Labtech

Tuberculosis MDR in Indian Scenario

Worldwide, the number of people infected with both HIV and tuberculosis (TB) is rising. In fact, TB has formed a lethal partnership with HIV.

Dr Harish Ahuja

Tuberculosis remains a worldwide public health problem despite the fact that the causative organism was discovered more than 100 years ago and highly effective drugs and vaccines are available now, making TB a preventable and curable disease.

TB is a specific infectious disease caused by Mycobacterium TB (MTB). The disease primarily affects lungs and causes pulmonary TB. It can also affect intestine, meninges, bones and joints, lymph glands, skin and other tissues of the body. The disease is usually chronic with varying clinical manifestations.

TB is as old as the mankind, and is the most common cause of death due to a single infectious agent worldwide in adults. According to conservative estimates, there are 15-20 million cases of infectious TB in the world. This infectious pool is maintained by the occurrence of 7.25 million new cases and three million deaths each year. The advanced countries have achieved spectacular results in the control of TB, while the problem is acute in developing countries which account for about 95 per cent of TB cases, with South-east Asia region, Western pacific and Africa being the worst affected regions.

Worldwide, the number of people infected with both HIV and TB is rising. In fact, TB has formed a lethal partnership with HIV. The HIV virus damages the body's natural defences, the immune system and accelerates the speed at which TB progresses from a harmless infection to a life-threatening condition. TB is already the opportunistic infection that most frequently kills HIV-infected people.

Multidrug-resistant TB

Multidrug-resistant TB (MDR-TB) caused by MTB, resistant to both isoniazid and rifampicin, with or without resistance to other drugs, is among the most worrisome elements of the pandemic of antibiotic resistance. Globally, about three per cent of all newly-diagnosed patients have MDR-TB. The proportion is higher in patients who have previously received anti-TB treatment reflecting the failure of programmes designed to ensure complete cure of patients with TB. While host genetic factors may probably contribute, incomplete and inadequate treatment is the most important factor leading to the development of MDR-TB. The definitive diagnosis of MDR-TB is difficult in resource-poor low-income regions because of non-availability of reliable laboratory facilities. Efficiently-run TB control programmes based on directly observed treatment short-course (DOTS) policy is essential for preventing the emergence of MDR-TB. Management of MDR-TB is a challenge which should be undertaken by experienced clinicians at centres equipped with reliable laboratory service for mycobacterial culture and 'in vitro' sensitivity testing, as it requires prolonged use of expensive second-line drugs with a significant potential for toxicity. Judicious use of drugs, supervised individualised treatment, focussed clinical, radiological and bacteriological follow up, use of surgery at the appropriate juncture, are key factors in the successful management of these patients. In certain areas, currently available programme /approach may not be adequate and innovative approaches such as DOTS-plus may have to be employed to effectively control MDR-TB.

Diagnosis of MDR TB

When a patient of TB on treatment fails to respond or deteriorates, one needs to consider: Was the initial diagnosis of TB correct? Is the patient taking drugs regularly and in adequate dosages? Is the drug resistance a probability? Is there some new disease that has occurred?

At times, review of diagnosis of TB may be necessary if initial diagnosis was not based on positive sputum smear. Any evidence of new disease in terms of symptoms, signs or abnormalities in investigations should be considered. At this stage, three specimens of sputum on three consecutive days should be examined for AFB and fresh chest X-Ray should be done. If the diagnosis is not in doubt, the patient has been fully compliant with treatment and no new disease is present, then drug resistant should be suspected. Unless the sputum is positive for AFB, one cannot diagnose MDR TB.

To confirm the resistance, it is desirable to have sputum culture for Mycobacteria and drug susceptibility tests. The diagnosis of MDR TB can be assumed on the basis of a clinical criterion; failure or relapse after two courses of chemotherapy, at least one of which was directly observed. This criterion defines the 'chronic cases' which are likely to be due to MDR bacilli; a chronic case of TB is a case that remains smear positive after completing a re-treatment regimen under supervision as defined by the WHO.

Management of MDR TB

Treatment of MDR TB is frustrating than drug susceptible TB. It is difficult to prescribe standard regimen for MDR TB cases. The treatment required is to be individually tailored. The drugs used in the treatment of MDR TB are generally less effective. Most experienced clinicians, recommend minimum of three or four and possible as many as six or seven drugs. The regimen should include at least three drugs for which the patient's organism have proven 'in vitro' susceptibility and preferably those which have not been used to treat the patient before.

