Multidrug-resistant tuberculosis (MDR-TB) is threatening control of TB in many parts of the world. As a result of limited treatment options, patients have a poor prognosis and low chances of cure. This situation can be exacerbated by HIV epidemics. In some cases, the risk exists of a real shift from susceptible to resistant strains. Despite its relevance, currently there are more contradictions and confusion surrounding MDR-TB than hard evidence. No randomized controlled trials have been performed and published evidence is limited. Rather than just the selection of expensive drugs, MDR-TB management requires well-structured programmes with a comprehensive approach, which involve the actions of a wide range of participants. Even with current investments in research and development, new drugs and vaccines will take many years to be applied in low and middle income countries. The most successful results will depend on the optimization of existing tools. The majority of the patients, even those with extensive patterns of bacilli resistance, have a possibility of cure if current clinical knowledge and effective logistics are applied. This paper is a critical review of current best practice regarding the diagnosis and treatment of MDR-TB.
Atre, S.R. and Mistry, N.F. ( 2005) Multidrug-resistant tuberculosis (MDR-TB) in India: An attempt to link biosocial determinants. J Public Health Policy26: 96-114.
2.
Aziz, M.A., Wright, A., Laszlo, A., De Muynck, A., Portaels, F., Van Deun, A. et al. (2006) Epidemiology of antituberculosis drug resistance (the Global Project on Anti-Tuberculosis Drug Resistance Surveillance): An updated analysis. Lancet368: 2142-2154.
3.
Barnard, M., Albert, H., Coetzee, G., O’Brien, R. and Bosman, M.E. ( 2008) Rapid molecular screening for multidrug-resistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med177: 787-792.
4.
Bashar, M., Alcabes, P., Rom, W.N. and Condos, R. ( 2001) Increased incidence of multidrug-resistant tuberculosis in diabetic patients on the Bellevue Chest Service, 1987 to 1997. Chest120: 1514-1519.
5.
Blower, S. and Supervie, V. ( 2007) Predicting the future of XDR tuberculosis. Lancet Infect Dis7: 443.
6.
Blower, S.M. and Chou, T. ( 2004) Modeling the emergence of the ‘hot zones’: Tuberculosis and the amplification dynamics of drug resistance. Nat Med10: 1111-1116.
7.
Bock, N.N., Jensen, P.A., Miller, B. and Nardell, E. ( 2007) Tuberculosis infection control in resource-limited settings in the era of expanding HIV care and treatment. J Infect Dis196 (Suppl 1): S108-S113.
8.
Burkhardt, J.E., Walterspiel, J.N. and Schaad, U.B. ( 1997) Quinolone arthropathy in animals versus children . Clin Infect Dis25: 1196-1204.
9.
Caminero, J. ( 2010) Multidrug-resistant tuberculosis: Epidemiology, risk factors and case-finding. Int J Tuberc Lung Dis (in press).
10.
Caminero, J.A. ( 2005) Management of multidrug-resistant tuberculosis and patients in retreatment. Eur Respir J25: 928-936.
11.
Caminero, J.A. ( 2006) Treatment of multidrug-resistant tuberculosis: Evidence and controversies. Int J Tuberc Lung Dis10: 829-837.
12.
Caminero, J.A. ( 2008) Likelihood of generating MDR-TB and XDR-TB under adequate national tuberculosis control programme implementation. Int J Tuberc Lung Dis12: 869-877.
13.
Caminero Luna. ( 2004) A Tuberculosis Guide for Specialist Physicians, International Union Against Tuberculosis and Lung Diseases, Imprimerie Chirat: Paris.
14.
CDC (1994) Multidrug-resistant tuberculosis in a hospital - Jersey City, New Jersey, 1990-1992. MMWR Morb Mortal Wkly Rep43: 417-419.
15.
Cheng, A.F., Yew, W.W., Chan, E.W., Chin, M.L., Hui, M.M. and Chan, R.C. ( 2004) Multiplex PCR amplimer conformation analysis for rapid detection of GYRA mutations in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother48: 596-601.
16.
Coker, R.J. ( 2004) Review: Multidrug-resistant tuberculosis: Public health challenges. Trop Med Int Health9: 25-40.
17.
