Drug-Resistant Tuberculosis and HIV

  • Sara C. Auld
  • Neel R. Gandhi
  • James C. M. Brust


Multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB are associated with substantially worse outcomes than drug-susceptible TB—especially in the setting of HIV co-infection. Although global TB incidence has decreased over the past decade, drug-resistant TB remains a substantial threat to control of TB worldwide. This chapter reviews the epidemiology of drug-resistant TB, common genetic mutations conferring resistance to first and second-line TB drugs, as well as current diagnostic methods and principles of treatment. Therapy for drug-resistant TB is complicated, associated with frequent side effects, and a field of active research. Several new and repurposed drugs, such as bedaquiline and delamanid, have recently come to market or are in active clinical development. Guidelines change frequently and consultation with a clinician who has expertise in the co-management of drug-resistant TB and HIV is recommended.


Multidrug-resistant Extensively drug-resistant MDR TB XDR TB Mono-resistance 


  1. 1.
    Crofton J, Mitchison DA (1948) Streptomycin treatment of pulmonary tuberculosis. Br Med J 2(4582):769–782CrossRefGoogle Scholar
  2. 2.
    Crofton J (2006) The MRC randomized trial of streptomycin and its legacy: a view from the clinical front line. J R Soc Med 99(10):531–534PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Bothwell LE, Podolsky SH (2016) The emergence of the randomized, controlled trial. N Engl J Med 375(6):501–504PubMedCrossRefGoogle Scholar
  4. 4.
    Crofton J, Mitchison DA (1948) Streptomycin resistance in pulmonary tuberculosis. Br Med J 2(4588):1009–1015PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Keshavjee S, Farmer PE (2012) Tuberculosis, drug resistance, and the history of modern medicine. N Engl J Med 367(10):931–936PubMedCrossRefGoogle Scholar
  6. 6.
    Cegielski JP (2010) Extensively drug-resistant tuberculosis: "there must be some kind of way out of here". Clin Infect Dis 50(Suppl 3):S195–S200PubMedCrossRefGoogle Scholar
  7. 7.
    Manten A, Van Wijngaarden LJ (1969) Development of drug resistance to rifampicin. Chemotherapy 14(2):93–100PubMedCrossRefGoogle Scholar
  8. 8.
    Steiner M, Chaves AD, Lyons HA, Steiner P, Portugaleza C (1970) Primary drug-resistant tuberculosis. N Engl J Med 283(25):1353–1358PubMedCrossRefGoogle Scholar
  9. 9.
    Pneumocystis pneumonia--Los Angeles (1981) MMWR Morb Mortal Wkly Rep 30(21):250–252Google Scholar
  10. 10.
    Barre-Sinoussi F, Chermann J, Rey F et al (1983) Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220(4599):868–871PubMedCrossRefGoogle Scholar
  11. 11.
    Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW (1993) The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 328(8):521–526PubMedCrossRefGoogle Scholar
  12. 12.
    Frieden TR, Fujiwara PI, Washko RM, Hamburg MA (1995) Tuberculosis in New York City--turning the tide. N Engl J Med 333(4):229–233PubMedCrossRefGoogle Scholar
  13. 13.
    Bloch AB, Cauthen GM, Onorato IM, Dansbury KG, Kelly GD, Driver CR (1994) Nationwide survey of drug-resistant tuberculosis in the United States. JAMA 271Google Scholar
  14. 14.
    Nosocomial transmission of multidrug-resistant tuberculosis to health-care workers and HIV-infected patients in an urban hospital--Florida (1990) MMWR Morb Mortal Wkly Rep 39(40):718–722Google Scholar
  15. 15.
    Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons--Florida and New York, 1988–1991. MMWR Morb Mortal Wkly Rep 1991; 40(34): 585–91Google Scholar
  16. 16.
    Iseman MD (1994) Evolution of drug-resistant tuberculosis: a tale of two species. Proc Natl Acad Sci U S A 91(7):2428–2429PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Multidrug-resistant tuberculosis outbreak on an HIV ward--Madrid, Spain, 1991-1995. MMWR Morb Mortal Wkly Rep 1996; 45(16): 330–333Google Scholar
  18. 18.
    Moro ML, Gori A, Errante I et al (1998) An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian Multidrug-Resistant Tuberculosis Outbreak Study Group. AIDS 12(9):1095–1102PubMedCrossRefGoogle Scholar
  19. 19.
    Ritacco V, Di Lonardo M, Reniero A et al (1997) Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 176(3):637–642PubMedCrossRefGoogle Scholar
  20. 20.
    Rullan JV, Herrera D, Cano R et al (1996) Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in Spain. Emerg Infect Dis 2(2):125–129PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Angarano G, Carbonara S, Costa D, Gori A (1998) Drug-resistant tuberculosis in human immunodeficiency virus infected persons in Italy. The Italian Drug-Resistant Tuberculosis Study Group. Int J Tuberc Lung Dis 2(4):303–311PubMedGoogle Scholar
  22. 22.
    Crawford JT (1994) Epidemiology of tuberculosis: the impact of HIV and multidrug-resistant strains. Immunobiology 191(4–5):337–343PubMedCrossRefGoogle Scholar
  23. 23.
    Pablos-Méndez A, Raviglione MC, Laszlo A et al (1998) Global surveillance for antituberculosis-drug resistance, 1994–1997. N Engl J Med 338(23):1641–1649PubMedCrossRefGoogle Scholar
  24. 24.
    Espinal MA, Laszlo A, Simonsen L et al (2001) Global trends in resistance to antituberculosis drugs. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 344(17):1294–1303PubMedCrossRefGoogle Scholar
  25. 25.
    Dye C, Espinal MA, Watt CJ, Mbiaga C, Williams BG (2002) Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 185(8):1197–1202PubMedCrossRefGoogle Scholar
  26. 26.
    Wells CD, Cegielski JP, Nelson LJ et al (2007) HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis 196(Suppl 1):S86–S107PubMedCrossRefGoogle Scholar
  27. 27.
    Vanacore P, Koehler B, Carbonara S et al (2004) Drug-resistant tuberculosis in HIV-infected persons: Italy 1999–2000. Infection 32(6):328–332PubMedCrossRefGoogle Scholar
  28. 28.
    Aguiar F, Vieira MA, Staviack A et al (2009) Prevalence of anti-tuberculosis drug resistance in an HIV/AIDS reference hospital in Rio de Janeiro, Brazil. Int J Tuberc Lung Dis 13(1):54–61PubMedGoogle Scholar
  29. 29.
    Palacios E, Franke M, Munoz M et al (2012) HIV-positive patients treated for multidrug-resistant tuberculosis: clinical outcomes in the HAART era. Int J Tuberc Lung Dis 16(3):348–354PubMedCrossRefGoogle Scholar
  30. 30.
