Extensively drug-resistant tuberculosis: Epidemiology and management challenges

Infectious Disease Clinics of North America

Volumn 24, Issue 3, 2010, Pages 705-725

  Dheda, Keertan ^a,b,c   Warren, Robin M ^d   Zumla, Alimuddin ^c   Grobusch, Martin P ^e,f  

^a UNIVERSITY OF CAPE TOWN   (South Africa)

^b UNIVERSITY OF CAPE TOWN   (South Africa)

^c ROYAL FREE AND UNIVERSITY COLLEGE MEDICAL SCHOOL   (United Kingdom)

^d UNIVERSITY OF STELLENBOSCH   (South Africa)

^e ACADEMIC MEDICAL CENTER   (Netherlands)

^f ALBERT SCHWEITZER HOSPITAL   (Gabon)

Author keywords

Epidemiology; Extensively drug resistant tuberculosis; HIV; Human; Survival

Indexed keywords

AMIKACIN; AMINOGLYCOSIDE ANTIBIOTIC AGENT; AMINOSALICYLIC ACID; AMOXICILLIN PLUS CLAVULANIC ACID; ANTIBIOTIC AGENT; BACTERIAL DNA; CAPREOMYCIN; CIPROFLOXACIN; CLARITHROMYCIN; CLOFAZIMINE; CYCLOSERINE; ETHAMBUTOL; ETHIONAMIDE; GATIFLOXACIN; ISONIAZID; KANAMYCIN; LEVOFLOXACIN; LINEZOLID; MOXIFLOXACIN; OFLOXACIN; PROTIONAMIDE; PYRAZINAMIDE; QUINOLINE DERIVED ANTIINFECTIVE AGENT; RIFAMPICIN; STREPTOMYCIN; TERIZIDONE; THIOACETAMIDE; TUBERCULOSTATIC AGENT; UNINDEXED DRUG; VIOMYCIN;

ANTIBIOTIC SENSITIVITY; BACTERIAL STRAIN; BACTERIAL TRANSMISSION; BACTERIUM CULTURE; CHINA; DIAGNOSTIC ACCURACY; DIAGNOSTIC ERROR; DNA FINGERPRINTING; EPIDEMIC; ESTONIA; EXTENSIVELY DRUG RESISTANT TUBERCULOSIS; GENOTYPE; HOSPITAL INFECTION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYPOKALEMIA; HYPOMAGNESEMIA; IRAN; JAPAN; KIDNEY FAILURE; LABORATORY TEST; MIXED INFECTION; MOLECULAR EPIDEMIOLOGY; MULTIDRUG RESISTANT TUBERCULOSIS; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; PANDEMIC; PATIENT COMPLIANCE; POLAND; PORTUGAL; POSTPRIMARY TUBERCULOSIS; PREVALENCE; RETREATMENT; REVIEW; SOUTH AFRICA; SPUTUM SMEAR; THERAPEUTIC ERROR; TUBERCULOSIS CONTROL; UNSPECIFIED SIDE EFFECT; UZBEKISTAN; VARIABLE NUMBER OF TANDEM REPEAT; BACTERIUM IDENTIFICATION; CLASSIFICATION; COMPLICATION; DRUG EFFECTS; EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS; GENETICS; ISOLATION AND PURIFICATION; MICROBIOLOGY; TREATMENT OUTCOME;

ANTITUBERCULAR AGENTS; BACTERIAL TYPING TECHNIQUES; DISEASE OUTBREAKS; DNA FINGERPRINTING; EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS; GENOTYPE; HIV INFECTIONS; HUMANS; MYCOBACTERIUM TUBERCULOSIS; TREATMENT OUTCOME;

EID: 77955240567     PISSN: 08915520     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.idc.2010.05.001     Document Type: Review

References (96)