Early drug susceptibility test results are usually not available with conventional methods, although the tests can be done far more rapidly. For example, nearly all sputum specimens that contain many organisms (smear positive) can be tested adequately with BACTEC system within two weeks. Four to six weeks are required for smear negative specimen. Such facilities are not easily available. Even then, drug susceptibility test should be done. Obtaining the result of susceptibility test allows the treatment to be modified in a timely manner to protect against further acquired drug resistance and to diminish the potential toxicity of empirical five or six drug regimen. Drug susceptibility test should not be used in isolation to clinical response to treatment. A patient with persistent positive smears and cultures, despite a regimen to which 'in vitro' susceptibility has been demonstrated, merits a complete re-evaluation of treatment strategy, and particularly require confirmation that the individual has actually adhered to the prescribed regimen.

Revolution

Understanding how MTB can acquire drug resistance is essential to prevent the emergence of drug resistant strains. Tubercle bacilli have spontaneous mutation of the bacterial chromosome that confer resistance to anti microbial agent. This mutation occurs at a low rate which varies depending upon the drug. By treating TB with two or more drugs in combination, mutant resistant to any single drug is killed by one or the other drugs in the regimen, and the selection of drug resistant organism can be prevented.

Prevalence in India

Historically, the problem of drug resistance was recognised in 1946 immediately following the introduction of streptomycin. A significant land mark soon followed with the discovery that multiple drug therapy was able to cure TB without development of drug resistance. Later on, it was shown that streptomycin resistance could be largely overcome with the addition of isoniazid and paraaminosalicylic acid, and that three drug regimen was able to cure TB patients who had no previous treatment in 100 per cent of cases without creating drug resistance. These warnings went unheeded and isoniazid resistance became a major problem. Fortunately, the introduction of rifampicin plus pyrazinamide containing treatment regimen helped to overcome and successfully treat even those patients with strains, who were initially resistant to isoniazid.

In India, there has been paucity of reports due to lack or limited access to testing drug susceptibility. Therefore, much of the drug resistance has been presumed clinically. The available literature indicates that primary/initial drug resistance is mainly to isoniazid. That too is also of varying order, but less than 20 per cent. Initial multi-drug resistance is probably very low. MDR- TB is more common in previously treated patients. It constitutes 33-35 per cent of patients who have failed with rifampicin containing regimen. Acquired resistance to rifampicin (33-35 per cent) and isoniazid (50-55 per cent) is substantial. Strains resistant to rifampicin were usually resistant to isoniazid, where as converse was not necessarily true. Few strains resist almost all known anti-TB drugs.

Clinical Significance

Today, the most widely accepted regimen is the combination of isoniazid, rifampicin, pyrazinamide and ethambutol or streptomycin daily for two months, followed by isoniazid and rifampicin daily for four additional months. This regimen is highly effective. Intermittent short course therapy with drug administration directly observed thrice a week in intensive phase and continuation phase is also equally effective. The presence of drug resistant organisms at the start of therapy increases the risk of treatment failure many folds. Initial resistance to single drug such as isoniazid or streptomycin could be treated successfully with six months of short course chemotherapy. The resistance to rifampicin is a serious problem. The success rate is much lower among patients with organism resistant to rifampicin and isoniazid. About 70-90 per cent patients with isoniazid and rifampicin resistant bacilli did not respond or relapsed to treatment with short course chemotherapy.

Cross Resistance

Cross resistance is of great practical and clinical importance especially in retreatment regimens as it will determine the use and sequence of administration of anti-TB drugs. Fortunately, little cross resistance is found between most anti-TB drugs.

Several investigations have confirmed the cross resistance among the aminoglycosides. Although kanamycin has chemical similarities to streptomycin, it is effective against streptomycin resistant organism. Kanamycin resistant organisms, however, are resistant to streptomycin. Strains of MTB that were resistant to kanamycin were resistant to amikacin in 50 per cent cases, whereas strains that were resistant to amikacin were almost always resistant to kanamycin.

Prevention of MDR TB

MDR TB is a man made problem and is thus amenable to corrective action. Developing countries have either no or limited access to testing for drug susceptibility. Even if such a facility was available, the cost of treatment for MDR disease is prohibitive and the only hope of overcoming it is 'prevention'. The most effective tool for preventing MDR TB is short course chemotherapy, adequate initial chemotherapy is most important in prevention. Fortunately, effective drugs are available. Initial intensive phase of two months with isoniazid, rifampicin, pyrazinamide and ethambutol is effective even in overcoming initial isoniazid resistance in most cases.The importance of MDR TB lies in its poor response to available treatment. In patients who are resistant to isoniazid and rifampicin, the results of treatment are very poor. Second and third line drugs are considerably less effective and there is no immediate hope for the development of new drugs. The overall cure rate among patients with MDR TB is about 50 per cent.

The writer is Chief Head of Pathology, Jaslok Hospital Mumbai
Email: hahuja786@hotmail.com