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Drug-Resistant Tuberculosis

What are the Treatment Options?

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Abstract

Drug-resistant tuberculosis (DR-TB) is an emerging global health threat as treatment involves complex multiple drug regimens, which are longer and more toxic than standard therapy and yet have worse outcomes. In the presence of resistance to one or more first-line drugs, an alternative regimen should be designed. A major problem is the almost complete lack of published evidence regarding the optimal drug combinations and duration of treatment for the different types of DR-TB. Current principles, some of which are based on expert opinion, are that at least three new anti-TB agents should be added to a failing regimen and four agents when multidrug resistance is suspected. All first-line oral anti-TB agents to which the Mycobacterium tuberculosis strains are susceptible should be used, plus one fluoroquinolone. In addition, one injectable anti-TB agent and one or more second-line oral anti-TB agents should be added to the regimen until the target number of drugs is reached. The duration of treatment depends on the type of drug resistance, the type and number of drugs used in the regimen, and the extent of the disease. All forms of DR-TB should receive daily, not intermittent, therapy and all doses should be directly observed. Because of the high rate of adverse drug effects, careful monitoring and appropriate management of these adverse reactions are important to achieve successful treatment. Supportive measures, such as adequate nutrition along with emotional and social supports, are an important part of the treatment. Careful consideration is required when dealing with pregnant or lactating women and HIV co-infected patients, as well as in treatment of extrapulmonary DR-TB.

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References

  1. World Health Organization (WHO). Global tuberculosis control: epidemiology, strategy, financing. WHO report 2009 (WHO/HTM/TB/2009.411) [online]. Available from URL: http://www.who.int/tb/publications/global_report/2009/en/index.html [Accessed 2011 Mar 2]

  2. World Health Organization (WHO). Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response (WHO/HTM/TB/2010.3) [online]. Available from URL: http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf [Accessed 2011 Mar 2]

  3. World Health Organization (WHO). Drug-resistant tuberculosis now at record levels (18 March 2010; Geneva/Washington, DC) [news release; online]. Available from URL: http://www.who.int/mediacentre/news/releases/2010/drug_resistant_tb_20100318/en/ [Accessed 2011 Mar 2]

  4. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients coinfected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006 Nov 4; 368(9547): 1575–80

    Article  PubMed  Google Scholar 

  5. Toman K, Frieden TR, Thomas R. Toman's tuberculosis case detection, treatment and monitoring: questions and answers. 2nd ed. (WHO/HTM/TB/2004.334) [online]. Available from URL: http://www.who.int/mediacentre/news/releases/2010/drug_resistant_tb_20100318/en/ [Accessed 2011 Mar 2]

  6. Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2009 Nov; 13(11): 1320–30

    PubMed  CAS  Google Scholar 

  7. Crofton J, Mitchison DA. Streptomycin resistance in pulmonary tuberculosis. Br Med J 1948 Dec 11; 2(4588): 1009–15

    Article  PubMed  CAS  Google Scholar 

  8. Gurumurthy P, Ramachandran G, Hemanth Kumar AK, et al. Malabsorption of rifampin and isoniazid in HIV-infected patients with and without tuberculosis. Clin Infect Dis 2004 Jan 15; 38(2): 280–3

    Article  PubMed  CAS  Google Scholar 

  9. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 1998 Jan; 2(1): 10–5

    PubMed  CAS  Google Scholar 

  10. van Altena R, van Soolingen D, van der Werf TS. Isoniazid resistant TB and non-compliance [letter]. Thorax 2004 Dec; 59(12): 1098; author reply 1098-9

    PubMed  Google Scholar 

  11. Weis SE, Slocum PC, Blais FX, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994 Apr 28; 330(17): 1179–84

    Article  PubMed  CAS  Google Scholar 

  12. Mathew JL. Fixed dose drug combination for treatment of tuberculosis. Indian Pediatr 2009 Oct; 46(10): 877–80

    PubMed  Google Scholar 

  13. March F, Garriga X, Rodrýguez P, et al. Acquired drug resistance in Mycobacterium tuberculosis isolates recovered from compliant patients with human immunodeficiency virus-associated tuberculosis. Clin Infect Dis 1997 Nov; 25(5): 1044–7

    Article  PubMed  CAS  Google Scholar 

  14. Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 2002; 62(15): 2169–83

    Article  PubMed  CAS  Google Scholar 

  15. Ling DI, Zwerling AA, Pai M. GenoType MTBDR assays for the diagnosis of multidrug-resistant tuberculosis: a meta-analysis. Eur Respir J 2008 Nov; 32(5): 1165–74

