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Published on 15 April 2011

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Managing multi-drug resistant tuberculosis

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Philip Martin Clark, PhD
Assistant Professor, Clinical Pharmacy Department, Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey

Sule Apikoglu-Rabus, PhD
Assistant Professor, Clinical Pharmacy Department, Faculty of Pharmacy, Marmara University, Istanbul, Turkey

Drug resistance has been defined as ‘the temporary or permanent capacity of organisms and their progeny to remain viable or to multiply in the presence of the concentration of the drug that would normally destroy or inhibit cell growth’.1

Development of resistance by strains of Mycobacterium tuberculosis to anti- TB agents occurs on the molecular level when a number of genetic mutations accumulate to produce a change either in the drug’s molecular target (receptor) or in the concentration of drug needed to effectively kill or inhibit growth of the pathogen.2,3

Examined from a clinical perspective, the causes of the spread of multidrugresistant tuberculosis (MDR-TB) include:

  • Late diagnosis
  • Inadequate isolation
  • Poor air-conditioning4
  • Inappropriate drug therapy, including poor prescribing practice5
  • Non-adherence to an effective regimen
  • Poor absorption.6

It is also believed that the increase in HIV has accelerated the spread of MDRTB, 1 as well as causing a high proportion of deaths.7 As seen in Russian prison and military populations, the combination of HIV plus extremely drug-resistant TB (XDR-TB) may pose even more of a health threat.8

Drug resistance increases TB mortality and morbidity, and makes TB more difficult to treat,4 thereby reducing cure rates.9 In addition, the costs of medication for treating MDR-TB patients are 50-200 times higher than for treating drug-susceptible TB patients, and the overall costs for cure are more than 10 times higher.10,11

Types of resistance
There are two main types of drug resistance: primary and acquired (secondary). Acquired drug resistance is identified in a patient who has taken antituberculosis agents for at least one month before the emergence of resistant strains; it is common among patients who are non-adherent. Primary resistance, however, commonly seen among patients infected with HIV, describes the identification of drug resistant strains of M. tuberculosis in a patient who has no history of treatment or has received less than one month of anti-tuberculosis chemotherapy. 1,4,12

MDR-TB is defined as a case of resistance to both isoniazid (INH) and rifampicin (RIF), and if untreated, death can occur between four and 10 weeks following diagnosis.13 Moreover, cases of resistance to both first- and secondline agents have led to the use of the term ‘extensively (or extremely) drug resistant tuberculosis’ (XDR-TB).14,15 XDR-TB is defined as resistance to INH and RIF (MDR-TB) plus resistance to flouroquinolones and at least one second-line injectable agent: amikacin, kanamycin and/or capreomycin.10,16

More than 41 countries have reported cases of XDR-TB15,16 which is associated with poorer initial treatment success, poorer long-term success and significantly lower survival than MDRTB. 16 Up to 40% of patients diagnosed with XDR-TB are untreatable with existing medication.17

Improper treatment of patients with drug-resistant TB, by using too few drugs for too short a time or relying on limited access to poor-quality second-line drugs, might lead to an increase in the incidence of XDR-TB.18 The term M/XDR-TB is also used to describe both MDR-TB and XDR-TB. Cases of XDR-TB can occur in patients with undiagnosed MDR-TB who are initially being treated with standard first-line therapy.

Epidemiology of drug-resistant TB
Recent World Health Organization (WHO) figures from drug susceptibility testing in approved facilities estimated a global figure of 440,000 cases of MDRTB (primary and acquired) arising in 2008 – that is, 3.6% out of all incident TB cases worldwide. Of these cases of MDR-TB, 94,000 were estimated to have developed acquired resistance. In terms of mortality, an estimated 150,000 deaths caused by MDR-TB occurred globally in 2008, 97,000 of which did not have HIV infection.10

Research by WHO and the International Union against Tuberculosis and Lung Disease (IUTLD) indicates that MDR-TB poses a serious public health threat in eastern Europe, particularly the Baltic countries such as Estonia; also in Russia and former Soviet countries such as Moldova, Kazakhstan, Uzbekistan and Azerbaijan; and in China and India.15,19 These latter two densely populated Asian countries contribute about half of MDRTB cases worldwide.10,20

Latest WHO figures indicate that the overall proportion of MDR-TB cases with XDR-TB is 5.4%.10

In addition, mortality related to XDR-TB is much higher than both drug-sensitive and MDR-TB. Patients with XDR-TB are 64% more likely to die during treatment than patients with MDR-TB.18