    Prach LM, Pascopella L, Barry PM et al (2013) Rifampin monoresistant tuberculosis and HIV comorbidity in California, 1993–2008: a retrospective cohort study. AIDS 27(16):2615–2622PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Ershova JV, Kurbatova EV, Moonan PK, Cegielski JP (2014) Mortality among tuberculosis patients with acquired resistance to second-line antituberculosis drugs--United States, 1993–2008. Clin Infect Dis 59(4):465–472PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Dubrovina I, Miskinis K, Lyepshina S et al (2008) Drug-resistant tuberculosis and HIV in Ukraine: a threatening convergence of two epidemics? Int J Tuberc Lung Dis 12(7):756–762PubMedGoogle Scholar
  33. 33.
    van den Hof S, Tursynbayeva A, Abildaev T et al (2013) Converging risk factors but no association between HIV infection and multidrug-resistant tuberculosis in Kazakhstan. Int J Tuberc Lung Dis 17(4):526–531PubMedCrossRefGoogle Scholar
  34. 34.
    Granich R (2008) HIV and MDR-TB in Ukraine: news from a hazardous MDR-TB and HIV site. Int J Tuberc Lung Dis 12(7):701PubMedGoogle Scholar
  35. 35.
    Morozova I, Riekstina V, Sture G, Wells C, Leimane V (2003) Impact of the growing HIV-1 epidemic on multidrug-resistant tuberculosis control in Latvia. Int J Tuberc Lung Dis 7(9):903–906PubMedGoogle Scholar
  36. 36.
    Post FA, Grint D, Werlinrud AM et al (2014) Multi-drug-resistant tuberculosis in HIV positive patients in Eastern Europe. J Infect 68(3):259–263PubMedCrossRefGoogle Scholar
  37. 37.
    Faustini A, Hall AJ, Perucci CA (2006) Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax 61(2):158–163PubMedCrossRefGoogle Scholar
  38. 38.
    Ruddy M, Balabanova Y, Graham C et al (2005) Rates of drug resistance and risk factor analysis in civilian and prison patients with tuberculosis in Samara Region, Russia. Thorax 60(2):130–135PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Khue PM, Phuc TQ, Hung NV, Jarlier V, Robert J (2008) Drug resistance and HIV co-infection among pulmonary tuberculosis patients in Haiphong City, Vietnam. Int J Tuberc Lung Dis 12(7):763–768PubMedGoogle Scholar
  40. 40.
    Hemhongsa P, Tasaneeyapan T, Swaddiwudhipong W et al (2008) TB, HIV-associated TB and multidrug-resistant TB on Thailand’s border with Myanmar, 2006–2007. Trop Med Int Health 13(10):1288–1296PubMedCrossRefGoogle Scholar
  41. 41.
    Sungkanuparph S, Eampokalap B, Chottanapund S, Thongyen S, Manosuthi W (2007) Impact of drug-resistant tuberculosis on the survival of HIV-infected patients. Int J Tuberc Lung Dis 11(3):325–330PubMedGoogle Scholar
  42. 42.
    Punnotok J, Shaffer N, Naiwatanakul T et al (2000) Human immunodeficiency virus-related tuberculosis and primary drug resistance in Bangkok, Thailand. Int J Tuberc Lung Dis 4(6):537–543PubMedGoogle Scholar
  43. 43.
    Nunes EA, De Capitani EM, Coelho E et al (2005) Patterns of anti-tuberculosis drug resistance among HIV-infected patients in Maputo, Mozambique, 2002–2003. Int J Tuberc Lung Dis 9(5):494–500PubMedGoogle Scholar
  44. 44.
    Nelson LJ, Talbot EA, Mwasekaga MJ et al (2005) Antituberculosis drug resistance and anonymous HIV surveillance in tuberculosis patients in Botswana, 2002. Lancet 366(9484):488–490PubMedCrossRefGoogle Scholar
  45. 45.
    Sacks LV, Pendle S, Orlovic D, Blumberg L, Constantinou C (1999) A comparison of outbreak- and nonoutbreak-related multidrug-resistant tuberculosis among human immunodeficiency virus-infected patients in a South African hospital. Clin Infect Dis 29(1):96–101PubMedCrossRefGoogle Scholar
  46. 46.
    Vorkas C, Kayira D, van der Horst C et al (2012) Tuberculosis drug resistance and outcomes among tuberculosis inpatients in Lilongwe, Malawi. Malawi Med J 24(2):21–24PubMedPubMedCentralGoogle Scholar
  47. 47.
    Rajasekaran S, Chandrasekar C, Mahilmaran A, Kanakaraj K, Karthikeyan DS, Suriakumar J (2009) HIV coinfection among multidrug resistant and extensively drug resistant tuberculosis patients--a trend. J Indian Med Assoc 107Google Scholar
  48. 48.
    Deivanayagam CN, Rajasekaran S, Venkatesan R, Mahilmaran A, Ahmed PR, Annadurai S (2002) Prevalence of acquired MDR-TB and HIV co-infection. Indian J Chest Dis Allied Sci 44Google Scholar
  49. 49.
    Magee MJ, Blumberg HM, Broz D, Furner SE, Samson L, Singh S (2012) Prevalence of drug resistant tuberculosis among patients at high-risk for HIV attending outpatient clinics in Delhi, India. Southeast Asian J Trop Med Public Health 43Google Scholar
  50. 50.
    Isaakidis P, Das M, Kumar AM et al (2014) Alarming levels of drug-resistant tuberculosis in HIV-infected patients in metropolitan Mumbai, India. PLoS One 9(10):e110461PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    He GX, Wang HY, Borgdorff MW et al (2011) Multidrug-resistant tuberculosis, People's Republic of China, 2007–2009. Emerg Infect Dis 17(10):1831–1838PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Lan R, Yang C, Lan L et al (2011) Mycobacterium tuberculosis and non-tuberculous mycobacteria isolates from HIV-infected patients in Guangxi, China. Int J Tuberc Lung Dis 15(12):1669–1675PubMedCrossRefGoogle Scholar
  53. 53.
    Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs--worldwide, 2000–2004. MMWR Morb Mortal Wkly Rep 2006; 55(11): 301–305Google Scholar
  54. 54.
    Shah NS, Wright A, Bai G et al (2007) Worldwide emergence of extensively drug-resistant Tuberculosis (XDR-TB). Emerg Infect Dis 13(3):380–387PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Gandhi NR, Moll A, Sturm AW et al (2006) 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 368(9547):1575–1580PubMedCrossRefGoogle Scholar
  56. 56.
    Gandhi NR, Shah NS, Andrews JR et al (2010) HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med 181(1):80–86PubMedCrossRefGoogle Scholar
  57. 57.