1. WHO Anti-tuberculosis drug resistance in the world: the WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2008, WHO, Geneva (Switzerland).
2. WHO Global tuberculosis control 2009: epidemiology, strategy, financing 2009, WHO, Geneva (Switzerland).
3. Wright A, Zignol M, Van Deun A, et al. Epidemiology of antituberculosis drug resistance 2002-07: an updated analysis of the global project on anti-tuberculosis drug resistance surveillance. Lancet 2009, 373(9678):1861-1873.
4. Yew W., Leung C. Management of multidrug-resistant tuberculosis: update 2007. Respirology 2008, 13(1):21-46.
5. Schaaf HS, Moll AP Dheda K Multidrug- and extensively drug-resistant tuberculosis in Africa and South America: epidemiology, diagnosis and management in adults and children. Clin Chest Med 2009, 30(4):667-683.
6. LoBue P. Extensively drug-resistant tuberculosis. Curr Opin Infect Dis 2009, 22(2):167-173.
7. Madariaga M.G., Lalloo U.G., Swindells S. Extensively drug-resistant tuberculosis. Am J Med 2008, 121(10):835-844.
8. Jassal M., Bishai W.R. Extensively drug-resistant tuberculosis. Lancet Infect Dis 2009, 9(1):19-30.
9. Scano F., Vitoria M., Burman W., et al. Management of HIV-infected patients with MDR- and XDR-TB in resource-limited settings. Int J Tuberc Lung Dis 2008, 12(12):1370-1375.
10. Sotgiu G., Ferrara G., Matteelli A., et al. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. Eur Respir J 2009, 33(4):871-881.
11. Orenstein E., Basu S., Shah N., et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis 2009, 9(3):153-161.
12. Ben Amor Y., Nemser B., Singh A., et al. Underreported threat of multidrug-resistant tuberculosis in Africa. Emerg Infect Dis 2008, 14(9):1345-1352.
13. Meskel D.W., Abate G., Lakew M., et al. Anti-tuberculosis drug resistance among retreatment patients seen at St Peter Tuberculosis Specialized Hospital. Ethiop Med J 2008, 46(3):219-225.
14. Kehinde A.O., Obaseki F.A., Ishola O.C., et al. Multidrug resistance to Mycobacterium tuberculosis in a tertiary hospital. J Natl Med Assoc 2007, 99(10):1185-1189.
15. Habeenzu C., Mitarai S., Lubasi D., et al. Tuberculosis and multidrug resistance in Zambian prisons, 2000-2001. Int J Tuberc Lung Dis 2007, 11(11):1216-1220.
16. Umubyeyi A.N., Vandebriel G., Gasana M., et al. Results of a national survey on drug resistance among pulmonary tuberculosis patients in Rwanda. Int J Tuberc Lung Dis 2007, 11(2):189-194.
17. Gandhi N.R., Moll A., Sturm A.W., et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006, 368(9547):1575-1580.
18. Dowdy D.W., Chaisson R.E., Maartens G., et al. Impact of enhanced tuberculosis diagnosis in South Africa: a mathematical model of expanded culture and drug susceptibility testing. Proc Natl Acad Sci U S A 2008, 105(32):11293-11298.
19. Basu S., Friedland G., Medlock J., et al. Averting epidemics of extensively drug-resistant tuberculosis. Proc Natl Acad Sci U S A 2009, 106(18):7672-7677.
20. Basu S., Andrews J., Poolman E., et al. Prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: an epidemiological modelling study. Lancet 2007, 370(9597):1500-1507.
21. Bonilla C.A., Crossa A., Jave H.O., et al. Management of extensively drug-resistant tuberculosis in Peru: cure is possible. PLoS One 2008, 3(8):e2957.
22. 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, 375(9728):1798-1807.
23. Mitnick C.D., Shin S.S., Seung K.J., et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008, 359(6):563-574.
24. Kamerbeek J., Schouls L., Kolk A., et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol 1997, 35(4):907-914.
25. Streicher E.M., Victor T.C., van der Spuy G., et al. Spoligotype signatures in the Mycobacterium tuberculosis complex. J Clin Microbiol 2007, 45(1):237-240.
26. Brudey K., Driscoll J.R., Rigouts L., et al. Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology. BMC Microbiol 2006, 6:23.
27. van Embden J.D., Cave M.D., Crawford J.T., et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol 1993, 31(2):406-409.
28. Supply P., Allix C., Lesjean S., et al. Proposal for standardization of optimized mycobacterial interspersed repetitive unit-variable-number tandem repeat typing of Mycobacterium tuberculosis. J Clin Microbiol 2006, 44(12):4498-4510.
