TB remains one of the world’s leading infectious causes of adult deaths; furthermore, multidrug-resistant strains of the disease are emerging as a considerable threat to human health and a danger to TB control in numerous “hot spots” throughout the world.

Definition

Strains of M.tuberculosis resistant to both isoniazid and rifampicin with or without resistance to other drugs have been termed multidrug-resistant strains. Multidrug-resistant tuberculosis (MDR-TB) is among the most worrisome elements of the pandemic of antibiotic resistance because TB patients that fail treatment have a high risk of death.
While resistance to either isoniazid or rifampicin may be managed with other first-line drugs, resistance to both isoniazid and rifampicin (MDR-TB) demands treatment with second-line drugs. These drugs have limited sterilising capacity and are not suitable for short course treatment. Thus, patients with MDR-TB require prolonged treatment with drugs that are less effective and more toxic1. Therefore, it is necessary to distinguish MDR-TB from mere drug-resistant tuberculosis by performing mycobacterial culture and sensitivity testing because the therapeutic implications are different.

Overview of the global situation of MDR TB

According to WHO, resistance to tuberculosis drugs is probably present everywhere in the world. Certainly, MDR-TB is present in five continents, a third of the countries surveyed having levels above 2% among new patients. In Latvia 30% of all patients presenting for treatment had MDR-TB. The region of Russia surveyed had 5% of TB patients with MDR-TB. In the Dominican Republic, 10% of TB patients had MDR-TB. In Africa, Ivory Coast has also witnessed the emergence of MDR-TB. Preliminary reports from Asia (India and China) show high levels of drug resistance as well. In the State of Delhi, India, 13% of all TB patients had MDR-TB.

Scenario In South- East Asia

India

Analysis of various studies in India has shown that the levels of drug resistance in newly detected cases have remained less than 5%. A retrospective analysis of various randomized clinical trials conducted by Tuberculosis Research Centre (TRC) with various rifampicin containing regimens in the intensive phase and with and without rifampicin in the continuation phase revealed an overall emergence of resistance to rifampicin in only 2% of patients, despite a high level (18%) of initial resistance to isoniazid either alone or in combination with other anti-TB drugs.10 Similar results were obtained in prospective studies conducted by NTI in patients on DOTS regimen in Bangalore.

Thailand

In Thailand the drug resistance status in 1999–2002 based on 1505 patients with no history of previous treatment was 9.5% for isoniazid, 8.2% to streptomycin and MDR-TB was 0.9%.

Nepal

For the same period, for Nepal corresponding figures for 755 patients were 5.4%, 8.9% and 1.9% respectively.

Philippines

Data from Makati Medical Centre DOTS Clinic (2003) indicates high incidence of MDR TB. Approximately 30% of isolates tested were resistant to all five first line drugs, 39.4% to four, 16.8% to three, 12.1% to two. Fluroquinolone resistance was noted in 40.9% isolates.

While MDR-TB afflicts countries with poor health infrastructure, it is just as likely to break out in industrialized economies. During the late 1980s and early 1990s outbreaks of MDR-TB in North America and Europe killed over 80% of those who contracted it. The major TB outbreak in New York in the early 1990s was primarily a MDR-TB epidemic, with one in ten cases being drug-resistant.

For more information on the Global Scenario of MDR TB see:

http://www.who.int/tb/publications/who_htm_tb_2004_343/en/index.html

http://whqlibdoc.who.int/hq/2000/WHO_CDS_TB_2000.278_intro.pdf

http://www.tballiance.org/2_1_2_MDR_TB.asp

Guidelines for Surveillance of Drug Resistance in Tuberculosis

http://whqlibdoc.who.int/publications/2003/9241546336.pdf

Key factors for the management of MDR TB are as follows:

• Diagnosis of MDR TB
• Reliable susceptibility testing
• Prevention of MDR TB
  • In new cases
  • In old cases
• Designing an appropriate regimen
  • Essential Drugs
  • Second line Drugs
  • Cross resistance
  • Ranking with respect to Efficacy, Cost, Tolerance
• Reliable drug supply of second line drugs

Treatment of MDR TB

It is important for the clinician to identify whether the patient is suffering from Drug resistant TB ( resistance to either INH or rifampicin ) or from MDR TB( resistance to both INH and rifampicin). This differentiation is important in order to decide the treatment regimens for the patient.

While resistance to either isoniazid or rifampicin may be managed with other first-line drugs, resistance to both isoniazid and rifampicin (MDR-TB) demands treatment with second-line drugs .

These drugs have limited sterilising capacity and are not suitable for short course treatment. Thus, patients with MDR-TB require prolonged treatment with drugs that are less effective and more toxic. Therefore, it is necessary to distinguish MDR-TB from mere drug-resistant tuberculosis by performing mycobacterial culture and sensitivity testing because the therapeutic implications are different.

Principles to be followed while treating MDR-TB patients:

Starting MDR-TB drug regimen

• Check the history of the patient carefully for previous treatment regimens.
• Check whether all drugs in the previous regimens have been taken and for how long.
• Determine the status of sputum smears at all junctures (in terms of positivity ,conversions and sensitivities – if available).
  
• Confirmed/ Strongly suspect MDR TB


• Counsel the Patient and family members
  
• Send Tissue / sputum for culture and sensitivity testing (if available)
  
• Start MDR Regimen
  

See the Guidelines for the management of Drug resistant Tuberculosis at
http://www.who.int/docstore/gtb/publications/gmdrt/PDF/tb96_210.pdf

Choice of drugs

• Add at least 3 new drugs.
• Preferably have an aminoglycoside (Streptomycin / Kanamycin / Amikacin/ Capreomycin).
• One fluoroquinolone (Ofloxacin / Ciprofloxacin / Levofloxacin).
• Ethionamide or Prothionamide
• Any one of the following: Cycloserine, PAS, Clofazimine or Moxifloxacin

The treatment of MDR TB has been increasingly successful over the last decade, with reported cure rates over 80% in many settings. This is especially true when fluoroquinolones and adjuvant surgical therapy are used.