Multidrug-resistant tuberculosis (MDR-TB) and extensively resistant tuberculosis (XDR-TB) are present in most regions of the world and represent a serious threat to the control of tuberculosis. They usually result from errors somewhere along the chain of management of the disease that favoured the selection of resistant mutants, progressively replacing drug-sensitive strains and transmitted to further patients. The currently recommended strategies for the control of this serious situation is the rapid identification of drug-resistant strains, careful drug management of patients with second-line drugs and prevention of the transmission of mycobacteria to contacts. Optimal selection and number of drugs and duration of treatment are not clearly defined. Prevention of the creation of additional cases of MDR-TB is crucial.
Tuberculosis, multidrug-resistant tuberculosis (MDR-TB), extensively resistant tuberculosis (XDR-TB), treatment
Jean-Pierre Zellweger has no conflicts of interest to declare. No funding was received for the publication of this article.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation
and reproduction provided the original author(s) and source are given appropriate credit.
May 27, 2015 Accepted:
June 29, 2015
Jean-Pierre Zellweger, Swiss Lung Association, Chutzenstrasse 10, 3000 Berne, Switzerland. E: firstname.lastname@example.org
Strains of Mycobacterium tuberculosis (M. tbc) are able, like other bacteria, to develop resistance against antibiotics. The first observations were published shortly after the introduction of streptomycin and were the basis of the current recommendation of combining several antibiotics for the treatment of tuberculosis (TB).1 Rigorous application of this principle could have possibly prevented the development of drug resistance. In spite of this, drug resistance against the most active antibiotics increased progressively and is currently a widespread phenomenon. Apart from resistance against single drugs, resistance against the two most active anti-TB drugs, isoniazid and rifampicin, known as multidrug resistance (MDR-TB), has increased and new forms of resistance have emerged, like the resistance against isoniazid, rifampicin, injectable drugs and quinolones, known as extensively drug-resistant strains (XDR-TB).
The latest reports from the World Health Organization (WHO) estimate the number of MDR-TB to half a million cases, of which 10 % are XDRTB, a large part being left untreated, with a high death burden.2 In some regions of the world or in some at-risk populations, like gold miners in South Africa, the rate of MDR-TB is increasing rapidly, particularly in previously treated cases, in spite of the fact that the global incidence rate in the same population had decreased during the same time period.3 Recent reports reveal alarming levels of drug-resistant TB in many Eastern European regions,4 such as Belarus, where the rates reach 35.3 % in new patients and 76.5 % among previously treated cases5 or in Ukraine, where the association with HIV seems to increase the problem.6 In Russia, if the current trends continue, the incidence of drug-resistant TB could be higher than the incidence of drug-sensitive TB within the next few years.7 Prisons seem to be places where the incidence of TB (including drug-resistant forms) is particularly high.7,8 In China, a recent survey concluded that the proportion of MDR-TB cases among new and previously treated patients is 5.7 % and 25.6 %, respectively, and the total number of MDR-TB cases is about 110,000.9 The increase in drugresistant TB is also observed in children in some regions of the world.10
Risk Factors for MDR-TB
Most surveys report an association between previous treatment for TB and high rates of drug resistance.11,12 The prevalence of MDR-TB is higher among patients who were already treated for TB and failed or recurred, but this group represents only a minority among all cases of TB. In absolute numbers, the majority of cases is observed in new patients, who never received a treatment before and who were contaminated by a patients harbouring a resistant strain.13 As a consequence, in some regions of the world, new patients are at high risk of having MDR-TB even in the absence of previous treatment.
Apart from close contact with a patient with drug-resistant TB, other factors associated with the presence of MDR-TB are migration, young age and HIV.14
One particular cause seems to be the induction of resistance by insufficient bioavailability of some anti-TB drugs such as rifampicin.15 Low serum levels of anti-TB drugs, which are observed in some patients,16 may induce the development of resistance against one or several drugs. Some studies have confirmed that patients with a low serum level of the first-line anti-TB drugs have a worse outcome than patients with a level within the expected range.17 This may also explain why some patients develop a drug-resistant form of TB in spite of full adherence to a correct treatment.18,19 One may suspect that drugs of low quality or insufficient bioavailability may contribute to the creation of drug resistance. How important this phenomenon may be in the progressive extension of MDR-TB in some regions is unclear. Studies are ongoing to decide if the recommended dose of rifampicin will have to be changed in the future.20
Why is MDR-TB Increasing in Some Regions of the World?
