Technical Report on critical concentrations for drug susceptibility testing of isoniazid and the rifamycins (rifampicin, rifabutin and rifapentine)

The critical concentrations for culture-based phenotypic drug susceptibility testing (DST) to first-line anti-TB drugs have been revised by the the World Health Organization (WHO). Critical concentrations for rifampicin have been lowered while those for isoniazid have been maintained at the present level. This update helps address the discordance observed between phenotypic and molecular methods to detect rifampicin resistance and improves the accuracy of DST. As a result patients with TB will have a more accurate diagnosis. This document is the outcome of a Technical Expert Group meeting convened by WHO in 2020 to assess the results of a systematic review of published literature on critical concentrations for DST of the most important first-line anti-TB drugs, isoniazid and the rifamycins (rifampicin, rifabutin and rifapentine). These critical concentrations had not been revised since 2008. New evidence over the past decade showed that critical concentrations used for phenotypic methods to detect rifampicin resistance may incorrectly classify strains with certain mutations. The following media were considered: Löwenstein-Jensen (LJ), Middlebrook 7H10 (7H10), Middlebrook 7H11 (7H11) and BACTEC™ Mycobacterial Growth Indicator Tube™ 960 (MGIT). Guidance has been provided to resolve discordance between genotypic and phenotypic results for these drugs and areas for further research have been highlighted. DST methods continue to have a very important role to identify resistance not detected by molecular assays and to support the interpretation of molecular assays results. However, they require sophisticated laboratory infrastructure, qualified staff and strict quality assurance procedures.Peer reviewe

Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

11 páginas, 2 figuras, 1 tablaInappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038)Peer reviewe

Impact of the host on the risk of emergence of bedaquiline resistance in Mycobacterium tuberculosis

Mon projet visait à décrire et caractériser l'émergence chez Mycobacterium tuberculosis de la résistance à la bédaquiline (BDQ). Dans une première étude, nous avons réalisé un test de fluctuation in vitro et adapté celui-ci pour la première fois in vivo dans des souris immunocompétentes et des souris immunodéprimées. Nous avons mis en évidence que l’immunodépression semblait augmenter le risque d’émergence de résistance mais cette augmentation ne serait pas due à une augmentation du taux de mutation mais à une hétérogénéité plus grande au sein de cette population avec des individus s’éloignant beaucoup des valeurs moyennes et hébergeant de grandes quantités de mutants. Dans un second travail, nous avons décrit le premier cas européen de sélection de résistance à la BDQ par mutation atpE. Enfin, nous avons réalisé une étude rétrospective de la sensibilité à la BDQ parmi toutes les souches MDR isolées en France entre 2018 et 2020. Une analyse génotypique et phénotypique a permis de mettre en évidence que des souches mutées sont classées phénotypiquement sensibles selon les critères actuels de l’OMS et que ces souches sont un mélange de souches sans augmentation de la CMI et de souches avec une minime augmentation de la CMI ne faisant pas classer la souche comme résistante. Pour conclure, nous avons montré que les travaux classiquement réalisés in vitro pour mesurer le taux de mutation ne donnent qu’une idée simplifiée de la complexité de l’émergence de la résistance in vivo. Nos travaux ont aussi montré qu’il est difficile avec les outils génotypiques et phénotypiques actuels de distinguer les souches de Mycobacterium tuberculosis sensibles des souches résistantes à la BDQ.The aim of my project was to describe and characterise the emergence of bedaquiline (BDQ) resistance in Mycobacterium tuberculosis. In a first study, we performed an in vitro fluctuation test and adapted it for the first time in vivo in immunocompetent and immunosuppressed mice. We found that immunosuppression appeared to increase the risk of resistance emergence, but this increase was not due to an increase in the mutation rate but to greater heterogeneity in this population, with individuals deviating significantly from the mean values and harbouring large numbers of mutants. In a second work, we described the first European case of selection for BDQ resistance by atpE mutation. Finally, we performed a retrospective study of BDQ susceptibility among all MDR strains isolated in France between 2018 and 2020. Genotypic and phenotypic analysis showed that mutated strains are classified as phenotypically susceptible according to the current WHO criteria and that these strains are a mixture of strains with no increase in MIC and strains with a minimal increase in MIC that do not classify the strain as resistant. In conclusion, we have shown that the work classically performed in vitro to measure mutation rate only gives a simplified idea of the complexity of the emergence of resistance in vivo. Our work has also shown that it is difficult with current genotypic and phenotypic tools to distinguish between Mycobacterium tuberculosis strains that are susceptible and those that are resistant to BDQ