Condos, R., Hadgiangelis, N., Leibert, E., Jacquette, G., Harkin, T. and Rom, W.N. ( 2008) Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis. Chest134: 187-192.
18.
Coronado, V.G., Beck-Sague, C.M., Hutton, M.D., Davis, B.J., Nicholas, P., Villareal, C. et al. (1993) Transmission of multidrug-resistant Mycobacterium tuberculosis among persons with human immunodeficiency virus infection in an urban hospital: Epidemiologic and restriction fragment length polymorphism analysis. J Infect Dis168: 1052-1055.
19.
Coyne, K.M., Pozniak, A.L., Lamorde, M. and Boffito, M.(2009) Pharmacology of second-line antituberculosis drugs and potential for interactions with antiretroviral agents. AIDS23: 437-446.
20.
De Vriese, A.S., Coster, R.V., Smet, J., Seneca, S., Lovering, A., Van Haute, L.L. et al. (2006) Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis42: 1111-1117.
21.
Diacon, A.H., Pym, A., Grobusch, M., Patientia, R., Rustomjee, R., Page-Shipp, L. et al. (2009) The diarylquinoline TMC207 for multidrug-resistant tuberculosis . N Engl J Med360: 2397-2405.
22.
Dietze, R., Hadad, D.J., Mcgee, B., Molino, L.P., Maciel, E.L., Peloquin, C.A. et al. (2008) Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med178: 1180-1185.
23.
Farmer, P., Bayona, J., Becerra, M., Furin, J., Henry, C., Hiatt, H. et al. (1998) The dilemma of MDR-TB in the global era. Int J Tuberc Lung Dis2: 869-876.
24.
Faustini, A., Hall, A.J. and Perucci, C.A. ( 2006) Risk factors for multidrug resistant tuberculosis in Europe: A systematic review. Thorax61: 158-163.
Fraser, A., Paul, M., Attamna, A. and Leibovici, L. ( 2006) Treatment of latent tuberculosis in persons at risk for multidrug-resistant tuberculosis: Systematic review. Int J Tuberc Lung Dis10: 19-23.
27.
Gandhi, N.R., Moll, A., Sturm, A.W., Pawinski, R., Govender, T., Lalloo, U. 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. Lancet368: 1575-1580.
28.
Harries, A.D., Zachariah, R. and Lawn, S.D. ( 2009) Providing HIV care for co-infected tuberculosis patients: A perspective from sub-Saharan Africa. Int J Tuberc Lung Dis13: 6-16.
29.
Hillemann, D., Rusch-Gerdes, S. and Richter, E.(2009) Feasibility of the genotype MTBDRsl assay for fluoroquinolone, amikacin-capreomycin, and ethambutol resistance testing of Mycobacterium tuberculosis strains and clinical specimens. J Clin Microbiol47: 1767-1772.
30.
Johnson, J.L., Hadad, D.J., Boom, W.H., Daley, C.L., Peloquin, C.A., Eisenach, K.D. et al. (2006) Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis10: 605-612.
31.
Kam, K.M., Yip, C.W., Cheung, T.L., Tang, H.S., Leung, O.C. and Chan, M.Y. ( 2006) Stepwise decrease in moxifloxacin susceptibility amongst clinical isolates of multidrug-resistant Mycobacterium tuberculosis: Correlation with ofloxacin susceptibility. Microb Drug Resist12: 7-11.
32.
Katiyar, S.K., Bihari, S., Prakash, S., Mamtani, M. and Kulkarni, H. ( 2008) A randomised controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis12: 139-145.
33.
Kim, S.J. ( 2005) Drug-susceptibility testing in tuberculosis: Methods and reliability of results. Eur Respir J25: 564-569.
34.
Kim, S.J., Espinal, M.A., Abe, C., Bai, G.H., Boulahbal, F., Fattorin, L. et al. (2004) Is second-line anti-tuberculosis drug susceptibility testing reliable? Int J Tuberc Lung Dis8: 1157-1158.
35.
Migliori, G.B., Besozzi, G., Girardi, E., Kliiman, K., Lange, C., Toungoussova, O.S. et al. (2007) Clinical and operational value of the extensively drug-resistant tuberculosis definition. Eur Respir J30: 623-626.
36.