There are many reasons for the increase of MDR-TB and XDR-TB worldwide, but they all have one point in common: there was some error along the chain of management, inducing a mutation in a strain of sensitive mycobacteria and the selection of mycobacteria that have become resistant to one or several antituberculous drugs, which will progressively replace the sensitive bacteria.21 Among the usual causes are inappropriate treatment of mycobacteria with an undetected resistance against a single drug, use of drugs of bad quality, insufficient drug dosage, changes in drug schedule or dosage and addition of a single drug to a failing regimen. Retreatment of patients with a recurrent episode of tuberculosis with the same drugs as for the first episode, without appropriate drug susceptibility testing (DST), is a possible cause of amplification of the drug-resistance pattern and transformation of a strain with single drug resistance to MDR-TB. This can happen even under normal programmatic conditions, if the drug sensitivity testing is not performed in suspect cases.22,23 Patients with an unsuspected drug resistance who are not cured at the first treatment attempt have a high risk of developing further resistance and harbour an MDR-TB strain.24–26 This is the reason why the ancient recommendation of WHO to use a retreatment regimen containing the same first-line drugs in addition to streptomycine, which has proven successful in settings with a low frequency of drug resistance,27 has been put into question28 and is now no more valid.29 Furthermore, some strains, like the Beijing genotype, seem to mutate more rapidly and be more virulent so that in some regions they progressively replace the other strains.30
The practical issue is that in many settings, if the DST of the strain are not performed rapidly (which is the norm in many regions lacking proper laboratory equipment), patients with MDR-TB will receive inadequate treatment for several weeks or months before the correct diagnosis is made and an appropriate treatment is started. The consequence is that many MDR-TB patients will have a prolonged period of infectiousness and be a danger to other patients and to the staff. Furthermore, as the cure rate of patients with MDR-TB strains is lower than the cure rate in patients with sensitive strains, some patients with MDR-TB can become chronic excretors (the author has observed a case surviving 27 years with a smear-positive pulmonary TB resistant to all anti-TB drugs known in the 1970s).
1. 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,
2. World Health Organization, Drug-resistant TB surveillance and
response. Geneva: World Health Organization; 2014. Report
3. van Halsema CL, Fielding KL, Chihota VN, et al., Trends in drugresistant
tuberculosis in a gold-mining workforce in South
Africa, 2002–2008, Int J Tuberc Lung Dis, 2012;16:967–73.
4. Falzon D, Infuso A, it-Belghiti F, In the European Union, TB
patients from former Soviet countries have a high risk of
multidrug resistance, Int J Tuberc Lung Dis, 2006;10:954–8.
5. Skrahina A, Hurevich H, Zalutskaya A, et al., Alarming levels of
drug-resistant tuberculosis in Belarus: results of a survey in
Minsk, Eur Respir J, 2012;39:1425–31.
6. Dubrovina I, Miskinis K, Lyepshina S, et al., Drug-resistant
tuberculosis and HIV in Ukraine: a threatening convergence of
two epidemics?, Int J Tuberc Lung Dis, 2008;12:756–62.
7. Yablonskii PK, Vizel AA, Galkin VB, Shulgina MV, Tuberculosis
in Russia. Its history and its status today, Am J Respir Crit
Care Med, 2015;191:372–6.
8. O’Grady J, Maeurer M, Atun R, et al., Tuberculosis in prisons:
anatomy of global neglect, Eur Respir J, 2011;38:752–4.
9. Zhao Y, Xu S, Wang L, et al., National survey of drug-resistant
tuberculosis in China, N Engl J Med, 2012;366:2161–70.
10. Seddon JA, Hesseling AC, Marais BJ, Jordaan A, Victor
T, Schaaf HS. The evolving epidemic of drug-resistant
tuberculosis among children in Cape Town, South Africa.
Int J Tuberc Lung Dis 2012;16:928–33.