    Chaisson RE, Martinson NA (2008) Tuberculosis in Africa—combating an HIV-Driven Crisis. N Engl J Med 358(11):1089–1092PubMedCrossRefGoogle Scholar
  58. 58.
    Dheda K, Shean K, Zumla A et al (2010) Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study. Lancet 375(9728):1798–1807PubMedCrossRefGoogle Scholar
  59. 59.
    Cox HS, McDermid C, Azevedo V et al (2010) Epidemic levels of drug resistant tuberculosis (MDR and XDR-TB) in a high HIV prevalence setting in Khayelitsha, South Africa. PLoS One 5(11):e13901PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    O'Donnell MR, Pillay M, Pillay M et al (2015) Primary capreomycin resistance is common and associated with early mortality in patients with extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa. J Acquir Immune Defic Syndr 69(5):536–543PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Zhao M, Li X, Xu P et al (2009) Transmission of MDR and XDR tuberculosis in Shanghai, China. PLoS One 4(2):e4370PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Dheda K, Gumbo T, Gandhi NR et al (2014) Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis. Lancet Respir Med 2(4):321–338PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Dheda K, Gumbo T, Maartens G, et al. (2017) The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir MedGoogle Scholar
  64. 64.
    World Health Organization. Global Tuberculosis Report 2017. Document no. WHO/HTM/TB/2017.23, GenevaGoogle Scholar
  65. 65.
    Zignol M, Dean AS, Falzon D et al (2016) Twenty years of global surveillance of antituberculosis-drug resistance. N Engl J Med 375(11):1081–1089PubMedCrossRefGoogle Scholar
  66. 66.
    Suchindran S, Brouwer ES, Van Rie A. Is HIV infection a risk factor for multi-drug resistant tuberculosis? A systematic review. PLoS One 2009; 4(5): e5561PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Mesfin YM, Hailemariam D, Biadgilign S, Kibret KT (2014) Association between HIV/AIDS and multi-drug resistance tuberculosis: a systematic review and meta-analysis. PLoS One 9(1):e82235PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Tappero JW, Bradford WZ, Agerton TB et al (2005) Serum concentrations of antimycobacterial drugs in patients with pulmonary tuberculosis in Botswana. Clin Infect Dis 41(4):461–469PubMedCrossRefGoogle Scholar
  69. 69.
    March F, Garriga X, Rodriguez P et al (1997) Acquired drug resistance in Mycobacterium tuberculosis isolates recovered from compliant patients with human immunodeficiency virus-associated tuberculosis. Clin Infect Dis 25(5):1044–1047PubMedCrossRefGoogle Scholar
  70. 70.
    Peloquin CA, Nitta AT, Burman WJ et al (1996) Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother 30(9):919–925PubMedCrossRefGoogle Scholar
  71. 71.
    Stott KE, Pertinez H, Sturkenboom MGG et al (2018) Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis. J Antimicrob Chemother 73(9):2305–2313PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Daskapan A, Idrus LR, Postma MJ, et al. (2018) A systematic review on the effect of HIV infection on the pharmacokinetics of first-line tuberculosis drugs. Clin PharmacokinetGoogle Scholar
  73. 73.
    David HL (1970) Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis. Appl Microbiol 20(5):810–814PubMedPubMedCentralGoogle Scholar
  74. 74.
    Rastogi N, David HL (1993) Mode of action of antituberculous drugs and mechanisms of drug resistance in Mycobacterium tuberculosis. Res Microbiol 144(2):133–143PubMedCrossRefGoogle Scholar
  75. 75.
    Ormerod LP (2005) Multidrug-resistant tuberculosis (MDR-TB): epidemiology, prevention and treatment. Br Med Bull 73–74(1):17–24PubMedCrossRefGoogle Scholar
  76. 76.
    Iseman MD (1999) Management of multidrug-resistant tuberculosis. Chemotherapy 45(Suppl 2):3–11PubMedCrossRefGoogle Scholar
  77. 77.
    Migliori GB, D'Arcy Richardson M, Sotgiu G, Lange C (2009) Multidrug-resistant and extensively drug-resistant tuberculosis in the West. Europe and United States: epidemiology, surveillance, and control. Clin Chest Med 30(4):637–665. viiPubMedCrossRefGoogle Scholar
  78. 78.
    Schaaf HS, Gie RP, Kennedy M, Beyers N, Hesseling PB, Donald PR (2002) Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 30-month follow-up. Pediatrics 109(5):765–771PubMedCrossRefGoogle Scholar
  79. 79.
    The global plan to stop TB 2006–2015. World Health OrganizationGoogle Scholar
  80. 80.
    The global MDR-TB and XDR-TB response plan 2007–2008. World Health OrganizationGoogle Scholar
  81. 81.
    Raviglione MC (2007) The new stop TB strategy and the global plan to stop TB, 2006–2015. Bull World Health Organ 85PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Steiner M, Cosio A (1966) Primary Tuberculosis in Children. N Engl J Med 274(14):755–759PubMedCrossRefGoogle Scholar
  83. 83.
    Tuberculosis outbreak among persons in a residential facility for HIV-infected persons--San Francisco. MMWR Morb Mortal Wkly Rep 1991; 40(38): 649–52Google Scholar
  84. 84.
    Small PM, Shafer RW, Hopewell PC et al (1993) Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 328(16):1137–1144PubMedCrossRefGoogle Scholar
  85. 85.
    Gandhi NR, Weissman D, Moodley P et al (2013) Nosocomial transmission of extensively drug-resistant tuberculosis in a rural hospital in South Africa. J Infect Dis 207(1):9–17PubMedCrossRefGoogle Scholar
  86. 86.
    Shah NS, Auld SC, Brust JCM et al (2017) Transmission of extensively drug-resistant tuberculosis in South Africa. N Engl J Med 376(3):243–253PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Zelner JL, Murray MB, Becerra MC et al (2016) Identifying hotspots of multidrug-resistant tuberculosis transmission using spatial and molecular genetic data. J Infect Dis 213(2):287–294PubMedCrossRefGoogle Scholar
  88. 88.
    Yang C, Luo T, Shen X, et al. (2016) Transmission of multidrug-resistant Mycobacterium tuberculosis in Shanghai, China: a retrospective observational study using whole-genome sequencing and epidemiological investigation. Lancet Infect DisGoogle Scholar
  89. 89.
    Yang C, Luo T, Shen X, et al. (2015) Whole-genome sequencing to delineate transmission of multidrug-resistant tuberculosis in Shanghai, China: a cross-sectional study. Union World Conference on Lung Health 2015; Cape Town, South AfricaGoogle Scholar
  90. 90.