Impact de l'hôte sur le risque d'émergence de résistance à la bédaquiline chez Mycobacterium tuberculosis

The aim of my project was to describe and characterise the emergence of bedaquiline (BDQ) resistance in Mycobacterium tuberculosis. In a first study, we performed an in vitro fluctuation test and adapted it for the first time in vivo in immunocompetent and immunosuppressed mice. We found that immunosuppression appeared to increase the risk of resistance emergence, but this increase was not due to an increase in the mutation rate but to greater heterogeneity in this population, with individuals deviating significantly from the mean values and harbouring large numbers of mutants. In a second work, we described the first European case of selection for BDQ resistance by atpE mutation. Finally, we performed a retrospective study of BDQ susceptibility among all MDR strains isolated in France between 2018 and 2020. Genotypic and phenotypic analysis showed that mutated strains are classified as phenotypically susceptible according to the current WHO criteria and that these strains are a mixture of strains with no increase in MIC and strains with a minimal increase in MIC that do not classify the strain as resistant. In conclusion, we have shown that the work classically performed in vitro to measure mutation rate only gives a simplified idea of the complexity of the emergence of resistance in vivo. Our work has also shown that it is difficult with current genotypic and phenotypic tools to distinguish between Mycobacterium tuberculosis strains that are susceptible and those that are resistant to BDQ.Mon projet visait à décrire et caractériser l'émergence chez Mycobacterium tuberculosis de la résistance à la bédaquiline (BDQ). Dans une première étude, nous avons réalisé un test de fluctuation in vitro et adapté celui-ci pour la première fois in vivo dans des souris immunocompétentes et des souris immunodéprimées. Nous avons mis en évidence que l’immunodépression semblait augmenter le risque d’émergence de résistance mais cette augmentation ne serait pas due à une augmentation du taux de mutation mais à une hétérogénéité plus grande au sein de cette population avec des individus s’éloignant beaucoup des valeurs moyennes et hébergeant de grandes quantités de mutants. Dans un second travail, nous avons décrit le premier cas européen de sélection de résistance à la BDQ par mutation atpE. Enfin, nous avons réalisé une étude rétrospective de la sensibilité à la BDQ parmi toutes les souches MDR isolées en France entre 2018 et 2020. Une analyse génotypique et phénotypique a permis de mettre en évidence que des souches mutées sont classées phénotypiquement sensibles selon les critères actuels de l’OMS et que ces souches sont un mélange de souches sans augmentation de la CMI et de souches avec une minime augmentation de la CMI ne faisant pas classer la souche comme résistante. Pour conclure, nous avons montré que les travaux classiquement réalisés in vitro pour mesurer le taux de mutation ne donnent qu’une idée simplifiée de la complexité de l’émergence de la résistance in vivo. Nos travaux ont aussi montré qu’il est difficile avec les outils génotypiques et phénotypiques actuels de distinguer les souches de Mycobacterium tuberculosis sensibles des souches résistantes à la BDQ

Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

Author : Antimycobacterial Susceptibility Testing Group - Sophia B. Georghiou (FIND, Geneva, Switzerland), Timothy C. Rodwell (FIND, Geneva, Switzerland, and Dept of Medicine, University of California, San Diego, CA, USA), Alexei Korobitsyn (Global TB Programme, World Health Organization, Geneva, Switzerland), Said H. Abbadi (Dept of Microbiology, Faculty of Medicine, Suez University, Suez, Egypt), Kanchan Ajbani (Dept of Microbiology, P.D. Hinduja Hospital and Medical Research Centre, Mumbai, India), Jan-Willem Alffenaar (Sydney Institute for Infectious Diseases, University of Sydney, Sydney, Australia, Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, Australia, and Westmead Hospital, Sydney, Australia), David Alland (Dept of Medicine and the Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ, USA), Nataly Alvarez (Unidad de Bacteriología y Micobacterias, Corporación para Investigaciones Biológicas (CIB), Medellín, Colombia), Sönke Andres (National and Supranational Reference Laboratory for Mycobacteria, Research Center Borstel, Borstel, Germany), Elisa Ardizzoni (Unit of Mycobacteriology, Dept of Biomedical Sciences, Institute of Tropical Medicine Antwerp, Antwerp, Belgium), Alexandra Aubry (Sorbonne Université, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, AP-HP, Hôpital Pitié-Salpêtrière, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Paris, France), Rossella Baldan (FIND, Geneva, Switzerland, and Institute for Infectious Diseases, University of Bern, Bern, Switzerland), Marie Ballif (Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland), Ivan Barilar (Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany, and German Center for Infection Research, Partner site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany), Erik C. Böttger (Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland), Soumitesh Chakravorty (Cepheid, Sunnyvale, CA, USA, and New Jersey Medical School, Rutgers University, Newark, NJ, USA), Pauline M. Claxton (Scottish Mycobacteria Reference Laboratory, Directorate of Laboratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK), Daniela M. Cirillo (Emerging Bacterial Pathogens Unit, IRCCS Ospedale San Raffaele, Milan, Italy), Iñaki Comas (Instituto de Biomedicina de Valencia IBV-CSIC, Spanish National Research Council, Valencia, Spain, and CIBER in Epidemiology and Public Health, Madrid, Spain), Chris Coulter (Queensland Mycobacterium Reference Laboratory, Pathology Queensland, Herston, Australia), Claudia M. Denkinger (FIND, Geneva, Switzerland, Division of Clinical Tropical Medicine, Centre of Infectious Diseases, Heidelberg University Hospital, Heidelberg, Germany, and German Centre for Infection Research (DZIF), partner site Heidelberg University Hospital, Heidelberg, Germany), Brigitta Derendinger (DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa), Edward P. Desmond (State Laboratories Division, Department of Health, Pearl City, HI, USA), Jurriaan E.M. de Steenwinkel (Dept of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands), Keertan Dheda (Centre for Lung Infection and Immunity, Division of Pulmonology, Dept of Medicine and UCT Lung Institute, and South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa, and Faculty of Infectious and Tropical Diseases, Dept of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK), Andreas H. Diacon (TASK, Cape Town, South Africa), David L. Dolinger (General Fluidics, Waltham, MA, USA), Kelly E. Dooley (Dept of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA), Matthias Egger (Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland, Centre for Infectious Disease Research and Epidemiology, University of Cape Town, Cape Town, South Africa, and Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK), Soudeh Ehsani (Joint Infectious Diseases Programme, Regional Office for Europe, World Health Organization, Copenhagen, Denmark), Maha R. Farhat (Dept of Biomedical Informatics, Harvard Medical School, Boston, MA, USA, and Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA), Lanfranco Fattorini (Dept of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy), Iris Finci (Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany, and German Center for Infection Research, Partner site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany), Laure Fournier Le Ray (Sorbonne Université, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, Paris, France), Victoria Furió (Instituto de Biomedicina de Valencia IBV-CSIC, Spanish National Research Council, Valencia, Spain), Ramona Groenheit (Dept of Microbiology, Public Health Agency of Sweden, Solna, Sweden), Tawanda Gumbo (Praedicare Inc, Dallas, TX, USA), Scott K. Heysell (Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA), Doris Hillemann (National and Supranational Reference Laboratory for Mycobacteria, Research Center Borstel, Borstel, Germany), Harald Hoffmann (Institute of Microbiology and Laboratory Medicine, Dept IML Red GmbH, WHO – Supranational Tuberculosis Reference Laboratory Munich-Gauting, Gauting, Germany, and SYNLAB Gauting, SYNLAB Human Genetics, Gauting, Germany), Po-Ren Hsueh (Depts of Laboratory Medicine and