11. Faustini A, Hall AJ, Perucci CA, Risk factors for multidrug
resistant tuberculosis in Europe: a systematic review, Thorax,
12. Lomtadze N, Aspindzelashvili R, Janjgava M, et al., Prevalence
and risk factors for multidrug-resistant tuberculosis in the
Republic of Georgia: a population-based study, Int J Tuberc
Lung Dis, 2009;13:68–73.
13. Royce S, Falzon D, van Weezenbeek C, et al., Multidrug
resistance in new tuberculosis patients: burden and
implications, Int J Tuberc Lung Dis, 2013;17:511–3.
14. Lange C, Abubakar I, Alffenaar JW, et al., Management of
patients with multidrug-resistant/extensively drug-resistant
tuberculosis in Europe: a TBNET consensus statement,
Eur Respir J, 2014;44:23–63.
15. Patel KB, Belmonte R, Crowe HM, Drug malabsorption and
resistant tuberculosis in HIV-infected patients, N Engl J Med,
16. Fahimi F, Tabarsi P, Kobarfard F, et al., Isoniazid, rifampicin and
pyrazinamide plasma concentrations 2 and 6 h post dose in
patients with pulmonary tuberculosis, Int J Tuberc Lung Dis,
17. Pasipanodya JG, McIlleron H, Burger A, et al., Serum drug
concentrations predictive of pulmonary tuberculosis
outcomes, J Infect Dis, 2013;208:1464–73.
18. Calver AD, Falmer AA, Murray M, et al., Emergence of
increased resistance and extensively drug-resistant
tuberculosis despite treatment adherence, South Africa,
Emerg Infect Dis, 2010;16:264–71.
19. Srivastava S, Pasipanodya JG, Meek C, et al., Multidrugresistant
tuberculosis not due to noncompliance but to
between-patient pharmacokinetic variability, J Infect Dis,
20. Boeree MJ, Diacon AH, Dawson R, et al., A dose-ranging
trial to optimize the dose of rifampin in the treatment of
tuberculosis, Am J Respir Crit Care Med, 2015;191:1058–65.
21. Caminero JA, Matteelli A, Loddenkemper R, Tuberculosis: are
we making it incurable?, Eur Respir J, 2013;42:5–8.
22. Otero L, Krapp F, Tomatis C, et al., High prevalence of primary
multidrug resistant tuberculosis in persons with no known
risk factors, PLoS ONE, 2011;6:e26276.
23. Caminero JA, Likelihood of generating MDR-TB and XDR-TB
under adequate National Tuberculosis Control Programme
implementation, Int J Tuberc Lung Dis, 2008;12:869–77.
24. Balabanova Y, Radiulyte B, Davidaviciene E, et al., Risk factors
for drug-resistant tuberculosis patients in Lithuania, 2002-
2008, Eur Respir J, 2012;39:1266–9.
25. van der Werf MJ, Langendam MW, Huitric E, Manissero
D, Multidrug resistance after inappropriate tuberculosis
treatment: a meta-analysis, Eur Respir J, 2012;39:1511–9.
26. Cox HS, Niemann S, Ismailov G, et al., Risk of acquired drug
resistance during short-course directly observed treatment
of tuberculosis in an area with high levels of drug resistance,
Clin Infect Dis, 2007;44:1421–7.
27. Gninafon M, Tawo L, Kassa F, et al., Outcome of tuberculosis
retreatment in routine conditions in Cotonou, Benin, Int J
Tuberc Lung Dis, 2004;8:1242–7.
28. Quy HT, Lan NT, Borgdorff MW, et al., Drug resistance among
failure and relapse cases of tuberculosis: is the standard
re-treatment regimen adequate?, Int J Tuberc Lung Dis,
29. Furin J, Gegia M, Mitnick C, et al., Eliminating the category II
retreatment regimen from national tuberculosis programme
guidelines: the Georgian experience, Bull World Health Organ,
30. Hanekom M, Gey van Pittius NC, McEvoy C, et al.,
Mycobacterium tuberculosis Beijing genotype: a template for
success, Tuberculosis (Edinb), 2011;91:510–23.
31. Borrell S, Gagneux S, Infectiousness, reproductive fitness and
evolution of drug-resistant Mycobacterium tuberculosis,
Int J Tuberc Lung Dis, 2009;13:1456–66.