    Sharma A, Hill A, Kurbatova E et al (2017) Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study. Lancet Infect Dis 17(7):707–715PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kendall EA, Fofana MO, Dowdy DW (2015) Burden of transmitted multidrug resistance in epidemics of tuberculosis: a transmission modelling analysis. Lancet Respir Med 3(12):963–972PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Koch AS, Brites D, Stucki D et al (2017) The Influence of HIV on the Evolution of Mycobacterium tuberculosis. Mol Biol Evol 34(7):1654–1668PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Kim SJ (2005) Drug-susceptibility testing in tuberculosis: methods and reliability of results. Eur Respir J 25(3):564–569PubMedCrossRefGoogle Scholar
  94. 94.
    Bottger EC (2011) The ins and outs of Mycobacterium tuberculosis drug susceptibility testing. Clin Microbiol Infect 17(8):1128–1134PubMedCrossRefGoogle Scholar
  95. 95.
    World Health Organization (2011) Noncommercial culture and drug-susceptibility testing methods for screening patients at risk for multidrug-resistant tuberculosis. World Health Organization, GenevaGoogle Scholar
  96. 96.
    Moore DA, Evans CA, Gilman RH et al (2006) Microscopic-observation drug-susceptibility assay for the diagnosis of TB. N Engl J Med 355(15):1539–1550PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Shah NS, Moodley P, Babaria P et al (2011) Rapid diagnosis of tuberculosis and multidrug resistance by the microscopic-observation drug-susceptibility assay. Am J Respir Crit Care Med 183(10):1427–1433PubMedCrossRefGoogle Scholar
  98. 98.
    Zhang H, Li D, Zhao L et al (2013) Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance. Nat Genet 45(10):1255–1260PubMedCrossRefGoogle Scholar
  99. 99.
    Zhang Y, Yew WW (2009) Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 13(11):1320–1330PubMedGoogle Scholar
  100. 100.
    Nebenzahl-Guimaraes H, Jacobson KR, Farhat MR, Murray MB (2014) Systematic review of allelic exchange experiments aimed at identifying mutations that confer drug resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 69(2):331–342PubMedCrossRefGoogle Scholar
  101. 101.
    Dheda K, Gumbo T, Maartens G et al (2017) The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 5:269–281PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Boehme CC, Nabeta P, Hillemann D et al (2010) Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 363(11):1005–1015PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Hillemann D, Weizenegger M, Kubica T, Richter E, Niemann S (2005) Use of the genotype MTBDR assay for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis complex isolates. J Clin Microbiol 43(8):3699–3703PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Walker TM, Cruz AL, Peto TE, Smith EG, Esmail H, Crook DW (2017) Tuberculosis is changing. Lancet Infect Dis 17(4):359–361PubMedCrossRefGoogle Scholar
  105. 105.
    Tukvadze N, Bablishvili N, Apsindzelashvili R, Blumberg HM, Kempker RR (2014) Performance of the MTBDRsl assay in Georgia. Int J Tuberc Lung Dis 18(2):233–239PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Tagliani E, Cabibbe AM, Miotto P et al (2015) Diagnostic performance of the new version (v2.0) of GenoType MTBDRsl assay for detection of resistance to fluoroquinolones and second-line injectable drugs: a multicenter study. J Clin Microbiol 53(9):2961–2969PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Miotto P, Tessema B, Tagliani E et al (2017) A standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis. Eur Respir J 50(6)PubMedCrossRefGoogle Scholar
  108. 108.
    Sandgren A, Strong M, Muthukrishnan P, Weiner BK, Church GM, Murray MB (2009) Tuberculosis drug resistance mutation database. PLoS Med 6(2):e2PubMedCrossRefGoogle Scholar
  109. 109.
    The Stop TB Partnership. Global Laboratory Initiative—Advancing TB diagnostics. (accessed 15 Jan 2018)
  110. 110.
    Albert H, Nathavitharana RR, Isaacs C, Pai M, Denkinger CM, Boehme CC (2016) Development, roll-out and impact of Xpert MTB/RIF for tuberculosis: what lessons have we learnt and how can we do better? Eur Respir J 48(2):516–525PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Shin SS, Modongo C, Boyd R et al (2017) High treatment success rates among HIV-infected multidrug-resistant tuberculosis patients after expansion of antiretroviral therapy in Botswana, 2006–2013. J Acquir Immune Defic Syndr 74(1):65–71PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Brust JCM, Shah NS, Mlisana K et al (2018) Improved survival and cure rates with concurrent treatment for multidrug-resistant tuberculosis-human immunodeficiency virus coinfection in South Africa. Clin Infect Dis 66(8):1246–1253PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Fox W, Ellard GA, Mitchison DA (1999) Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis 3Google Scholar
  114. 114.
    Frieden TR, Sherman LF, Maw KL et al (1996) A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 276(15):1229–1235PubMedCrossRefGoogle Scholar
  115. 115.
    Tierney DB, Franke MF, Becerra MC et al (2014) Time to culture conversion and regimen composition in multidrug-resistant tuberculosis treatment. PLoS One 9(9):e108035PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    American Thoracic Society, CDC, and Infectious Diseases Society of America (2003) Treatment of tuberculosis. MMWR 52(RR-11)Google Scholar
  117. 117.
    World Health Organization (2008) Guidelines for the programmatic management of drug-resistant tuberculosis. In: WHO/HTM/TB/2008, vol 402. Geneva, SwitzerlandGoogle Scholar
  118. 118.
    Falzon D, Jaramillo E, Schunemann HJ et al (2011) WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 38(3):516–528PubMedCrossRefGoogle Scholar
  119. 119.
    World Health Organization. Treatment guidelines for drug-resistant tuberculosis: 2016 update; October 2016 Revision. WHO/HTM/TB/2016.04; Geneva, Switzerland, 2016Google Scholar
  120. 120.
    Clinical and Laboratory Standards Institute TNCfCLS. Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes: approved Standard. NCCLS Document 2003; M24-A. Wayne, PA, USA: NCCLS, 2011.Google Scholar
  121. 121.
    Tomioka H, Sato K, Akaki T, Kajitani H, Kawahara S, Sakatani M (1999) Comparative in vitro antimicrobial activities of the newly synthesized quinolone HSR-903, sitafloxacin (DU-6859a), gatifloxacin (AM-1155), and levofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex. Antimicrob Agents Chemother 43(12):3001–3004PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Ruiz-Serrano MJ, Alcala L, Martinez L et al (2000) In vitro activities of six fluoroquinolones against 250 clinical isolates of Mycobacterium tuberculosis susceptible or resistant to first-line antituberculosis drugs. Antimicrob Agents Chemother 44(9):2567–2568PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Rodriguez JC, Ruiz M, Lopez M, Royo G (2002) In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis. Int J Antimicrob Agents 20(6):464–467PubMedCrossRefGoogle Scholar
  124. 124.