    Article  PubMed  CAS  Google Scholar 

  16. 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 Apr 1; 177(7): 787–92

    Article  PubMed  Google Scholar 

  17. World Health Organization (WHO).Treatment of tuberculosis: guidelines — 4th ed. (WHO/HTM/TB/2009.420) [on line]. Available from URL: http://www.who.int/tb/publications/tb_treatmentguidelines/en/index.html [Accessed 2011 Mar 2]

  18. World Health Organization (WHO). Guidelines for the programmatic management of drug-resistant tuberculosis (WHO/HTM/TB/2008.402). Emergency update 2008 [online]. Available from URL: http://whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf [Accessed 2011 Mar 2]

  19. Park-Wyllie LY, Juurlink DN, Kopp A, et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med 2006 Mar 30; 354(13): 1352–61

    Article  PubMed  CAS  Google Scholar 

  20. Faustini A, Hall AJ, Perucci CA. Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax 2006 Feb; 61(2): 158–63

    Article  PubMed  CAS  Google Scholar 

  21. Bastian I, Colebunders R. Treatment and prevention of multidrug-resistant tuberculosis. Drugs 1999 Oct; 58(4): 633–61

    Article  PubMed  CAS  Google Scholar 

  22. American Thoracic Society, CDC, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003 Jun 20; 52(RR-11): 1–77

    Google Scholar 

  23. Katiyar SK, Bihari S, Prakash S, et al. A randomised controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2008 Feb; 12(2): 139–45

    PubMed  CAS  Google Scholar 

  24. Zhong M, Wang Y, Sun C, et al. Growth of rifampin-dependent Mycobacterium tuberculosis in conditions without rifampin [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi 2002 Oct; 25(10): 588–90

    PubMed  Google Scholar 

  25. Zhong M, Zhang X, Wang Y, et al. An interesting case of rifampicin-dependent/-enhanced multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2010 Jan; 14(1): 40–4

    PubMed  CAS  Google Scholar 

  26. Mitnick C, Bayona J, Palacios E, et al. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003 Jan 9; 348(2): 119–28

    Article  PubMed  Google Scholar 

  27. Louw GE, Warren RM, Donald PR, et al. Frequency and implications of pyrazinamide resistance in managing previously treated tuberculosis patients. Int J Tuberc Lung Dis 2006 Jul; 10(7): 802–7

    PubMed  CAS  Google Scholar 

  28. Mphahlele M, Syre H, Valvatne H, et al. Pyrazinamide resistance among South African multidrug-resistant Mycobacterium tuberculosis isolates. J Clin Microbiol 2008 Oct; 46(10): 3459–64

    Article  PubMed  CAS  Google Scholar 

  29. World Health Organization (WHO). Guidelines for the programmatic management of drug-resistant tuberculosis (WHO/HTM/TB/2006.361) [online]. Available from URL: http://whqlibdoc.who.int/publications/2006/9241546956_eng.pdf [Accessed 2011 Mar 2]

  30. Caminero JA, Sotgiu G, Zumla A, et al. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis 2010 Sep; 10(9): 621–9

    Article  PubMed  CAS  Google Scholar 

  31. Kim DH, Kim HJ, Park SK, et al. Treatment outcomes and survival based on drug resistance patterns in multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010 Jul 1; 182(1): 113–9

    Article  PubMed  Google Scholar 

  32. Peloquin CA, Hadad DJ, Molino LP, et al. Population pharmacokinetics of levofloxacin, gatifloxacin, and moxi-floxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother 2008 Mar; 52(3): 852–7

    Article  PubMed  CAS  Google Scholar 

  33. Kennedy N, Berger L, Curram J, et al. Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis. Clin Infect Dis 1996 May; 22(5): 827–33

    Article  PubMed  CAS  Google Scholar 

  34. Ziganshina LE, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev 2008 Jan 23; (1): CD004795

  35. Alangaden GJ, Manavathu EK, Vakulenko SB, et al. Characterization of fluoroquinolone-resistant mutant strains of Mycobacterium tuberculosis selected in the laboratory and isolated from patients. Antimicrob Agents Chemother 1995 Aug; 39(8): 1700–3

    Article  PubMed  CAS  Google Scholar 

  36. Kam KM, Yip CW, Cheung TL, et al. Stepwise decrease in moxifloxacin susceptibility amongst clinical isolates of multidrug-resistant Mycobacterium tuberculosis: correlation with ofloxacin susceptibility. Microb Drug Resist 2006 Spring; 12(1): 7–11

    Article  PubMed  CAS  Google Scholar 

  37. Cheng AF, Yew WW, Chan EW, et al. Multiplex PCR amplimer conformation analysis for rapid detection of gyrA mutations in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother 2004 Feb; 48(2): 596–601

    Article  PubMed  CAS  Google Scholar 

  38. Yew WW, Chan CK, Leung CC, et al. Comparative roles of levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis: preliminary results of a retrospective study from Hong Kong. Chest 2003 Oct; 124(4): 1476–81