Treatment approaches
To tackle the problem of drug-resistant tuberculosis, concerted political will and global strategies are needed to meet the pressing demands for prompt pointof- care diagnosis, for supply of qualityassured second-line anti-TB drugs and for treatment delivery. These demands are particularly acute in resource-poor settings.8

To treat MDR-TB, it is generally accepted that therapy should begin with at least five agents to which the pathogen is sensitive, three of which should be new.1 If possible, these should include an injectable agent (e.g. amikacin, capreomycin) and a fluoroquinolone. Once the sputum culture is negative (conversion), the number of agents can be reduced, with the maintenance therapy usually being provided with at least three drugs to which the strain of TB has shown sensitivity.12

Second-line agents which have been used include p-aminosalicylic acid, capreomycin, clofazimine, cycloserine, ethionamide/prothionamide, amikacin, kanamycin, streptomycin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin and rifabutin.21,22 Newer third-line agents can also be used such as imipenem, macrolides, amoxicillin/clavulanate and linezolide, especially when drug sensitivity testing has been performed.21

Some of the measures which should be implemented in the prevention and treatment of drug-resistant TB are:

  • Confirmed and suspected patients should be placed in isolation1
  • Patients should immediately receive either hospital-based or domiciliary directly observed therapy (DOT)
  • Cultures should be performed monthly to monitor response of MDR-TB to therapy. Repeat drug susceptibility studies should be ordered when cultures remain positive after three months
  • The most potent drugs should be used initially and in maximum combinations; effective agents should not be kept in reserve1
  • A single drug should never be added to a failing regimen
  • All drugs should be given as a single, daily dose except para-aminosalicylic acid (PAS)
  • Up to two years of therapy is recommended after conversion of culture to negative21
  • Where chemotherapy fails, thoracic surgery should be considered.

Barriers to successful treatment
One of the greatest obstacles to successful treatment of resistant TB is poverty. Underprivileged patients can neither meet the costs of treatment (direct or indirect) nor do they have access to specialist TB physician/center.23 Secondly, there is a clear correlation between late diagnosis of disease – which causes a delay in initiating effective treatment – and unsuccessful clinical outcomes.24 The tragic consequences of late diagnosis in terms of the development and spread of MDR-TB highlight the importance of providing access to and promptly acting on the results of drug sensitivity testing.8,23,25

It has been observed that patients with MDR-TB plus low hematocrit or low body mass index have predicted poor treatment outcomes, both during therapy and follow-up.24

The final, but arguably the most important barrier to successful MDRTB treatment is non-adherence to treatment.26

Adherence to treatment
Multidrug-resistant tuberculosis emerged largely because of widespread nonadherence to tuberculosis treatment.27 Because TB is an infectious and contagious disease, adherence is possibly more important than with other chronic illnesses.28

It is vital not only that the patient be adherent in terms of drug administration, but that clinicians themselves adhere to therapeutic guidelines.12 Pharmacists have a pivotal role both in improving adherence and in preventing inappropriate prescribing.29

DOTS and DOTS-plus
The basic tenets of ‘directly observed therapy – short course’ (DOTS) include a short, standardised, six-month chemotherapy regimen for TB patients whose disease is sensitive to first-line medication (isoniazid, rifampicin, pyrazinomide and ethambutol), and where the administration of every single dose is visually supervised. The patient attends an outpatient clinic three times a week or a health worker visits the patient’s house to personally ensure the patient takes his/her medication.12,30-32

Although DOT is one of the most successful and effective means of increasing adherence to TB therapy, on its own it may not be sufficient. It is important that healthcare providers such as pharmacists be equipped to communicate with the patients.

In addition, patient-centered strategies should be developed. For example, appropriate incentives can be used, behaviour-modifying and motivational educational programmes can be initiated and trusting lines of communication between patient and health personnel can be established to allow for the expression of genuine concern and regular follow-up of treatment.33,34

The advent of DOTS expansion or DOT-plus – that is, directly observed therapy specifically designed for patients with drug-resistant TB – is a more recent development. Despite being relatively novel, it has been argued that DOTS expansion may become the major priority in global TB control. Using the principles developed in DOTS, DOTplus programmes have been developed for administrating MDR-TB therapy. Because minor drugs are more expensive and more toxic than first-line agents, the patients should receive their medicines every day and at different times during the day.35

Apart from the directly observed aspect of therapy, good clinical outcomes in terms of cure rate are partially achieved by ensuring:

  • Access to low-price anti-tuberculosis drugs
  • Aggressive management of adverse events
  • Nursing and community health care
  • Psychosocial support.24,36

The advantage of using community healthcare workers, such as community pharmacists, is that it lowers the cost of therapy compared to hospitalisation and it also avoids the risk of nosocomial spread of MDR-TB. Wider availability of second-line drugs should always be in the context of a high-quality care and follow-up.16

Where appropriate, DOTS-plus TB control programmes should also be integrated with HIV management programmes.7

If we extrapolate the beneficial results of DOT short course to DOT-plus, then we can anticipate that where economic conditions are poor, the effectiveness of DOT-plus programmes for patients with MDR-TB may be marked. On the other hand, in more developed countries, selective use of direct observation may also yield successful outcomes.

References
1. Kant S et al. BioScience Trend, 2010;4:48-55
2. Gillespie SH. Antimicrobial Agents and Chemotherapy 2002;46:267-74
3. Van Rie A et al. J Clin Microbiol 2001;39:636-41
4. Pablos-Mendez A et al. N Engl J Med 1998;338:1641-49
5. Udwadia ZF et al. PLoS One 2010;5:e12023
6. Nations JA et al. Dis Mon 2006;52:435-40
7. Calver AD et al. Emerg Infect Dis 2010;16:264-71
8. Strategies for confronting the global MDR and XDR TB crisis. In: Institute of Medicine (IOM). 2009. Addressing the threat of drug-resistant tuberculosis: a realistic assessment of the challenge: Workshop summary. Washington, DC: The National Academic Press; p97-108
9. Dye C et al. Lancet, 1998;352:1886-91
10. World Health Organization. Multidrug and extensively drug resistant TB (M/XDR-TB): 2010 global report on surveillance and response. Geneva: WHO Press, 2010
11. I nge LD & Wilson JW. Am Fam Physician 2008;78:457-65
12. Joint Tuberculosis Committee of the British Thoracic Society. Thorax 1998;53:536-48
13. Reischl U. Frontiers in Bioscience 1996;1:e72-e77
14. Snider DE & Castro KG. N Engl J Med 1998;338:1689-90
15. Kawamura LM. MDR/XDR TB: Global Problem, domestic implications. www.cdc.gov/tb/CE/ mdrandxdrtb/transcript.htm
16. Chan ED & Iseman MD. Curr Opin Infect Dis 2008;21:587-95
17. The global spread of MDR-TB and XDR-TB. In: Institute of Medicine (IOM). 2009. Addressing the threat of drug-resistant-tuberculosis: a realistic assessment of the challenge: Workshop summary. Washington, DC: The National Academic Press; p19-34
18. Wright A et al. Morbidity and Mortality Weekly Report 2006;55:301-05
19. Zignol M et al. The Journal of Infectious Diseases 2006;194:479-85
20. Espinal M et al. N Engl J Med 2001;344:1294-1303
21. McDonald R & Seaworth B. Averting Disaster: Principles in Preventing and Managing Drug- Resistant TB; web-based seminar, 2008. www.cdc. gov/TB/CE/mdrandxdrtb/mdrxdr_webinar_final. ppt#612,93
22. Blumberg HM et al. Am J Respir Crit Care Med 2003;167:603-62
23. Farmer P. N Engl J Med 2001;345:208-210
24. Mitnick C et al. N Engl J Med 2003;348:119-28
25. Farmer P et al. J Res Dis 2000;21:53-56
26. World Health Organization. Adherence to longterm therapies: evidence for action. Geneva: WHO, 2003
27. Charles P. Felton National Tuberculosis Center. Adherence to Treatment for Latent Tuberculosis Infection: A Manual for Health Care Providers. New York: 2005
28. Taylor HG. Am Pharm 1992;32:41-44
29. Ellis SL et al. Pharmacotherapy 2000;20:429-35
30. World Health Organization. Tuberculosis Fact Sheet No.104. Geneva: WHO, 2005
31. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. Third edition. Geneva: WHO; 2003
32. Garner P & Volmink J. BMJ;2003:327, 823-824
33. Volmink J et al. Lancet 2000;355:1345-50
34. Volmink J & Garner P. Cochrane Database Syst Rev 2007;(4):CD003343
35. Gbayisomore A et al. Curr Opin Infect Dis 2000;13:155-59
36. Kim JY et al. Tuberculosis 2003;83:59-65



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