Migliori, G.B., Eker, B., Richardson, M.D., Sotgiu, G., Zellweger, J.P., Skrahina, A. et al. (2009) A retrospective TBnet assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis. Eur Respir J34: 387-393.
37.
Miotto, P., Piana, F., Cirillo, D.M. and Migliori, G.B. ( 2008) Genotype MTBDRplus: A further step toward rapid identification of drug-resistant Mycobacterium tuberculosis. J Clin Microbiol46: 393-394.
38.
Mitnick, C., Bayona, J., Palacios, E., Shin, S., Furin, J., Alcantara, F. et al. (2003) Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med348: 119-128.
39.
Mitnick, C.D., Shin, S.S., Seung, K.J., Rich, M.L., Atwood, S.S., Furin, J.J. et al. (2008) Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med359: 563-574.
40.
Monedero, I. and Caminero Luna, J. ( 2009) MDR/ XDR-TB management. What it was, current standards and what is ahead. Expert Rev Respir Med3: 133-145.
41.
Nathanson, E., Gupta, R., Huamani, P., Leimane, V., Pasechnikov, A.D., Tupasi, T.E. et al. (2004) Adverse events in the treatment of multidrug-resistant tuberculosis: Results from the DOTS-plus initiative. Int J Tuberc Lung Dis8: 1382-1384.
42.
Ntziora, F. and Falagas, M.E. ( 2007) Linezolid for the treatment of patients with central nervous system infection. Ann Pharmacother41: 296-308.
43.
O’Brien, R.J. and Spigelman, M. ( 2005) New drugs for tuberculosis: Current status and future prospects. Clin Chest Med26: 327-340, vii.
44.
Pablos-Mendez, A., Gowda, D.K. and Frieden, T.R. ( 2002) Controlling multidrug-resistant tuberculosis and access to expensive drugs: A rational framework. Bull World Health Organ80: 489-495; discussion 495-500.
45.
Park, I.N., Hong, S.B., Oh, Y.M., Kim, M.N., Lim, C.M., Lee, S.D. et al. (2006) Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis. J Antimicrob Chemother58: 701-704.
46.
Peloquin, C.A., Hadad, D.J., Molino, L.P., Palaci, M., Boom, W.H., Dietze, R. et al. (2008) Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother52: 852-857.
47.
Richter, E., Rüsch-Gerdes, S. and Hillemann, D.(2009) Drug-susceptibility testing in tb: current status and future prospects . Expert Rev Respir Med3: 497-510.
48.
Samper, S., Martin, C., Pinedo, A., Rivero, A., Blazquez, J., Baquero, F. et al. (1997) Transmission between HIV-infected patients of multidrug-resistant tuberculosis caused by Mycobacterium bovis. AIDS11: 1237-1242.
49.
Scano, F., Vitoria, M., Burman, W., Harries, A.D., Gilks, C.F. and Havlir, D. ( 2008) Management of HIV-infected patients with MDR- and XDR-TB in resource-limited settings. Int J Tuberc Lung Dis12: 1370-1375.
50.
Schaaf, H.S., Victor, T.C., Venter, A., Brittle, W., Jordaan, A.M., Hesseling, A.C. et al. (2009) Ethionamide cross- and co-resistance in children with isoniazid-resistant tuberculosis. Int J Tuberc Lung Dis13: 1355-1359.
51.
Selwyn, P.A., Hartel, D., Lewis, V.A., Schoenbaum, E.E., Vermund, S.H., Klein, R.S. et al. (1989) A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med320: 545-550.
52.
Skenders, G., Fry, A.M., Prokopovica, I., Greckoseja, S., Broka, L., Metchock, B. et al. (2005) Multidrug-resistant tuberculosis detection, Latvia. Emerg Infect Dis11: 1461-1463.
53.
Somocurcio, J.G., Sotomayor, A., Shin, S., Portilla, S., Valcarcel, M., Guerra, D. et al. (2007) Surgery for patients with drug-resistant tuberculosis: Report of 121 cases receiving community-based treatment in Lima, Peru. Thorax62: 416-421.
54.
Sotgiu, G., Ferrara, G., Matteelli, A., Richardson, M.D., Centis, R., Ruesch-Gerdes, S. et al. (2009) Epidemiology and clinical management of XDR-TB: A systematic review by TBnet. Eur Respir J33: 871-881.
