Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Epidemiology of extensively drug-resistant tuberculosis

Scott K Heysell, MD, MPH
Gerald Friedland, MD
Section Editor
C Fordham von Reyn, MD
Deputy Editor
Elinor L Baron, MD, DTMH


Mycobacterium tuberculosis is an ancient human pathogen, which has plagued countless human societies despite the introduction of curative and preventive therapy in the last century [1]. In recent years, international attention has turned toward the evolving burden of drug resistance. Multidrug-resistant tuberculosis (MDR-TB) has emerged in epidemic proportions in the wake of widespread HIV infection in the world's poorest populations, including sub-Saharan Africa. Extensively drug-resistant tuberculosis (XDR-TB) was first reported in 2006 but has now been documented on six continents [2]. These trends are critically important for global health, since drug-resistant tuberculosis (TB) mortality rates are high and second- and third-line agents for the treatment of drug-resistant TB are less potent and less tolerable than first-line therapies.

This topic will focus specifically on the epidemiology and clinical features of XDR-TB. Information on MDR-TB, drug-susceptible TB, and the diagnosis of tuberculosis are discussed in detail elsewhere. (See "Clinical manifestations and complications of pulmonary tuberculosis" and "Epidemiology, clinical manifestations, and diagnosis of tuberculosis in HIV-infected patients" and "Treatment of drug-resistant pulmonary tuberculosis in adults".)


Multidrug-resistant tuberculosis (MDR-TB) is defined as laboratory-confirmed resistance to the two most potent first-line medications, isoniazid and rifampin [3]. Since 2007, extensively drug-resistant tuberculosis (XDR-TB) has been defined as resistance to both isoniazid and rifampin with additional resistance to at least one fluoroquinolone and one injectable agent (amikacin, kanamycin, or capreomycin) [4,5].

M. tuberculosis strains resistant to all locally tested medications have been defined as "totally drug-resistant" (TDR-TB) [6,7]. However, these TDR isolates were not tested against a complete panel of second-line antituberculosis drugs, including cycloserine, terizidone, clofazimine, linezolid, the carbapenems, and the novel agents bedaquiline and delamanid. Regardless, reports of TDR-TB raise epidemiologic concerns regarding the ability to track complex resistance patterns in resource-limited settings [8]. The emergence of TDR-TB also highlights the limited availability of susceptibility testing for the less commonly used antituberculosis drugs, the concern for amplified drug resistance in the face of weakly potent drug combinations, the relative inability to predict synergy or drug activity at the site of infection, and the need for optimized pharmacokinetic strategies and entirely new antituberculosis drug regimens.