29. Oelemann M.C., Diel R., Vatin V., et al. Assessment of an optimized mycobacterial interspersed repetitive- unit-variable-number tandem-repeat typing system combined with spoligotyping for population-based molecular epidemiology studies of tuberculosis. J Clin Microbiol 2007, 45(3):691-697.
30. Allix-Beguec C., Fauville-Dufaux M., Supply P. Three-year population-based evaluation of standardized mycobacterial interspersed repetitive-unit-variable-number tandem-repeat typing of Mycobacterium tuberculosis. J Clin Microbiol 2008, 46(4):1398-1406.
31. Hanekom M., van der Spuy G.D., Gey van Pittius N.C., et al. Discordance between mycobacterial interspersed repetitive-unit-variable-number tandem-repeat typing and IS6110 restriction fragment length polymorphism genotyping for analysis of Mycobacterium tuberculosis Beijing strains in a setting of high incidence of tuberculosis. J Clin Microbiol 2008, 46(10):3338-3345.
32. Small P.M., Hopewell P.C., Singh S.P., et al. The epidemiology of tuberculosis in San Francisco. A population-based study using conventional and molecular methods. N Engl J Med 1994, 330(24):1703-1709.
33. Hermans P.W., Messadi F., Guebrexabher H., et al. Analysis of the population structure of Mycobacterium tuberculosis in Ethiopia, Tunisia, and the Netherlands: usefulness of DNA typing for global tuberculosis epidemiology. J Infect Dis 1995, 171(6):1504-1513.
34. Warren R., Hauman J., Beyers N., et al. Unexpectedly high strain diversity of Mycobacterium tuberculosis in a high-incidence community. S Afr Med J 1996, 86(1):45-49.
35. Alland D., Kalkut G.E., Moss A.R., et al. Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods. N Engl J Med 1994, 330(24):1710-1716.
36. van Rie A., Warren R., Richardson M., et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999, 341(16):1174-1179.
37. van Rie A., Warren R.M., Beyers N., et al. Transmission of a multidrug-resistant Mycobacterium tuberculosis strain resembling "strain W" among noninstitutionalized, human immunodeficiency virus-seronegative patients. J Infect Dis 1999, 180(5):1608-1615.
38. Van Rie A., Warren R., Richardson M., et al. Classification of drug-resistant tuberculosis in an epidemic area. Lancet 2000, 356(9223):22-25.
39. Michalak K., Austin C., Diesel S., et al. Mycobacterium tuberculosis infection as a zoonotic disease: transmission between humans and elephants. Emerg Infect Dis 1998, 4(2):283-287.
40. Verver S., Warren R.M., Munch Z., et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area. Lancet 2004, 363(9404):212-214.
41. Heyns L., Gie R.P., Goussard P., et al. Nosocomial transmission of Mycobacterium tuberculosis in kangaroo mother care units: a risk in tuberculosis-endemic areas. Acta Paediatr 2006, 95(5):535-539.
42. Richardson M., Carroll N.M., Engelke E., et al. Multiple Mycobacterium tuberculosis strains in early cultures from patients in a high-incidence community setting. J Clin Microbiol 2002, 40(8):2750-2754.
43. Small P.M., McClenny N.B., Singh S.P., et al. Molecular strain typing of Mycobacterium tuberculosis to confirm cross-contamination in the mycobacteriology laboratory and modification of procedures to minimize occurrence of false-positive cultures. J Clin Microbiol 1993, 31(7):1677-1682.
44. Behr M.A., Warren S.A., Salamon H., et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999, 353(9151):444-449.
45. Weyer K Survey of tuberculosis drug resistance; Western Cape Available at:, Accessed September 2009. http://www.Sahealthinfo.Org/tb/tbdrugresistance.Htm.
46. Li X., Zhang Y., Shen X., et al. Transmission of drug-resistant tuberculosis among treated patients in Shanghai, China. J Infect Dis 2007, 195(6):864-869.
47. Andrews J.R., Gandhi N.R., Moodley P., et al. Exogenous reinfection as a cause of multidrug-resistant and extensively drug-resistant tuberculosis in rural South Africa. J Infect Dis 2008, 198(11):1582-1589.
48. van Rie A., Victor T.C., Richardson M., et al. Reinfection and mixed infection cause changing Mycobacterium tuberculosis drug-resistance patterns. Am J Respir Crit Care Med 2005, 172(5):636-642.
49. Bifani P.J., Mathema B., Liu Z., et al. Identification of a W variant outbreak of Mycobacterium tuberculosis via population-based molecular epidemiology. JAMA 1999, 282(24):2321-2327.