55.
Sterling, T.R., Lehmann, H.P. and Frieden, T.R. ( 2003) Impact of Dots compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: Decision analysis. BMJ326: 574.
56.
Suchindran, S., Brouwer, E.S. and Van Rie, A. ( 2009) Is HIV infection a risk factor for multi-drug resistant tuberculosis? A systematic review. PLoS One4: e5561.
57.
Telenti, A., Imboden, P., Marchesi, F., Schmidheini, T. and Bodmer, T. ( 1993) Direct, automated detection of rifampin-resistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis. Antimicrob Agents Chemother37: 2054-2058.
58.
Tsukamura, M. ( 1969) Cross-resistance relationships between capreomycin, kanamycin, and viomycin resistances in tubercle bacilli from patients. Am Rev Respir Dis99: 780-782.
59.
Tsukamura, M. and Mizuno, S. ( 1980) Studies on the cross-resistance of Mycobacterium tuberculosis, strain H37Rv, to aminoglycoside- and peptide-antibiotics. Microbiol Immunol24: 777-787.
60.
Van Den Boogaard, J., Kibiki, G.S., Kisanga, E.R., Boeree, M.J. and Aarnoutse, R.E.(2009) New drugs against tuberculosis: problems, progress and evaluation of agents in clinical development. Antimicrob Agents Chemother53: 849-862.
61.
Van Deun, A., Salim, M.A., Das, A.P., Bastian, I. and Portaels, F. ( 2004) Results of a standardised regimen for multidrug-resistant tuberculosis in Bangladesh. Int J Tuberc Lung Dis8: 560-567.
62.
WHO (2004) Anti-tuberculosis Drug Resistance in the World. Third Global Report. WHO/Htm/Tb/2004.343. World Health Organization: Geneva.
63.
WHO (2007) The Global MDR-TB and XDR-TB Response Plan. World Health Organization: Geneva.
64.
WHO (2008a) Anti-tuberculosis Drug Resistance in the World. Fourth Global Report. WHO/Htm/Tb/ 2008.394. World Health Organization: Geneva.
65.
WHO (2008b) Guidelines for the Programmatic Management of Drug-resistant Tuberculosis. An Emergency Update. WHO/Htm/Tb/2008.402. World Health Organization: Geneva.
66.
WHO (2009a) Countries that Had Reported at Least One XDR-TB Case by September 2009. World Health Organization: Geneva.
67.
WHO (2009b) Global Tuberculosis Control: A Short Update to the 2009 Report. World Health Organization: Geneva.
68.
WHO (2009c) Treatment of Tuberculosis: Guidelines for National Programmes. WHO/HTM/TB/2009.420. vol. 4th edition . World Health Organization: Geneva .
69.
WHO (2009d) WHO Policy on TB Infection Control in Health-care Facilities, Congregate Settings and Households. WHO/Htm/Tb/2009.419. World Health Organization: Geneva, 1-40.
70.
Yagui, M., Perales, M.T., Asencios, L., Vergara, L., Suarez, C., Yale, G. et al. (2006) Timely diagnosis of MDR-TB under program conditions: Is rapid drug susceptibility testing sufficient? Int J Tuberc Lung Dis10: 838-843.
71.
Yew, W.W., Chan, C.K., Leung, C.C., Chau, C.H., Tam, C.M., Wong, P.C. et al. (2003) Comparative roles of levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis: Preliminary results of a retrospective study from Hong Kong. Chest124: 1476-1481.
72.
Yong Kim, J., Shakow, A., Mate, K., Vanderwarker, C., Gupta, R. and Farmer, P. ( 2005) Limited good and limited vision: Multidrug-resistant tuberculosis and global health policy. Soc Sci Med61: 847-859.
73.
Ziganshina, L.E. and Squire, S.B. ( 2008) Fluoroquinolones for treating tuberculosis. Cochrane Database Syst RevCD004795.
74.
Zignol, M., Hosseini, M.S., Wright, A., Weezenbeek, C.L., Nunn, P., Watt, C.J. et al. (2006) Global incidence of multidrug-resistant tuberculosis . J Infect Dis194: 479-485.