Drug resistance was first noted in the 1940s when streptomycin was formally studied as monotherapy for the treatment of tuberculosis [9]. As a result, subsequent therapeutic interventions utilized multidrug regimens to decrease the risk of drug resistance.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jan 25, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. World Health Organization. Global tuberculosis report 2015. http://www.who.int/tb/publications/global_report/en/ (Accessed on April 28, 2016).
  2. World Health Organization. The WHO Global Laboratory Initiative. http://www.who.int/tb/dots/laboratory/gli/en/index.html (Accessed on March 01, 2009).
  3. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City--turning the tide. N Engl J Med 1995; 333:229.
  4. Report WHO/HTM/TB/2006.375 (World Health Organization, Geneva, 2006).
  5. Centers for Disease Control and Prevention. Revised definition of extensively drug-resistant tuberculosis. MMWR Morbid Mortal Wkly Rep 2006; 55:1176.
  6. Velayati AA, Masjedi MR, Farnia P, et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. Chest 2009; 136:420.
  7. Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2012; 54:579.
  8. Shah NS, Richardson J, Moodley P, et al. Increasing drug resistance in extensively drug-resistant tuberculosis, South Africa. Emerg Infect Dis 2011; 17:510.
  9. STREPTOMYCIN treatment of pulmonary tuberculosis. Br Med J 1948; 2:769.
  10. Centers for Disease Control and Prevention (CDC). Multidrug-resistant tuberculosis outbreak on an HIV ward--Madrid, Spain, 1991-1995. MMWR Morb Mortal Wkly Rep 1996; 45:330.
  11. Ritacco V, Di Lonardo M, Reniero A, et al. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 1997; 176:637.
  12. Moro ML, Gori A, Errante I, et al. An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian Multidrug-Resistant Tuberculosis Outbreak Study Group. AIDS 1998; 12:1095.
  13. From the Centers for Disease Control and Prevention. Tuberculosis treatment interruptions--Ivanovo Oblast, Russian Federation, 1999. JAMA 2001; 285:1953.
  14. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989; 320:545.
  15. Raviglione MC, Harries AD, Msiska R, et al. Tuberculosis and HIV: current status in Africa. AIDS 1997; 11 Suppl B:S115.
  16. World Health Organization. Drug-Resistant TB Surveillance and Response: Supplement Global Tuberculosis Report 2014. WHO, Geneva 2014.
  17. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368:1575.
  18. Friedland G, Moll AP, Shenoi SV, et al. Extensively and multidrug resistant tuberculosis (XDR/MDR TB) in Tugela Ferry, South Africa; Five years later. Oral Late Breaker. International Union Against TB and Lung Disease, Kuala Lumpur, Malaysia, November 2012
  19. Gandhi NR, Shah NS, Andrews JR, et al. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med 2010; 181:80.
  20. Gandhi NR, Weissman D, Moodley P, et al. Nosocomial transmission of extensively drug-resistant tuberculosis in a rural hospital in South Africa. J Infect Dis 2013; 207:9.
  21. Friedland GH. N'Galy Mann Lecture: Confronting HIV and TB from the Bronx, NY to Tugela Ferry, South Africa. Conference on Retroviruses and Opportunistic Infections, Boston, MA February 22, 2016.
  22. Lim JR, Gandhi NR, Mthiyane T, et al. Incidence and Geographic Distribution of Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal Province, South Africa. PLoS One 2015; 10:e0132076.
  23. Shah NS, Auld SC, Brust JC, et al. Transmission of Extensively Drug-Resistant Tuberculosis in South Africa. N Engl J Med 2017; 376:243.
  24. Report WHO/HTM/TB/2008.394. (World Health Organization. Antituberculosis drug resistance in the world, Report No.4, 2008).
  25. Centers for Disease Control and Prevention (CDC). Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs--worldwide, 2000-2004. MMWR Morb Mortal Wkly Rep 2006; 55:301.
  26. Shah NS, Wright A, Bai GH, et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 2007; 13:380.
  27. Raviglione MC. Facing extensively drug-resistant tuberculosis--a hope and a challenge. N Engl J Med 2008; 359:636.
  28. World Health Organization. Global Tuberculosis Report 2014. WHO, Geneva 2014.
  29. Shah NS, Pratt R, Armstrong L, et al. Extensively drug-resistant tuberculosis in the United States, 1993-2007. JAMA 2008; 300:2153.
  30. Thornton JA, Harrison MJ. Letter: Duration of action of AH8165. Br J Anaesth 1975; 47:1033.
  31. Sonnenberg P, Murray J, Glynn JR, et al. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001; 358:1687.
  32. Andrews JR, Gandhi NR, Moodley P, et al. Exogenous reinfection as a cause of multidrug-resistant and extensively drug-resistant tuberculosis in rural South Africa. J Infect Dis 2008; 198:1582.
  33. Cox HS, Sibilia K, Feuerriegel S, et al. Emergence of extensive drug resistance during treatment for multidrug-resistant tuberculosis. N Engl J Med 2008; 359:2398.
  34. Cegielski JP, Dalton T, Yagui M, et al. Extensive drug resistance acquired during treatment of multidrug-resistant tuberculosis. Clin Infect Dis 2014; 59:1049.
  35. Zhao Y, Xu S, Wang L, et al. National survey of drug-resistant tuberculosis in China. N Engl J Med 2012; 366:2161.
  36. Isaakidis P, Das M, Kumar AM, et al. Alarming levels of drug-resistant tuberculosis in HIV-infected patients in metropolitan Mumbai, India. PLoS One 2014; 9:e110461.
  37. Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response. WHO/HTM/TB/2010.3
  38. Daftary A, Padayatchi N, O'Donnell M. Preferential adherence to antiretroviral therapy over tuberculosis treatment: a qualitative study of drug-resistant TB/HIV co-infected patients in South Africa. Glob Public Health 2014; 9:1107.
  39. Raykhert I, Miskinis K, Lepshyna S, et al. HIV seroprevalence among new TB patients in the civilian and prisoner populations of Donetsk Oblast, Ukraine. Scand J Infect Dis 2008; 40:655.
  40. Jeon CY, Hwang SH, Min JH, et al. Extensively drug-resistant tuberculosis in South Korea: risk factors and treatment outcomes among patients at a tertiary referral hospital. Clin Infect Dis 2008; 46:42.
  41. Banerjee R, Allen J, Westenhouse J, et al. Extensively drug-resistant tuberculosis in california, 1993-2006. Clin Infect Dis 2008; 47:450.
  42. Friedland G. Tuberculosis, drug resistance, and HIV/AIDS: a triple threat. Curr Infect Dis Rep 2007; 9:252.
  43. Shenoi S, Friedland G. Extensively drug-resistant tuberculosis: a new face to an old pathogen. Annu Rev Med 2009; 60:307.
  44. Galgalo T, Dalal S, Cain KP, et al. Tuberculosis risk among staff of a large public hospital in Kenya. Int J Tuberc Lung Dis 2008; 12:949.
  45. Naidoo S, Jinabhai CC. TB in health care workers in KwaZulu-Natal, South Africa. Int J Tuberc Lung Dis 2006; 10:676.
  46. O'Donnell MR, Jarand J, Loveday M, et al. High incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers. Ann Intern Med 2010; 153:516.
  47. Moll, AP, Gandhi, N, Andrews, J, et al. Extensively Drug-Resistant (XDR) TB More Common than MDR TB in Tugela Ferry, South Africa with Evidence for Resistance Amplification Over Time. International Union Against Tuberculosis and Lung Disease, 38th, Cape Town, 2007.
  48. Dubrovina I, Miskinis K, Lyepshina S, et al. Drug-resistant tuberculosis and HIV in Ukraine: a threatening convergence of two epidemics? Int J Tuberc Lung Dis 2008; 12:756.
  49. Gilbert JA, Long EF, Brooks RP, et al. Integrating Community-Based Interventions to Reverse the Convergent TB/HIV Epidemics in Rural South Africa. PLoS One 2015; 10:e0126267.
  50. Barnard M, Albert H, Coetzee G, et al. Rapid molecular screening for multidrug-resistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med 2008; 177:787.
  51. Tortoli E, Marcelli F. Use of the INNO LiPA Rif.TB for detection of Mycobacterium tuberculosis DNA directly in clinical specimens and for simultaneous determination of rifampin susceptibility. Eur J Clin Microbiol Infect Dis 2007; 26:51.