50. Victor T.C., Streicher E.M., Kewley C., et al. Spread of an emerging Mycobacterium tuberculosis drug-resistant strain in the Western Cape of South Africa. Int J Tuberc Lung Dis 2007, 11(2):195-201.
51. Andersson D.I. The biological cost of mutational antibiotic resistance: any practical conclusions?. Curr Opin Microbiol 2006, 9(5):461-465.
52. Gagneux S., Long C.D., Small P.M., et al. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 2006, 312(5782):1944-1946.
53. European Concerted Action on New Generation Genetic Markers and Techniques for the Epidemiology and Control of Tuberculosis. Beijing/W genotype Mycobacterium tuberculosis and drug resistance. Emerg Infect Dis 2006, 12(5):736-743.
54. Strauss O.J., Warren R.M., Jordaan A., et al. Spread of a low-fitness drug-resistant Mycobacterium tuberculosis strain in a setting of high human immunodeficiency virus prevalence. J Clin Microbiol 2008, 46(4):1514-1516.
55. Johnson R., Streicher E.M., Louw G.E., et al. Drug resistance in Mycobacterium tuberculosis. Curr Issues Mol Biol 2006, 8(2):97-111.
56. Centers for Disease Control and Prevention (CDC). Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs-worldwide, 2000-2004. MMWR Morb Mortal Wkly Rep 2006, 55(11):301-305.
57. Pillay M., Sturm A.W. Evolution of the extensively drug-resistant F15/LAM4/KZN strain of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa. Clin Infect Dis 2007, 45(11):1409-1414.
58. Mlambo C.K., Warren R.M., Poswa X., et al. Genotypic diversity of extensively drug-resistant tuberculosis (XDR-TB) in South Africa. Int J Tuberc Lung Dis 2008, 12(1):99-104.
59. Kliiman K., Altraja A. Predictors of poor treatment outcome in multi- and extensively drug-resistant pulmonary TB. Eur Respir J 2009, 33(5):1085-1094.
60. Sun Z., Chao Y., Zhang X., et al. Characterization of extensively drug-resistant Mycobacterium tuberculosis clinical isolates in China. J Clin Microbiol 2008, 46(12):4075-4077.
61. Zhao M., Li X., Xu P., et al. Transmission of MDR and XDR tuberculosis in Shanghai, China. PLoS One 2009, 4(2):e4370.
62. Ano H., Matsumoto T., Suetake T., et al. Relationship between the isoniazid-resistant mutation KATGS315 T and the prevalence of MDR-/XDR-TB in Osaka, Japan. Int J Tuberc Lung Dis 2008, 12(11):1300-1305.
63. Iwamoto T., Yoshida S., Suzuki K., et al. Population structure analysis of the Mycobacterium tuberculosis Beijing family indicates an association between certain sublineages and multidrug resistance. Antimicrobial Agents Chemother 2008, 52(10):3805-3809.
64. Cox H.S., Sibilia K., Feuerriegel S., et al. Emergence of extensive drug resistance during treatment for multidrug-resistant tuberculosis. N Engl J Med 2008, 359(22):2398-2400.
65. Masjedi M.R., Farnia P., Sorooch S., et al. Extensively drug-resistant tuberculosis: 2 years of surveillance in Iran. Clin Infect Dis 2006, 43(7):841-847.
66. Velayati A.A., Masjedi M.R., Farnia P., et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest 2009, 136(2):420-425.
67. Augustynowicz-Kopec E., Zwolska Z. Pneumonol Alergol Pol 2007, 75(1):32-39. [in Polish].
68. Perdigao J., Macedo R., Joao I., et al. Multidrug-resistant tuberculosis in Lisbon, Portugal: a molecular epidemiological perspective. Microb Drug Resist 2008, 14(2):133-143.
69. Drobniewski F., Rusch-Gerdes S., Hoffner S. Antimicrobial susceptibility testing of Mycobacterium tuberculosis (EUCAST document E.Def 8.1)-report of the Subcommittee on Antimicrobial Susceptibility Testing of Mycobacterium tuberculosis of the European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Clin Microbiol Infect 2007, 13(12):1144-1156.
70. Kim S.J. Drug-susceptibility testing in tuberculosis: methods and reliability of results. Eur Respir J 2005, 25(3):564-569.
71. Sirgel F.A., Wiid I., van Helden P.D. Measuring inhibitory concentrations in mycobacteria. Methods in molecular biology: mycobacterium protocols 2008, 173-186. The Human Press Inc, New York. T. Parish, A.C. Brown (Eds.).
72. Perkins M.D., Cunningham J. Facing the crisis: improving the diagnosis of tuberculosis in the HIV era. J Infect Dis 2007, 196(Suppl 1):S15-S27.
73. Johnson R., Jordaan A.M., Pretorius L., et al. Ethambutol resistance testing by mutation detection. Int J Tuberc Lung Dis 2006, 10(1):68-73.
74. Gandhi NR, Nunn P, Dheda K, et al. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet 2010, 375(9728):1830-1843.