32. Dharmadhikari AS, Basaraba RJ, Van Der Walt ML, et al., Natural
infection of guinea pigs exposed to patients with highly drugresistant
tuberculosis, Tuberculosis (Edinb), 2011;91:329–38.
33. Dharmadhikari AS, Nardell E, Serial acid fast bacilli smear and culture conversion rates over 26 weeks in a cohort of
93 sputum culture-positive tuberculosis (TB), Clin Infect Dis,
34. Dharmadhikari AS, Mphahlele M, Stoltz A, et al., Surgical face
masks worn by patients with multidrug-resistant tuberculosis:
impact on infectivity of air on a hospital ward, Am J Respir
Crit Care Med, 2012;185:1104–9.
35. Migliori GB, Sotgiu G, D’Ambrosio L, et al., TB and MDR/
XDR-TB in European Union and European Economic
Area countries: managed or mismanaged?, Eur Resp J,
36. Chaisson RE, Nuermberger EL, Confronting multidrugresistant
tuberculosis, N Engl J Med, 2012;366:2223–4.
37. Wolinsky E, Reginster RA, Steenken W Jr, Drug-resistant
tubercle bacilli in patients under treatment with streptomycin,
Am Rev Tuberc, 1948;58:335–43.
38. Frieden TR, Sterling T, Pablos-Mendez A, et al., The emergence
of drug-resistant tuberculosis in New York City, N Engl J Med,
39. Goble M, Iseman MD, Madsen LA, et al., Treatment of 171
patients with pulmonary tuberculosis resistant to isoniazid
and rifampin, N Engl J Med, 1993;328:527–32.
40. Iseman MD, Treatment of multidrug-resistant tuberculosis,
N Engl J Med, 1993;329:784–91.
41. World Health Organization, Guidelines for the management
of drug-resistant tuberculosis. Geneva, 1997. Available at:
(accessed 23 June 2015).
42. World Health Organization. Guidelines for the programmatic
management of drug-resistant tuberculosis. Emergency
update 2008. Geneva, 2008. Available at : //whqlibdoc.
23 June 2015).
43. World Health Organization, Management of MDR-TB: A
field guide. A companion document to Guidelines for the
programmatic management of drug-resistant tuberculosis.
Geneva, 2009. Available at: //whqlibdoc.who.int/
23 June 2015).
44. World Health Organization, Guidelines for the programmatic
management of drug-resistant tuberculosis. 2011 update.
Geneva, 2011. Available at: //whqlibdoc.who.int/
23 June 2015).
45. Falzon D, Jaramillo E, Schunemann HJ, et al., WHO guidelines
for the programmatic management of drug-resistant
tuberculosis: 2011 update, Eur Respir J, 2011;38:516–28.
46. World Health Organization, Companion handbook to
the WHO guidelines for the programmatic management
of drug-resistant tuberculosis. WHO/HTM/TB/2014.11
ed. Geneva,2014. Available at: //apps.who.int/iris/
(accessed 23 June 2015).
47. Caminero J, Guidelines for clinical and operational
management of drug-resistant tuberculosis. Paris:
International Union against Tuberculosis and Lung Disease;
2013. Available at: //www.theunion.org/what-we-do/
(accessed 24 June 2015).
48. Furin J, The clinical management of drug-resistant
tuberculosis, Curr Opin Pulm Med, 2007;13:212–7.
49. Ahuja SD, Ashkin D, Avendano M, et al., Multidrug resistant
pulmonary tuberculosis treatment regimens and patient
outcomes: an individual patient data meta-analysis of 9,153
patients, PLoS Medicine, 2012;9:e1001300.
50. World Health Organization, Global Tuberculosis report 2014:
WHO; 2014. Report No.: WHO/HTM/TB/2014.08. Available at:
main_text.pdf (accessed 23 June 2015).
51. 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,
52. Aung KJ, Van Deun A, Declercq E, et al., Successful ‘9-month
Bangladesh regimen’ for multidrug-resistant tuberculosis
among over 500 consecutive patients, Int J Tuberc Lung Dis,
53. Piubello A, Harouna SH, Souleymane MB, et al., High cure
rate with standardised short-course multidrug-resistant
tuberculosis treatment in Niger: no relapses, Int J Tuberc Lung
54. Kuaban C, Noeske J, Rieder HL, et al., High effectiveness
of a 12-month regimen for MDR-TB patients in Cameroon,
Int J Tuberc Lung Dis, 2015;19:517–24.
