The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Post Date: 
The Lancet Respiratory Medicine

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms—including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions—are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Dheda K, Gumbo T, Maartens G, Dooley KE, McNerney R, Murray M, Furin J, Nardell EA, London L, Lessem E, Theron G, van Helden P, Niemann S, Merker M, rer nat, Dowdy D, Van Rie A, Siu GKH, Pasipanodya JG, Rodrigues C, Clark TG, Sirgel FA, Esmail A, Lin HH, Atre SR, Schaaf HS, Chang KC, Lange C, Nahid P, Udwadia ZF, Horsburgh CR, Churchyard GJ, Menzies D, Hesseling AC, Nuermberger E, McIlleron H, Fennelly KP, Goemaere E, Jaramillo E, Low M, Jara CM, Padayatchi N, Warren RM. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med. 2017 Apr;(5)4.
  • Lung Infection and Immunity Unit, Department of Medicine, Division of Pulmonology and UCT Lung Institute, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa
  • Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX
  • Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
  • Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD
  • Department of Global Health and Social Medicine, Department of Medicine, Harvard Medical School, Boston, MA
  • TH Chan School of Public Health, Department of Medicine, Harvard Medical School, Boston, MA
  • School of Public Health and Medicine, University of Cape Town, Cape Town, South Africa
  • Treatment Action Group, New York, NY
  • SA MRC Centre for Tuberculosis Research/DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg, South Africa
  • Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Schleswig-Holstein, Germany
  • Division of Clinical Infectious Diseases, German Center for Infection Research, Research Center Borstel, Borstel, Schleswig-Holstein, Germany
  • German Centre for Infection Research (DZIF), Partner Site Borstel, Borstel, Schleswig-Holstein, Germany
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
  • University of North Carolina at Chapel Hill, Chapel Hill, NC
  • International Health Unit, Epidemiology and Social Medicine, Faculty of Medicine, University of Antwerp, Antwerp, Belgium
  • Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
  • Department of Microbiology, P.D. Hinduja National Hospital & Medical Research Centre, Mumbai, India
  • Faculty of Infectious and Tropical Diseases and Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK
  • Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
  • Medical College, Hospital and Research Centre, Pimpri, Pune, India
  • Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
  • Tuberculosis and Chest Service, Centre for Health Protection, Department of Health, Hong Kong SAR, China
  • International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
  • Department of Medicine, Karolinska Institute, Stockholm, Sweden
  • Department of Medicine, University of Namibia School of Medicine, Windhoek, Namibia
  • Division of Pulmonary and Critical Care, San Francisco General Hospital, University of California, San Francisco, CA
  • Pulmonary Department, Hinduja Hospital & Research Center, Mumbai, India
  • Schools of Public Health Medicine, Boston University, Boston, MA
  • Aurum Institute, Johannesburg, South Africa
  • School of Public Health, University of Witwatersrand, Johannesburg, South Africa
  • Advancing Treatment and Care for TB/HIV, South African Medical Research Council, Johannesburg, South Africa
  • Montreal Chest Institute, McGill University, Montreal, QC, Canada
  • Pulmonary Clinical Medicine Section, Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD
  • MSF South Africa, Cape Town, South Africa
  • School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa
  • World Health Organization, Geneva, Switzerland
  • Treatment Action Campaign, Johannesburg, South Africa
  • Socios en Salud, Lima, Peru
  • Centre for the AIDS Programme of Research in South Africa (CAPRISA), MRC HIV-TB Pathogenesis and Treatment Research Unit, Durban, South Africa