75. Kruuner A., Yates M.D., Drobniewski F.A. Evaluation of MGIT 960-based antimicrobial testing and determination of critical concentrations of first- and second-line antimicrobial drugs with drug-resistant clinical strains of Mycobacterium tuberculosis. J Clin Microbiol 2006, 44(3):811-818.
76. Pfyffer G.E., Bonato D.A., Ebrahimzadeh A., et al. Multicenter laboratory validation of susceptibility testing of Mycobacterium tuberculosis against classical second-line and newer antimicrobial drugs by using the radiometric BACTEC 460 technique and the proportion method with solid media. J Clin Microbiol 1999, 37(10):3179-3186.
77. Rusch-Gerdes S., Pfyffer G.E., Casal M., et al. Multicenter laboratory validation of the BACTEC MGIT 960 technique for testing susceptibilities of Mycobacterium tuberculosis to classical second-line drugs and newer antimicrobials. J Clin Microbiol 2006, 44(3):688-692.
78. Hawkins J.E. Drug susceptibility testing. The mycobacteria. A sourcebook. Part a 1984, 177-193. Marcel Dekker, New York. G.P. Kubica, L.G. Wayne (Eds.).
79. WHO Guidelines for surveillance of drug resistance in tuberculosis 2009, WHO, France, Available at:, Accessed May 4, 2010. http://whqlibdoc.who.int/publications/2009/9789241598675_eng.pdf, 4th edition.
80. Sandgren A., Strong M., Muthukrishnan P., et al. Tuberculosis drug resistance mutation database. PLoS Med 2009, 6(2):e2.
81. Springer B., Lucke K., Calligaris-Maibach R., et al. Quantitative drug susceptibility testing of Mycobacterium tuberculosis by use of MGIT 960 and epicenter instrumentation. J Clin Microbiol 2009, 47(6):1773-1780.
82. Kam K.M., Yip C.W., Cheung T.L., et al. Stepwise decrease in moxifloxacin susceptibility amongst clinical isolates of multidrug-resistant Mycobacterium tuberculosis: correlation with ofloxacin susceptibility. Microb Drug Resist 2006, 12(1):7-11.
83. Warren R.M., Streicher E.M., van Pittius N.C., et al. The clinical relevance of mycobacterial pharmacogenetics. Tuberculosis (Edinb) 2009, 89(3):199-202.
84. Ling D.I., Zwerling A.A., Pai M. Genotype MTBDR assays for the diagnosis of multidrug-resistant tuberculosis: a meta-analysis. Eur Respir J 2008, 32(5):1165-1174.
85. Pai M., Kalantri S., Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: part II. Active tuberculosis and drug resistance. Expert Rev Mol Diagn 2006, 6(3):423-432.
86. Barnard M., Albert H., Coetzee G., et al. Rapid molecular screening for multidrug-resistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med 2008, 177(7):787-792.
87. O'Brien R. New diagnostic methods for tuberculosis. APHL 5th National Conference on Laboratory Aspects of Tuberculosis San Diego 11-13 2008, Available at:, Accessed May 5, 2010. http://www.aphl.org/profdev/conferences/proceedings/Documents/2008TBconference/009-OBrien.pdf.
88. Moore D.A., Evans C.A., Gilman R.H., et al. Microscopic-observation drug-susceptibility assay for the diagnosis of TB. N Engl J Med 2006, 355(15):1539-1550.
89. Martin A., Panaiotov S., Portaels F., et al. The nitrate reductase assay for the rapid detection of isoniazid and rifampicin resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother 2008, 62(1):56-64.
90. Hoek K.G., Gey van Pittius N.C., Moolman-Smook H., et al. Fluorometric assay for testing rifampin susceptibility of Mycobacterium tuberculosis complex. J Clin Microbiol 2008, 46(4):1369-1373.
91. Pietzka A.T., Indra A., Stoger A., et al. Rapid identification of multidrug-resistant Mycobacterium tuberculosis isolates by RPOB gene scanning using high-resolution melting curve PCR analysis. J Antimicrob Chemother 2009, 63(6):1121-1127.
92. Moll A.P., Friedland G., Gandhi N., et al. Extensively drug-resistant tuberculosis (XDR-TB). Tuberculosis. A comprehensive clinical reference 2009, 551-557. Elsevier, St Louis (MO). 1st edition. S.H. Schaaf, A.I. Zumla (Eds.).
93. WHO Guidelines for the programmatic management of drug-resistant tuberculosis: emergency update 2008 2008, WHO, Geneva (Switzerland).
94. Katiyar S., 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, 12(2):139-145.
95. Bateman C. XDR TB-humane confinement 'a priority'. S Afr Med J 2007, 97(11):1026. 28, 30.
96. Singh J.A., Upshur R., Padayatchi N. XDR-TB in South Africa: no time for denial or complacency. PLoS Med 2007, 4(1):e50.