55. Katiyar SK, Bihari S, Prakash S, et al., A randomised controlled
trial of high-dose isoniazid adjuvant therapy for multidrugresistant
tuberculosis, Int J Tuberc Lung Dis, 2008;12:139–45.
56. Yew WW, Nuermberger E, High-dose fluoroquinolones in
short-course regimens for treatment of MDR-TB: the way
forward?, Int J Tuberc Lung Dis, 2013;17:853–4.
57. Xu HB, Jiang RH, Li L, Xiao HP, Linezolid in the treatment of
MDR-TB: a retrospective clinical study, Int J Tuberc Lung Dis,
58. Tang S, Yao L, Hao X, et al., Efficacy, safety and tolerability
of linezolid for the treatment of XDR-TB: a study in China,
Eur Respir J, 2015;45:161–70.
59. Xu HB, Jiang RH, Xiao HP, Clofazimine in the treatment
of multidrug-resistant tuberculosis, Clin Microbiol Infect,
60. Gopal M, Padayatchi N, Metcalfe JZ, O’Donnell MR, Systematic
review of clofazimine for the treatment of drug-resistant
tuberculosis [Review article], Int J Tuberc Lung Dis,
61. Alsaad N, Wilffert B, van Altena R, et al., Potential
antimicrobial agents for the treatment of multidrug-resistant
tuberculosis, Eur Respir J, 2014;43:884–97.
62. Torun T, Gungor G, Ozmen I, et al., Side effects associated
with the treatment of multidrug-resistant tuberculosis,
Int J Tuberc Lung Dis, 2005;9:1373–7.
63. Bloss E, Kuksa L, Holtz TH, et al., Adverse events related to
multidrug-resistant tuberculosis treatment, Latvia, 2000–2004,
Int J Tuberc Lung Dis, 2010;14:275–81.
64. Dartois V, Barry CE, Clinical pharmacology and lesion
penetrating properties of second- and third-line
antituberculous agents used in the management of
multidrug-resistant (MDR) and extensively-drug resistant
(XDR) tuberculosis, Curr Clin Pharmacol, 2010;5:96–114.
65. Loddenkemper R, Sotgiu G, Mitnick CD, Cost of tuberculosis in
the era of multidrug resistance: will it become unaffordable?,
Eur Respir J, 2012;40:9–11.
66. Kempker RR, Vashakidze S, Solomonia N, et al., Surgical
treatment of drug-resistant tuberculosis, Lancet Infect Dis,
67. Gegia M, Kalandadze I, Kempker RR, et al., Adjunctive
surgery improves treatment outcomes among patients
with multidrug-resistant and extensively drug-resistant
tuberculosis, Int J Infect Dis, 2012;16:e391–6.
68. World Health Organization regional office for Europe, The role
of surgery in the treatment of pulmonary TB and multidrugand
extensively drug-resistant TB. Copenhagen: WHO regional
Office for Europe, 2014.
69. Bamrah S, Brostrom R, Dorina F, et al., Treatment for LTBI in
contacts of MDR-TB patients, Federated States of Micronesia,
2009–2012, Int J Tuberc Lung Dis, 2014;18:912–8.
70. Seddon JA, Godfrey-Faussett P, Hesseling AC, et al.,
Management of children exposed to multidrug-resistant
Mycobacterium tuberculosis, Lancet Infect Dis,
71. Diacon AH, Dawson R, Hanekom M, et al., Early bactericidal
activity of delamanid (OPC-67683) in smear-positive
pulmonary tuberculosis patients, Int J Tuberc Lung Dis,
72. Gler MT, Skripconoka V, Sanchez-Garavito E, et al., Delamanid
for multidrug-resistant pulmonary tuberculosis, N Engl J Med,
73. Diacon AH, Donald PR, Pym A, et al., Randomized pilot trial of
eight weeks of bedaquiline (TMC207) treatment for multidrugresistant
tuberculosis: long-term outcome, tolerability, and
effect on emergence of drug resistance, Antimicrob Agents
74. Dawson R, Diacon AH, Everitt D, et al., Efficiency and safety
of the combination of moxifloxacin, pretomanid (PA-824),
and pyrazinamide during the first 8 weeks of antituberculosis
treatment: a phase 2b, open-label, partly randomised trial in
patients with drug-susceptible or drug-resistant pulmonary
tuberculosis, Lancet, 2015;385:1738–47.
