Ministry of Public Health, Bangkok, Thailand.
Mubin Kazi: Department of Microbiology, P. D. Hinduja Hospital and Medical Research Centre, Mumbai, India.
Seungmo Kim: The Korean Institute of Tuberculosis, Cheongju-si, Republic of Korea.
Phalin Kamolwat: Division of Tuberculosis, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
Greta Musteikiene: Department of Pulmonology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Catherine Ann Sacopon: National Tuberculosis Reference Laboratory, Research Institute for Tropical Medicine, Manila, Philippines.
Sabira Tahseen: National TB Reference laboratory, National TB Control Program, Islamabad, Pakistan.
Laima Vasiliauskaitė: Institute of Biomedical Sciences, Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
Mei-Hua Wu: Tuberculosis Research Center, Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan.
Shaheed Vally Omar: Center for Tuberculosis, National and WHO Supranational TB Reference Laboratory, National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa.
Bedaquiline Drug Resistance Emergence Assessment in Multidrug-resistant tuberculosis (MDR-TB) (DREAM) was a 5-year (2015 to 2019) phenotypic drug resistance surveillance study across 11 countries. DREAM assessed the susceptibility of 5,036 MDR-TB isolates of bedaquiline treatment-naive patients to bedaquiline and other antituberculosis drugs by the 7H9 broth microdilution (BMD) and 7H10/7H11 agar dilution (AD) MIC methods. Bedaquiline AD MIC quality control (QC) range for the H37Rv reference strain was unchanged, but the BMD MIC QC range (0.015 to 0.12 μg/ml) was adjusted compared with ranges from a multilaboratory, multicountry reproducibility study conforming to Clinical and Laboratory Standards Institute Tier-2 criteria. Epidemiological cutoff values of 0.12 μg/ml by BMD and 0.25 μg/ml by AD were consistent with previous bedaquiline breakpoints. An area of technical uncertainty or intermediate category was set at 0.25 μg/ml and 0.5 μg/ml for BMD and AD, respectively. When applied to the 5,036 MDR-TB isolates, bedaquiline-susceptible, -intermediate, and -resistant rates were 97.9%, 1.5%, and 0.6%, respectively, for BMD and 98.8%, 0.8%, and 0.4% for AD. Resistance rates were the following: 35.1% ofloxacin, 34.2% levofloxacin, 33.3% moxifloxacin, 1.5% linezolid, and 2% clofazimine. Phenotypic cross-resistance between bedaquiline and clofazimine was 0.4% in MDR-TB and 1% in pre-extensively drug-resistant (pre-XDR-TB)/XDR-TB populations. Coresistance to bedaquiline and linezolid and clofazimine and linezolid were 0.1% and 0.3%, respectively, in MDR-TB and 0.2% and 0.4%, respectively, in pre-XDR-TB/XDR-TB populations. Resistance rates to bedaquiline appear to be low in the bedaquiline-treatment-naive population. No treatment-limiting patterns for cross-resistance and coresistance have been identified with key TB drugs to date.
