The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis.
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.
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. Electronic address: keertan.dheda@uct.ac.za.
Keertan
K
Dheda
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
Tawanda
T
Gumbo
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Gary
G
Maartens
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Kelly E
KE
Dooley
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.
Ruth
R
McNerney
Department of Global Health and Social Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
Megan
M
Murray
Department of Global Health and Social Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
Jennifer
J
Furin
TH Chan School of Public Health, Department of Medicine, Harvard Medical School, Boston, MA, USA.
Edward A
EA
Nardell
School of Public Health and Medicine, University of Cape Town, Cape Town, South Africa.
Leslie
L
London
Treatment Action Group, New York, NY, USA.
Erica
E
Lessem
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.
Grant
G
Theron
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.
Paul
P
van Helden
Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Schleswig-Holstein, Germany; German Centre for Infection Research (DZIF), Partner Site Borstel, Borstel, Schleswig-Holstein, Germany.
Stefan
S
Niemann
Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Schleswig-Holstein, Germany.
Matthias
M
Merker
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
David
D
Dowdy
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; International Health Unit, Epidemiology and Social Medicine, Faculty of Medicine, University of Antwerp, Antwerp, Belgium.
Annelies
A
Van Rie
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.
Gilman K H
GK
Siu
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
Jotam G
JG
Pasipanodya
Department of Microbiology, P.D. Hinduja National Hospital & Medical Research Centre, Mumbai, India.
Camilla
C
Rodrigues
Faculty of Infectious and Tropical Diseases and Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
Taane G
TG
Clark
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.
Frik A
FA
Sirgel
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.
Aliasgar
A
Esmail
Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
Hsien-Ho
HH
Lin
Center for Clinical Global Health Education (CCGHE), Johns Hopkins University, Baltimore, MD, USA; Medical College, Hospital and Research Centre, Pimpri, Pune, India.
Sachin R
SR
Atre
Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
H Simon
HS
Schaaf
Tuberculosis and Chest Service, Centre for Health Protection, Department of Health, Hong Kong SAR, China.
Kwok Chiu
KC
Chang
Division of Clinical Infectious Diseases, German Center for Infection Research, Research Center Borstel, Borstel, Schleswig-Holstein, Germany; 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.
Christoph
C
Lange
Division of Pulmonary and Critical Care, San Francisco General Hospital, University of California, San Francisco, CA, USA.
Payam
P
Nahid
Pulmonary Department, Hinduja Hospital & Research Center, Mumbai, India.
Zarir F
ZF
Udwadia
Schools of Public Health Medicine, Boston University, Boston, MA, USA.
C Robert
CR
Horsburgh
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.
Gavin J
GJ
Churchyard
Montreal Chest Institute, McGill University, Montreal, QC, Canada.
Dick
D
Menzies
Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Anneke C
AC
Hesseling
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Eric
E
Nuermberger
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Helen
H
McIlleron
Pulmonary Clinical Medicine Section, Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.
Kevin P
KP
Fennelly
MSF South Africa, Cape Town, South Africa; School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
Eric
E
Goemaere
World Health Organization, Geneva, Switzerland.
Ernesto
E
Jaramillo
Treatment Action Campaign, Johannesburg, South Africa.
Marcus
M
Low
Socios en Salud, Lima, Peru.
Carolina Morán
CM
Jara
Centre for the AIDS Programme of Research in South Africa (CAPRISA), MRC HIV-TB Pathogenesis and Treatment Research Unit, Durban, South Africa.
Nesri
N
Padayatchi
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.
Robin M
RM
Warren