75. World Health Organization, The use of bedaquiline in the
treatment of multidrug-resistant tuberculosis, Interim Policy
Guidance, Geneva, 2013.
76. World Health Organization, The use of delamanid in the
treatment of multidrug-resistant tuberculosis, Interim Policy
Guidance, Geneva, 2014.
77. Kakkar AK, Dahiya N, Bedaquiline for the treatment of
resistant tuberculosis: promises and pitfalls, Tuberculosis
78. Furin J, Bayona J, Becerra M, et al., Programmatic
management of multidrug-resistant tuberculosis: models
from three countries, Int J Tuberc Lung Dis, 2011;15:1294–300.
79. Nathanson E, Nunn P, Uplekar M, et al., MDR tuberculosis-
-critical steps for prevention and control, N Engl J Med,
80. World Health Organization, Roadmap to prevent and combat
drug-resistant tuberculosis. Copenhagen: WHO regional office
for Europe, 2011.
81. World Health Organization, Consolidated action plan
to prevent and combat multidrug- and extensively
drug-resistant tuberculosis in the WHO European Region
2011–2015, Geneva: WHO, 2011.
82. Boehme CC, Nicol MP, Nabeta P, et al., Feasibility, diagnostic
accuracy, and effectiveness of decentralised use of the Xpert
MTB/RIF test for diagnosis of tuberculosis and multidrug
resistance: a multicentre implementation study, Lancet,
83. Rachow A, Zumla A, Heinrich N, et al., Rapid and accurate
detection of Mycobacterium tuberculosis in sputum samples
by Cepheid Xpert MTB/RIF assay-a clinical validation study,
PLoS ONE, 2011;6:e20458.
84. World Health Organization, Automated real-time nucleic acid
amplification technology for rapid and simultaneous detection
of tuberculosis and rifampicin resistance: Xpert MTB/RIF assay
for the diagnosis of pulmonary and extrapulmonary TB in
adults and children 2014. Available at: //apps.who.int/iris/
24 June 2015).
85. Gler MT, Podewils LJ, Munez N, et al., Impact of patient and
program factors on default during treatment of multidrugresistant
tuberculosis, Int J Tuberc Lung Dis, 2012;16:955–60.
86. Chiang CY, Van Deun A, Enarson DA, A poor drug-resistant
tuberculosis programme is worse than no programme: time for
a change [Perspective], Int J Tuberc Lung Dis, 2013;17:714–8.
87. Lonnroth K, Migliori GB, Abubakar I, et al., Towards
tuberculosis elimination: an action framework for lowincidence
countries, Eur Respir J, 2015;45:928–52.
88. Uplekar M, Weil D, Lonnroth K, et al., WHO’s new End TB
Strategy, Lancet, 2015;385:1799–801.
89. Spigelman M, Woosley R, Gheuens J, New initiative speeds
tuberculosis drug development: novel drug regimens
become possible in years, not decades, Int J Tuberc Lung Dis,
90. Kaufmann SH, Lange C, Rao M, et al., Progress in tuberculosis
vaccine development and host-directed therapies-a state of
the art review, Lancet Respir Med, 2014;2:301–20.
91. Ndiaye BP, Thienemann F, Ota M, et al., Safety,
immunogenicity, and efficacy of the candidate tuberculosis
vaccine MVA85A in healthy adults infected with HIV-1: a
randomised, placebo-controlled, phase 2 trial, Lancet Respir
92. Abubakar I, Dara M, Manissero D, Zumla A, Tackling the
spread of drug-resistant tuberculosis in Europe, Lancet,
93. Veen J, Drug resistant tuberculosis: back to sanatoria, surgery
and cod-liver oil?, Eur Respir J, 1995;8:1073–5.