Internal Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung, Taiwan, and Depts of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan), Yi Hu (School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China), Hairong Huang (Beijing Chest Hospital, Capital Medical University, Beijing, China), Alamdar Hussain (National TB Reference Laboratory, National TB Control Program, Pakistan), Farzana Ismail (Centre for Tuberculosis, National and Supranational TB Reference Laboratory, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa, and Dept of Medical Microbiology, University of Pretoria, Pretoria, South Africa), Kiyohiko Izumi (Dept of Epidemiology and Clinical Research, Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Kiyose, Japan), Tomasz Jagielski (Dept of Medical Microbiology, Institute of Microbiology, Faculty of Biology, University of Warsaw, Warsaw, Poland), John L. Johnson (Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, USA), Priti Kambli (Dept of Microbiology, P.D. Hinduja Hospital and Medical Research Centre, Mumbai, India), Koné Kaniga (Johnson & Johnson Global Public Health, Division of Janssen Pharmaceutica, Titusville, NJ, USA), G.H.R. Eranga Karunaratne (Dept of Microbiology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka, and Faculty of Science, Horizon Campus, Malabe, Sri Lanka), Meenu Kaushal Sharma (National Reference Centre for Mycobacteriology, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada), Peter M. Keller (Institute for Infectious Diseases, University of Bern, Bern, Switzerland), Ellis C. Kelly (Dept of Genetics, University of Cambridge, Cambridge, UK), Margarita Kholina (Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia), Mikashmi Kohli (FIND, Geneva, Switzerland), Katharina Kranzer (Dept of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK, Dept of Infectious Diseases and Tropical Medicine, Ludwig Maximilian University of Munich, Munich, Germany, and Biomedical Research and Training Institute, Harare, Zimbabwe), Ian F. Laurenson (Scottish Mycobacteria Reference Laboratory, Directorate of Laboratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK), Jason Limberis (Dept of Medicine, Division of Experimental Medicine, University of California San Francisco, San Francisco, CA, USA), S-Y. Grace Lin (Microbial Diseases Laboratory, California Department of Public Health, Richmond, CA, USA), Yongge Liu (Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD, USA), Alexandre López-Gavín (Hospital Clínic, Universitat de Barcelona, Barcelona, Spain), Anna Lyander (Clinical Genomics Stockholm, Science for Life Laboratory, Solna, Sweden, and School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden), Diana Machado (Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, Lisbon, Portugal), Elena Martinez (Centre for Infectious Diseases and Microbiology – Public Health, Westmead Hospital and NSW Health Pathology, Sydney, Australia), Faisal Masood (National TB Reference Laboratory, National TB Control Program, Pakistan), Satoshi Mitarai (Dept of Mycobacterium Reference and Research, Research Institute of Tuberculosis, Japan Anti-tuberculosis Association, Kiyose, Japan), Nomonde R. Mvelase (Dept of Medical Microbiology, National Health Laboratory Service, Durban, South Africa, and School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa), Stefan Niemann (Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany, and German Center for Infection Research, Partner site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany), Vladyslav Nikolayevskyy (Dept of Infectious Diseases, Imperial College London, London, UK), Florian P. Maurer (National and Supranational Reference Laboratory for Mycobacteria, Research Center Borstel, Borstel, Germany, German Center for Infection Research, Partner site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany, and Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany), Matthias Merker (Evolution of the Resistome, Research Center Borstel, Borstel, Germany), Paolo Miotto (Emerging Bacterial Pathogens Unit, IRCCS Ospedale San Raffaele, Milan, Italy), Shaheed V. Omar (Centre for Tuberculosis, National and Supranational TB Reference Laboratory, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa, and Dept of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa), Ralf Otto-Knapp (German Central Committee against Tuberculosis, Berlin, Germany), Moisés Palaci (Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil), Juan José Palacios Gutiérrez (Unidad de Referencia Regional de Micobacterias, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain), Sharon J. Peacock (Dept of Medicine, University of Cambridge, Cambridge, UK), Charles A. Peloquin (College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA), Jennifer Perera (Dept of Microbiology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka), Catherine Pierre-Audigier (CMIP Institut Pasteur, Paris, France, and Laboratoire de Bactériologie, Hôpital Bichat-Claude Bernard, Paris France), Suporn Pholwat (Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA), James E. Posey (Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA), Therdsak Prammananan (National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, Thailand), Leen Rigouts (Unit of Mycobacteriology, Dept of Biomedical Sciences, Institute of Tropical Medicine Antwerp, Antwerp, Belgium), Jaime Robledo (Unidad de Bacteriología y Micobacterias, Corporación para Investigaciones Biológicas (CIB), Medellín, Colombia, and Escuela de Ciencias de la Salud, Universidad Pontificia Bolivariana (UPB), Medellín, Colombia), Neesha Rockwood (Dept of Microbiology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka, Dept of Infectious Diseases, Imperial College London, London, UK, and Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa), Camilla Rodrigues (Dept of Microbiology, P.D. Hinduja Hospital and Medical Research Centre, Mumbai, India), Max Salfinger (University of South Florida College of Public Health and Morsani College of Medicine, Tampa, FL, USA), Marcos C. Schechter (Emory University School of Medicine, Dept of Medicine, Division of Infectious Diseases, Atlanta, GA, USA), Marva Seifert (Dept of Medicine, University of California, San Diego, CA, USA), Sarah Sengstake (Unit of Mycobacteriology, Dept of Biomedical Sciences, Institute of Tropical Medicine Antwerp, Antwerp, Belgium), Thomas Shinnick (Independent Consultant, Atlanta, GA, USA), Natalia Shubladze (National Reference Laboratory, National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia), Vitali Sintchenko (Sydney Institute for Infectious Diseases, University of Sydney, Sydney, Australia, and NSW Mycobacterium Reference Laboratory, Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Sydney, Australia), Frederick Sirgel (DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa), Sulochana Somasundaram (National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chennai, India), Timothy R. Sterling (Vanderbilt University Medical Center, Nashville, TN, USA), Andrea Spitaleri (Emerging Bacterial Pathogens Unit, IRCCS Ospedale San Raffaele, Milan, Italy, and Vita-Salute San Raffaele University, Milan, Italy), Elizabeth Streicher (DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa), Philip Supply (Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL – Center for Infection and Immunity of Lille, F-59000 Lille, France), Erik Svensson (International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark), Elisa Tagliani (Emerging Bacterial Pathogens Unit, IRCCS Ospedale San Raffaele, Milan, Italy), Sabira Tahseen (National TB Reference Laboratory, National TB Control Program, Pakistan), Akiko Takaki (Dept of Mycobacterium Reference and Research, Research Institute of Tuberculosis, Japan Anti-tuberculosis Association, Kiyose, Japan), Grant Theron (DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa), Gabriela Torrea (Unit of Mycobacteriology, Dept of Biomedical Sciences, Institute of Tropical Medicine Antwerp, Antwerp, Belgium), Armand Van Deun (Independent Consultant, Leuven, Belgium), Jakko van Ingen (Radboudumc Center for Infectious Diseases, Dept of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands), Annelies Van Rie (Tuberculosis Omics Research Consortium, Family Medicine and Population health, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium), Dick van Soolingen (Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment, Bilthoven, The Netherlands), Roger Vargas Jr (Dept of Biomedical Informatics, Harvard Medical School, Boston, MA, USA, and Center for Computational Biomedicine, Harvard Medical School, Boston, MA, USA), Amour Venter (TASK, Cape Town, South Africa), Nicolas Veziris (Sorbonne Université, Centre d'Immunologie et des Maladies Infectieuses (Cimi-Paris), UMR 1135, Département de Bactériologie, Hôpital Saint-Antoine, Centre National de Référence des Mycobactéries, APHP, Sorbonne Université, Paris, France), Cristina Villellas (Janssen Research and Development, Beerse, Belgium), Miguel Viveiros (Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, Lisbon, Portugal), Robin Warren (DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa), Shu'an Wen (Beijing Chest Hospital, Capital Medical University, Beijing, China), Jim Werngren (Dept of Microbiology, Public Health Agency of Sweden, Solna, Sweden), Robert J. Wilkinson (Dept of Infectious Diseases, Imperial College London, London, UK, Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa, and The Francis Crick Institute, London, UK), Caie Yang (Dept of Clinical Laboratory, The Eighth Medical Center of People's Liberation Army General Hospital, Beijing, China), F. Ferda Yılmaz (Ege University, Faculty of Pharmacy, Dept of Pharmaceutical Microbiology, Bornova, İzmir, Turkey), Tingting Zhang (Beijing Chest Hospital, Capital Medical University, Beijing, China), Danila Zimenkov (Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia), Nazir Ismail (Global TB Programme, World Health Organization, Geneva, Switzerland), Thomas Schön (Dept of Infectious Diseases, Kalmar County Hospital, Linköping University, Kalmar, Sweden, Unit of Infection and Inflammation, Dept of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden, and Dept of Infectious Diseases, Linköping University Hospital, Linköping, Sweden) and Claudio U. Köser (Dept of Genetics, University of Cambridge, Cambridge, UK).International audienc

Impact of the revised definition of extensively drug resistant tuberculosis

International audienc