    Gillespie SH, Billington O (1999) Activity of moxifloxacin against mycobacteria. J Antimicrob Chemother 44(3):393–395PubMedCrossRefGoogle Scholar
  125. 125.
    Tortoli E, Dionisio D, Fabbri C (2004) Evaluation of moxifloxacin activity in vitro against Mycobacterium tuberculosis, including resistant and multidrug-resistant strains. J Chemother 16(4):334–336PubMedCrossRefGoogle Scholar
  126. 126.
    Chien JY, Chien ST, Chiu WY, Yu CJ, Hsueh PR (2016) Moxifloxacin improves treatment outcomes in patients with ofloxacin-resistant multidrug-resistant tuberculosis. Antimicrob Agents Chemother 60(8):4708–4716PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Koh WJ, Lee SH, Kang YA et al (2013) Comparison of levofloxacin versus moxifloxacin for multidrug-resistant tuberculosis. Am J Respir Crit Care Med 188(7):858–864PubMedCrossRefGoogle Scholar
  128. 128.
    Kang YA, Shim TS, Koh WJ et al (2016) Choice between levofloxacin and moxifloxacin and multidrug-resistant tuberculosis treatment outcomes. Ann Am Thorac Soc 13(3):364–370PubMedCrossRefGoogle Scholar
  129. 129.
    Davies Forsman L, Giske CG, Bruchfeld J, Schon T, Jureen P, Angeby K (2015) Meropenem-clavulanic acid has high in vitro activity against multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 59(6):3630–3632PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Van Deun A, Maug AK, Salim MA et al (2010) Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 182(5):684–692PubMedCrossRefGoogle Scholar
  131. 131.
    Aung KJ, Van Deun A, Declercq E et al (2014) Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis 18(10):1180–1187PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Piubello A, Harouna SH, Souleymane MB et al (2014) High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis 18(10):1188–1194PubMedCrossRefGoogle Scholar
  133. 133.
    Kuaban C, Noeske J, Rieder HL, Ait-Khaled N, Abena Foe JL, Trebucq A (2015) High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon. Int J Tuberc Lung Dis 19(5):517–524PubMedCrossRefGoogle Scholar
  134. 134.
    Trebucq A, Schwoebel V, Kashongwe Z, et al. (2017) Treatment outcome with a short multidrug-resistant tuberculosis regimen in nine African countries. Int J Tuberc Lung DisGoogle Scholar
  135. 135.
    Nunn AJ, Phillips PPJ, Meredith SK et al (2019) A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med 380(13):1201–1213PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Dheda K, Cox H, Esmail A, Wasserman S, Chang KC, Lange C (2018) Recent controversies about MDR and XDR-TB: Global implementation of the WHO shorter MDR-TB regimen and bedaquiline for all with MDR-TB? Respirology 23(1):36–45PubMedCrossRefGoogle Scholar
  137. 137.
    Mannheimer SB, Sepkowitz KA, Stoeckle M, Friedman CR, Hafner A, Riley LW (1997) Risk factors and outcome of human immunodeficiency virus-infected patients with sporadic multidrug-resistant tuberculosis in New York City. Int J Tuberc Lung Dis 1(4):319–325PubMedGoogle Scholar
  138. 138.
    Park MM, Davis AL, Schluger NW, Cohen H, Rom WN (1996) Outcome of MDR-TB patients, 1983–1993. Prolonged survival with appropriate therapy. Am J Respir Crit Care Med 153(1):317–324PubMedCrossRefGoogle Scholar
  139. 139.
    van Altena R, de Vries G, Haar CH et al (2015) Highly successful treatment outcome of multidrug-resistant tuberculosis in the Netherlands, 2000–2009. Int J Tuberc Lung Dis 19(4):406–412PubMedCrossRefGoogle Scholar
  140. 140.
    Brust JC, Gandhi NR, Carrara H, Osburn G, Padayatchi N (2010) High treatment failure and default rates for patients with multidrug-resistant tuberculosis in KwaZulu-Natal, South Africa, 2000–2003. Int J Tuberc Lung Dis 14(4):413–419PubMedPubMedCentralGoogle Scholar
  141. 141.
    Farley JE, Ram M, Pan W et al (2011) Outcomes of multi-drug resistant tuberculosis (MDR-TB) among a cohort of South African patients with high HIV prevalence. PLoS One 6(7):e20436PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP (2009) Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis 9PubMedCrossRefGoogle Scholar
  143. 143.
    Satti H, McLaughlin MM, Hedt-Gauthier B et al (2012) Outcomes of multidrug-resistant tuberculosis treatment with early initiation of antiretroviral therapy for HIV co-infected patients in Lesotho. PLoS One 7(10):e46943PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    O'Donnell MR, Padayatchi N, Kvasnovsky C, Werner L, Master I, Horsburgh CR Jr (2013) Treatment outcomes for extensively drug-resistant tuberculosis and HIV co-infection. Emerg Infect Dis 19(3):416–424PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Isaakidis P, Casas EC, Das M, Tseretopoulou X, Ntzani EE, Ford N (2015) Treatment outcomes for HIV and MDR-TB co-infected adults and children: systematic review and meta-analysis. Int J Tuberc Lung Dis 19(8):969–978PubMedCrossRefGoogle Scholar
  146. 146.
    Brust JCM, Shah NS, Mlisana K et al (2017) Improved survival and cure rates with concurrent treatment for MDR-TB/HIV co-infection in South Africa. Clin Infect DisGoogle Scholar
  147. 147.
    Abdool Karim SS, Naidoo K, Grobler A et al (2011) Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 365(16):1492–1501PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Havlir DV, Kendall MA, Ive P et al (2011) Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 365(16):1482–1491PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Blanc FX, Sok T, Laureillard D et al (2011) Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 365(16):1471–1481PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Dooley KE, Kim PS, Williams SD, Hafner R (2012) TB and HIV Therapeutics: pharmacology research priorities. AIDS Res Treat 2012:874083PubMedPubMedCentralGoogle Scholar
  151. 151.
    Diacon AH, Pym A, Grobusch M et al (2009) The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 360(23):2397–2405PubMedCrossRefGoogle Scholar
  152. 152.
    Diacon AH, Pym A, Grobusch MP et al (2014) Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med 371(8):723–732PubMedCrossRefGoogle Scholar
  153. 153.
    Pym AS, Diacon AH, Tang SJ et al (2016) Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J 47(2):564–574PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Borisov SE, Dheda K, Enwerem M et al (2017) Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 49(5)Google Scholar
  155. 155.
    Bastard M, Huerga H, Hayrapetyan A, et al. Safety of multidrug-resistant tuberculosis treatment amongst patients receiving bedaquiline in a compassionate use programme in Armenia and Georgia. 48th Union World Conference on Lung Health 11–14 October, 2017; Guadalajara, Mexico (OA-163-13)Google Scholar
  156. 156.