    Article  PubMed  CAS  Google Scholar 

  39. Dheda K, Shean K, Zumla A, et al. Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study. Lancet 2010 May 22; 375(9728): 1798–807

    Article  PubMed  Google Scholar 

  40. Morlock GP, Metchock B, Sikes D, et al. ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 2003 Dec; 47(12): 3799–805

    Article  PubMed  CAS  Google Scholar 

  41. Warren RM, Streicher EM, Gey van Pittius NC, et al. The clinical relevance of Mycobacterial pharmacogenetics. Tuberculosis (Edinb) 2009 May; 89(3): 199–202

    Article  CAS  Google Scholar 

  42. Lew W, Pai M, Oxlade O, et al. Initial drug resistance and tuberculosis treatment outcomes: systematic review and meta-analysis. Ann Intern Med 2008 Jul 15; 149(2): 123–34

    PubMed  Google Scholar 

  43. Menzies D, Benedetti A, Paydar A, et al. Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: a systematic review and meta-analysis. PLoS Med 2009 Sep; 6(9): e1000146

    Article  PubMed  Google Scholar 

  44. Johnston JC, Shahidi NC, Sadatsafavi M, et al. Treatment outcomes of multidrug-resistant tuberculosis: a systematic review and meta-analysis. PLoS One 2009 Sep 9; 4(9): e6914

    Article  PubMed  Google Scholar 

  45. Orenstein EW, Basu S, Shah NS, et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis 2009 Mar; 9(3): 153–61

    Article  PubMed  Google Scholar 

  46. Dorman SE, Johnson JL, Goldberg S, et al. Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2009 Aug 1; 180(3): 273–80

    Article  PubMed  CAS  Google Scholar 

  47. Fox W, Ellard GA, Mitchison DA. 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 1999; 3: S231–79

    PubMed  CAS  Google Scholar 

  48. Hannan MM, Desmond EP, Morlock GP, et al. Pyrazinamide-monoresistant Mycobacterium tuberculosis in the United States. J Clin Microbiol 2001 Feb; 39(2): 647–50

    Article  PubMed  CAS  Google Scholar 

  49. US Standard from the National Committee for Clinical Laboratory Standards. Susceptibility testing of Mycobacteria, Nocardiae, and other aerobic actinomycetes; approved standard, M24-A. Wayne (IN): NCCLS, 2003

    Google Scholar 

  50. Tenover FC, Crawford JT, Huebner RE, et al. The resurgence of tuberculosis: is your laboratory ready? J Clin Microbiol 1993 Apr; 31(4): 767–70

    PubMed  CAS  Google Scholar 

  51. Caminero JA. Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Lung Dis 2006 Aug; 10(8): 829–37

    PubMed  CAS  Google Scholar 

  52. Van Deun A, Salim MA, Das AP, et al. Results of a standardised regimen for multidrug-resistant tuberculosis in Bangladesh. Int J Tuberc Lung Dis 2004 May; 8(5): 560–7

    PubMed  Google Scholar 

  53. Van Deun A, Maug AK, Salim MA, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010 Sep 1; 182(5): 684–92

    Article  PubMed  Google Scholar 

  54. Tsukamura M, Mizuno S. Cross-resistant relationships among the aminoglucoside antibiotics in Mycobacterium tuberculosis. J Gen Microbiol 1975 Jun; 88(2): 269–74

    Article  PubMed  CAS  Google Scholar 

  55. Chambers HF, Kocagöz T, Sipit T, et al. Activity of amoxicillin/clavulanate in patients with tuberculosis. Clin Infect Dis 1998 Apr; 26(4): 874–7

    Article  PubMed  CAS  Google Scholar 

  56. Jagannath C, Reddy MV, Kailasam S, et al. Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis: in vitro, intracellular, and in vivo studies. Am J Respir Crit Care Med 1995 Apr; 151(4): 1083–6

    PubMed  CAS  Google Scholar 

  57. Luna-Herrera J, Reddy VM, Daneluzzi D, et al. Antituberculosis activity of clarithromycin. Antimicrob Agents Chemother 1995 Dec; 39(12): 2692–5

    Article  PubMed  CAS  Google Scholar 

  58. The Collaborative Group for Meta-Analysis of Individual Patient Data in Multi-drug Resistant Tuberculosis (MDR TB). Evidence for new MDR TB treatment recommendations [oral presentation]. North American Region Meeting of the International Union Against Tuberculosis And Lung Disease; 2011 Feb 24–26; Vancouver (BC)

  59. Sotgiu G, Ferrara G, Matteelli A, et al. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. Eur Respir J 2009 Apr; 33(4): 871–81