    Skrahina A, Solodovnikova V, Vetushko D, et al. The use of bedaquiline to treat patients with multi- and extensively drug-resistant tuberculosis in Belarus. 48th Union World Conference on Lung Health 11–14 October, 2017; Guadalajara, Mexico (OA-189-13)Google Scholar
  157. 157.
    Schnippel K, Ndjeka N, Maartens G et al (2018) Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. In: Lancet Respir MedGoogle Scholar
  158. 158.
    Ismail NA, Omar SV, Joseph L et al (2018) Defining bedaquiline susceptibility, resistance, cross-resistance and associated genetic determinants: a retrospective cohort study. EBioMedicine 28:136–142PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Gler MT, Skripconoka V, Sanchez-Garavito E et al (2012) Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med 366(23):2151–2160PubMedCrossRefGoogle Scholar
  160. 160.
    von Groote-Bidlingmaier F, Patientia R, Sanchez E et al (2019) Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial. Lancet Respir Med 7(3):249–259CrossRefGoogle Scholar
  161. 161.
    WHO position statement on the use of delamanid for multidrug-resistant tuberculosis. World Health Organization; 2018Google Scholar
  162. 162.
    Lomtadze N. Adverse events and serious adverse events among patients receiving MDR-TB treatment with bedaquiline and delamanid. 48th Union World Conference on Lung Health 11–14 October, 2017; Guadalajara, MexicoGoogle Scholar
  163. 163.
    Dooley KE, Rosenkranz SL, Conradie F, et al. QT Effects of Bedaquiline, Delamanid or both in MDR-TB Patients: The Deliberate Trial. In: Conference on Retroviruses and Opportunistic Infections 2019, Seattle, Washington; 2019Google Scholar
  164. 164.
    Conradie F, Diacon AH, Everitt D, et al. The NIX-TB trial of pretomanid, bedaquiline and linezolid to treat XDR-TB. Programs and Abstracts of the Conference on Retroviruses and Opportunistic Infections, Feb 13-17, 2017. Seattle, WA. Abstract #80LB. 2017Google Scholar
  165. 165.
    Conradie F, Diacon A, Howell P, et al. Sustained high rate of successful treatment outcomes: Interim results of 75 patients in the Nix-TB clinical study of pretomanid, bedaquiline and linezolid. . 49th Union World Conference on Lung Health The Hague, Netherlands 24–27 October 2018 Abstract OA03–213-25Google Scholar
  166. 166.
    Cox H, Ford N (2012) Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis 16(4):447–454PubMedCrossRefGoogle Scholar
  167. 167.
    Sotgiu G, Centis R, D'Ambrosio L et al (2012) Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 40(6):1430–1442PubMedCrossRefGoogle Scholar
  168. 168.
    Hughes J, Isaakidis P, Andries A et al (2015) Linezolid for multidrug-resistant tuberculosis in HIV-infected and -uninfected patients. Eur Respir J 46(1):271–274PubMedCrossRefGoogle Scholar
  169. 169.
    Lee M, Lee J, Carroll MW et al (2012) Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med 367(16):1508–1518PubMedCrossRefGoogle Scholar
  170. 170.
    Wallis RS, Dawson R, Friedrich SO et al (2014) Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis. PLoS One 9(4):e94462PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Tasneen R, Betoudji F, Tyagi S et al (2015) Contribution of oxazolidinones to the efficacy of novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis. Antimicrob Agents Chemother 60(1):270–277PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Barry VC, Belton JG, Conalty ML et al (1957) A new series of phenazines (rimino-compounds) with high antituberculosis activity. Nature 179(4568):1013–1015PubMedCrossRefGoogle Scholar
  173. 173.
    Gopal M, Padayatchi N, Metcalfe JZ, O'Donnell MR (2013) Systematic review of clofazimine for the treatment of drug-resistant tuberculosis. Int J Tuberc Lung Dis 17(8):1001–1007PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Cholo MC, Mothiba MT, Fourie B, Anderson R (2017) Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline. J Antimicrob Chemother 72(2):338–353PubMedCrossRefGoogle Scholar
  175. 175.
    Dey T, Brigden G, Cox H, Shubber Z, Cooke G, Ford N (2013) Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother 68(2):284–293PubMedCrossRefGoogle Scholar
  176. 176.
    Moore VJ (1983) A review of side-effects experienced by patients taking clofazimine. Lepr Rev 54(4):327–335PubMedGoogle Scholar
  177. 177.
    Hartkoorn RC, Uplekar S, Cole ST (2014) Cross-resistance between clofazimine and bedaquiline through upregulation of MmpL5 in Mycobacterium tuberculosis. Antimicrob Agents Chemother 58(5):2979–2981PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Hwang TJ, Dotsenko S, Jafarov A et al (2014) Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis: analysis of published guidance and meta-analysis of cohort studies. BMJ Open 4(1):e004143PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D. Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis. Lancet Infect Dis 2017; 17(2): 223–234PubMedCrossRefGoogle Scholar
  180. 180.
    Denkinger CM, Pai M, Dowdy DW (2014) Do we need to detect isoniazid resistance in addition to rifampicin resistance in diagnostic tests for tuberculosis? PLoS One 9(1):e84197PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    WHO treatment guidelines for isoniazid-resistant tuberculosis: supplement to the WHO treatment guidelines for drug-resistant tuberculosis. World Health Organization, Geneva, 2018Google Scholar
  182. 182.
    Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30 months. Am Rev Respir Dis 1977; 115(5): 727–735Google Scholar
  183. 183.
    Shah NS, Pratt R, Armstrong L, Robison V, Castro KG, Cegielski JP (2008) Extensively drug-resistant tuberculosis in the United States, 1993–2007. JAMA 300(18):2153–2160PubMedCrossRefGoogle Scholar
  184. 184.
    Falzon D, Gandhi N, Migliori GB et al (2013) Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J 42(1):156–168PubMedCrossRefGoogle Scholar
  185. 185.
    Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C (2012) Totally drug-resistant tuberculosis in India. Clin Infect Dis 54(4):579–581PubMedCrossRefGoogle Scholar
  186. 186.
    Migliori GB, Sotgiu G, Gandhi NR et al (2013) Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J 42(1):169–179PubMedCrossRefGoogle Scholar
  187. 187.
    Velayati AA, Masjedi MR, Farnia P et al (2009) Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. Chest 136(2):420–425PubMedCrossRefGoogle Scholar
  188. 188.
    Ndjeka N, Conradie F, Schnippel K et al (2015) Treatment of drug-resistant tuberculosis with bedaquiline in a high HIV prevalence setting: an interim cohort analysis. Int J Tuberc Lung Dis 19(8):979–985PubMedCrossRefGoogle Scholar
  189. 189.
    Meintjes G (2014) Management of drug-resistant TB in patients with HIV co-infection. J Int AIDS Soc 17(4 Suppl 3):19508PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Furin JJ, Mitnick CD, Shin SS et al (2001) Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 5(7):648–655PubMedGoogle Scholar
  191. 191.
    Shin SS, Pasechnikov AD, Gelmanova IY et al (2007) Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. Int J Tuberc Lung Dis 11(12):1314–1320PubMedGoogle Scholar
  192. 192.
    Bloss E, Kuksa L, Holtz TH et al (2010) Adverse events related to multidrug-resistant tuberculosis treatment, Latvia, 2000–2004. Int J Tuberc Lung Dis 14(3):275–281PubMedGoogle Scholar
  193. 193.
    Torun T, Gungor G, Ozmen I et al (2005) Side effects associated with the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 9(12):1373–1377PubMedGoogle Scholar
  194. 194.
    Nathanson E, Gupta R, Huamani P et al (2004) Adverse events in the treatment of multidrug-resistant tuberculosis: results from the DOTS-Plus initiative. Int J Tuberc Lung Dis 8(11):1382–1384PubMedGoogle Scholar
  195. 195.
    Baghaei P, Tabarsi P, Dorriz D et al (2011) Adverse effects of multidrug-resistant tuberculosis treatment with a standardized regimen: a report from Iran. Am J Ther 18(2):e29–e34PubMedCrossRefGoogle Scholar
  196. 196.
    Vega P, Sweetland A, Acha J et al (2004) Psychiatric issues in the management of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 8(6):749–759PubMedGoogle Scholar
  197. 197.
    Brust JC, Shah NS, van der Merwe TL et al (2013) Adverse events in an integrated home-based treatment program for MDR-TB and HIV in KwaZulu-Natal, South Africa. J Acquir Immune Defic Syndr 62(4):436–440PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Isaakidis P, Varghese B, Mansoor H et al (2012) Adverse events among HIV/MDR-TB co-infected patients receiving antiretroviral and second line anti-TB treatment in Mumbai, India. PLoS One 7(7):e40781PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Shringarpure KS, Isaakidis P, Sagili KD, Baxi RK, Das M, Daftary A (2016) When treatment is more challenging than the disease: a qualitative study of MDR-TB patient retention. PLoS One 11(3):e0150849PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Deshmukh RD, Dhande DJ, Sachdeva KS et al (2015) Patient and provider reported reasons for lost to follow up in MDRTB treatment: a qualitative study from a drug resistant TB Centre in India. PLoS One 10(8):e0135802PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Jiang M, Karasawa T, Steyger PS (2017) Aminoglycoside-Induced Cochleotoxicity: A Review. Front Cell Neurosci 11:308PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Schacht J (1999) Biochemistry and pharmacology of aminoglycoside-induced hearing loss. Acta Physiol Pharmacol Ther Latinoam 49(4):251–256PubMedGoogle Scholar
  203. 203.
    Modongo C, Sobota RS, Kesenogile B et al (2014) Successful MDR-TB treatment regimens including amikacin are associated with high rates of hearing loss. BMC Infect Dis 14:542PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Klis S, Stienstra Y, Phillips RO, Abass KM, Tuah W, van der Werf TS. Long term streptomycin toxicity in the treatment of Buruli Ulcer: follow-up of participants in the BURULICO drug trial. PLoS Negl Trop Dis 2014; 8(3): e2739PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Modongo C, Pasipanodya JG, Zetola NM, Williams SM, Sirugo G, Gumbo T (2015) Amikacin concentrations predictive of ototoxicity in multidrug-resistant tuberculosis patients. Antimicrob Agents Chemother 59(10):6337–6343PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    van Altena R, Dijkstra JA, van der Meer ME et al (2017) Reduced chance of hearing loss associated with therapeutic drug monitoring of aminoglycosides in the treatment of multidrug-resistant tuberculosis. Antimicrob Agents Chemother:61(3)Google Scholar
  207. 207.
    Seddon JA, Godfrey-Faussett P, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS (2012) Hearing loss in patients on treatment for drug-resistant tuberculosis. Eur Respir J 40(5):1277–1286PubMedCrossRefGoogle Scholar
  208. 208.
    Dutta BS, Hassan G, Waseem Q, Saheer S, Singh A (2012) Ethionamide-induced hypothyroidism. Int J Tuberc Lung Dis 16(1):141PubMedCrossRefGoogle Scholar
  209. 209.
    Satti H, Mafukidze A, Jooste PL, MM ML, Farmer PE, Seung KJ (2012) High rate of hypothyroidism among patients treated for multidrug-resistant tuberculosis in Lesotho. Int J Tuberc Lung DisGoogle Scholar
  210. 210.
    Andries A, Isaakidis P, Das M et al (2013) High rate of hypothyroidism in multidrug-resistant tuberculosis patients co-infected with HIV in Mumbai, India. PLoS One 8(10):e78313PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Lee SS, Lee CM, Kim TH et al (2016) Frequency and risk factors of drug-induced liver injury during treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 20(6):800–805PubMedCrossRefGoogle Scholar
  212. 212.
    Keshavjee S, Gelmanova IY, Shin SS et al (2012) Hepatotoxicity during treatment for multidrug-resistant tuberculosis: occurrence, management and outcome. Int J Tuberc Lung Dis 16(5):596–603PubMedCrossRefGoogle Scholar
  213. 213.
    Saukkonen JJ, Cohn DL, Jasmer RM et al (2006) An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 174(8):935–952PubMedCrossRefGoogle Scholar
  214. 214.
    World Health Organization. Policy guidance on drug-susceptibility testing (DST) of second-line antituberculosis drugs. 2008; WHO/HTM/TB/2008.392Google Scholar
  215. 215.
    Franke MF, Appleton SC, Mitnick CD et al (2013) Aggressive regimens for multidrug-resistant tuberculosis reduce recurrence. Clin Infect Dis 56(6):770–776PubMedCrossRefGoogle Scholar
  216. 216.
    Ahmad Khan F, Gelmanova IY, Franke MF et al (2016) aggressive regimens reduce risk of recurrence after successful treatment of MDR-TB. Clin Infect Dis 63(2):214–220PubMedCrossRefGoogle Scholar
  217. 217.