    Article  PubMed  CAS  Google Scholar 

  60. Kim SJ, Espinal MA, Abe C, et al. Is second-line anti-tuberculosis drug susceptibility testing reliable? Int J Tuberc Lung Dis 2004 Sep; 8(9): 1157–8

    PubMed  CAS  Google Scholar 

  61. Dheda K, Warren RM, Zumla A, et al. Extensively drug-resistant tuberculosis: epidemiology and management challenges. Infect Dis Clin North Am 2010 Sep; 24(3): 705–25

    Article  PubMed  Google Scholar 

  62. Duff P. Antibiotic selection in obstetric patients. Infect Dis Clin North Am 1997 Mar; 11(1): 1–12

    Article  PubMed  CAS  Google Scholar 

  63. Drobac PC, del Castillo H, Sweetland A, et al. Treatment of multidrug-resistant tuberculosis during pregnancy: long-term follow-up of 6 children with intrauterine exposure to second-line agents. Clin Infect Dis 2005 Jun 1; 40(11): 1689–92

    Article  PubMed  CAS  Google Scholar 

  64. Mukherjee JS, Joseph JK, Rich ML, et al. Clinical and programmatic considerations in the treatment of MDR-TB in children: a series of 16 patients from Lima, Peru. Int J Tuberc Lung Dis 2003 Jul; 7(7): 637–44

    PubMed  CAS  Google Scholar 

  65. Drobac PC, Mukherjee JS, Joseph JK, et al. Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics 2006 Jun; 117(6): 2022–9

    Article  PubMed  Google Scholar 

  66. Nunn P, Kibuga D, Gathua S, et al. Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet 1991 Mar 16; 337(8742): 627–30

    Article  PubMed  CAS  Google Scholar 

  67. Watkins WM, Mungai M, Muhia DK, et al. Cutaneous hypersensitivity reactions to thiacetazone, HIV infection and thiacetazone concentrations in plasma. Br J Clin Pharmacol 1996 Feb; 41(2): 160–2

    Article  PubMed  CAS  Google Scholar 

  68. Breen RA, Lipman MC, Johnson MA. Increased incidence of peripheral neuropathy with co-administration of stavudine and isoniazid in HIV-infected individuals [letter]. AIDS 2000 Mar 31; 14(5): 615

    Article  PubMed  CAS  Google Scholar 

  69. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002 Jan 4; 16(1): 75–83

    Article  PubMed  CAS  Google Scholar 

  70. Marks DJ, Dheda K, Dawson R, et al. Adverse events to antituberculosis therapy: influence of HIV and antiretroviral drugs. Int J STD AIDS 2009 May; 20(5): 339–45

    Article  PubMed  CAS  Google Scholar 

  71. Holdiness MR. Cerebrospinal fluid pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1985 Nov–Dec; 10(6): 532–4

    Article  PubMed  CAS  Google Scholar 

  72. Teixeira L, Perkins MD, Johnson JL, et al. Infection and disease among household contacts of patients with multi-drug-resistant tuberculosis. Int J Tuberc Lung Dis 2001 Apr; 5(4): 321–8

    PubMed  CAS  Google Scholar 

  73. Becerra MC, Appleton SC, Franke MF, et al. Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study. Lancet 2011 Jan 8; 377(9760): 147–52

    Article  PubMed  Google Scholar 

  74. 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 Oct 19; 153(8): 516–22

    PubMed  Google Scholar 

  75. Jarand J, Shean K, O'Donnell M, et al. Extensively drug-resistant tuberculosis (XDR-TB) among health care workers in South Africa. Trop Med Int Health 2010 Oct; 15(10): 1179–84

    Article  PubMed  Google Scholar 

  76. Papastavros T, Dolovich LR, Holbrook A, et al. Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis. CMAJ 2002 Jul 23; 167(2): 131–6

    PubMed  Google Scholar 

  77. Ridzon R, Meador J, Maxwell R, et al. Asymptomatic hepatitis in persons who received alternative preventive therapy with pyrazinamide and ofloxacin. Clin Infect Dis 1997 Jun; 24(6): 1264–5

    Article  PubMed  CAS  Google Scholar 

  78. Pomerantz BJ, Cleveland Jr JC, Olson HK, et al. Pulmonary resection for multi-drug resistant tuberculosis. J Thorac Cardiovasc Surg 2001 Mar; 121(3): 448–53

    Article  PubMed  CAS  Google Scholar 

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  1. Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University, Room K1.24, 3650 St. Urbain St, Montreal, Quebec, Canada, H2X 2P4

    Amr S. Albanna &  Dick Menzies

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Albanna, A.S., Menzies, D. Drug-Resistant Tuberculosis. Drugs 71, 815–825 (2011). https://doi.org/10.2165/11585440-000000000-00000

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