    Bastos ML, Hussain H, Weyer K et al (2014) Treatment outcomes of patients with multidrug-resistant and extensively drug-resistant tuberculosis according to drug susceptibility testing to first- and second-line drugs: an individual patient data meta-analysis. Clin Infect Dis 59(10):1364–1374PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Moyo S, Cox HS, Hughes J et al (2015) Loss from treatment for drug resistant tuberculosis: risk factors and patient outcomes in a community-based program in Khayelitsha, South Africa. PLoS One 10(3):e0118919PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Elliott E, Draper HR, Baitsiwe P, Claassens MM (2014) Factors affecting treatment outcomes in drug-resistant tuberculosis cases in the Northern Cape, South Africa. Public Health Action 4(3):201–203PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Toczek A, Cox H, du Cros P, Cooke G, Ford N. Strategies for reducing treatment default in drug-resistant tuberculosis: systematic review and meta-analysis. Int J Tuberc Lung Dis 2013; 17(3): 299–307PubMedCrossRefGoogle Scholar
  221. 221.
    Brust JC, Shah NS, Scott M et al (2012) Integrated, home-based treatment for MDR-TB and HIV in rural South Africa: an alternate model of care. Int J Tuberc Lung Dis 16(8):998–1004PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Mitnick C, Bayona J, Palacios E et al (2003) Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 348(2):119–128PubMedCrossRefGoogle Scholar
  223. 223.
    Heller T, Lessells RJ, Wallrauch CG et al Community-based treatment for multidrug-resistant tuberculosis in rural KwaZulu-Natal, South Africa. Int J Tuberc Lung Dis 14(4):420–426Google Scholar
  224. 224.
    Ho J, Byrne AL, Linh NN, Jaramillo E, Fox GJ (2017) Decentralized care for multidrug-resistant tuberculosis: a systematic review and meta-analysis. Bull World Health Organ 95(8):584–593PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Weiss P, Chen W, Cook VJ, Johnston JC (2014) Treatment outcomes from community-based drug resistant tuberculosis treatment programs: a systematic review and meta-analysis. BMC Infect Dis 14:333PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Okello D, Floyd K, Adatu F, Odeke R, Gargioni G (2003) Cost and cost-effectiveness of community-based care for tuberculosis patients in rural Uganda. Int J Tuberc Lung Dis 7(9 Suppl 1):S72–S79PubMedGoogle Scholar
  227. 227.
    Sinanovic E, Floyd K, Dudley L, Azevedo V, Grant R, Maher D (2003) Cost and cost-effectiveness of community-based care for tuberculosis in Cape Town, South Africa. Int J Tuberc Lung Dis 7(9 Suppl 1):S56–S62PubMedGoogle Scholar
  228. 228.
    Loveday M, Wallengren K, Brust J et al (2015) Community-based care vs. centralised hospitalisation for MDR-TB patients, KwaZulu-Natal, South Africa. Int J Tuberc Lung Dis 19(2):163–171PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Loveday M, Padayatchi N, Wallengren K et al (2014) Association between health systems performance and treatment outcomes in patients co-infected with MDR-TB and HIV in KwaZulu-Natal, South Africa: implications for TB programmes. PLoS One 9(4):e94016PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Perelman MI, Strelzov VP (1997) Surgery for pulmonary tuberculosis. World J Surg 21(5):457–467PubMedCrossRefGoogle Scholar
  231. 231.
    Davies HM (1930) The use of surgery in pulmonary tuberculosis. Br Med J 1(3614):687–689PubMedPubMedCentralCrossRefGoogle Scholar
  232. 232.
    Schiffbauer HE (1930) Indications for surgery in pulmonary tuberculosis. Calif Western Med 32(4):245–248Google Scholar
  233. 233.
    Gravesen J, The surgery of pulmonary tuberculosis main principles (1936) Br Med J 2(3944):269–272PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Kempker RR, Vashakidze S, Solomonia N, Dzidzikashvili N, Blumberg HM (2012) Surgical treatment of drug-resistant tuberculosis. Lancet Infect Dis 12(2):157–166PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Xu HB, Jiang RH, Li L (2011) Pulmonary resection for patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. J Antimicrob Chemother 66(8):1687–1695PubMedCrossRefGoogle Scholar
  236. 236.
    Marrone MT, Venkataramanan V, Goodman M, Hill AC, Jereb JA, Mase SR (2013) Surgical interventions for drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis 17(1):6–16PubMedCrossRefGoogle Scholar
  237. 237.
    Fox GJ, Mitnick CD, Benedetti A et al (2016) Surgery as an adjunctive treatment for multidrug-resistant tuberculosis: an individual patient data metaanalysis. Clin Infect Dis 62(7):887–895PubMedCrossRefGoogle Scholar
  238. 238.
    Harris RC, Khan MS, Martin LJ et al (2016) The effect of surgery on the outcome of treatment for multidrug-resistant tuberculosis: a systematic review and meta-analysis. BMC Infect Dis 16:262PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    WHO treatment guidelines for drug-resistant tuberculosis: 2016 update. WHO; 2016Google Scholar
  240. 240.
    Dheda K, Limberis JD, Pietersen E et al (2017) Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study. Lancet Respir Med 5(4):269–281PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    National action plan to combat multidrug-resistant tuberculosis. MMWR Recomm Rep 1992; 41(Rr-11): 5–48Google Scholar
  242. 242.
    O'Donnell MR, Daftary A, Frick M et al (2016) Re-inventing adherence: toward a patient-centered model of care for drug-resistant tuberculosis and HIV. Int J Tuberc Lung Dis 20(4):430–434PubMedPubMedCentralCrossRefGoogle Scholar
  243. 243.
    Acha J, Sweetland A, Guerra D, Chalco K, Castillo H, Palacios E (2007) Psychosocial support groups for patients with multidrug-resistant tuberculosis: five years of experience. Glob Public Health 2(4):404–417PubMedCrossRefGoogle Scholar
  244. 244.
    Khanal S, Elsey H, King R, Baral SC, Bhatta BR, Newell JN (2017) Development of a patient-centred, psychosocial support intervention for Multi-Drug-Resistant Tuberculosis (MDR-TB) Care in Nepal. PLoS One 12(1):e0167559PubMedPubMedCentralCrossRefGoogle Scholar
  245. 245.
    Tola HH, Shojaeizadeh D, Tol A et al (2016) Psychological and educational intervention to improve tuberculosis treatment Adherence in Ethiopia based on health belief model: a cluster randomized control trial. PLoS One 11(5):e0155147PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Thomas BE, Shanmugam P, Malaisamy M et al (2016) Psycho-socio-economic issues challenging multidrug resistant tuberculosis patients: a systematic review. PLoS One 11(1):e0147397PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sara C. Auld
    • 1
  • Neel R. Gandhi
    • 2
  • James C. M. Brust
    • 3
  1. 1.School of Medicine and Rollins School of Public HealthEmory UniversityAtlantaUSA
  2. 2.Rollins School of Public Health and School of MedicineEmory UniversityAtlantaUSA
  3. 3.Albert Einstein College of MedicineMontefiore Medical CenterBronxUSA

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