Indian Pediatrics 1998; 35:715-718 

Multidrug Resistant Tuberculosis

Many bacteria develop natural resistance to a drug without any previous exposure. Tubercle bacilli are known to undergo spontaneous mutations for drug resistance. Such a natural resistance to different drugs may exist at various rates. It is estimated that resistance to Isoniazid occurs in about 1 in 106 organisms and to Rifampicin in 1 in 108 organisms. The incidence of natural resistance to both the drugs would be as low as 1 in 1014 organisms. The frequency of drug resistance to Streptomycin is 1 in 106 organisms and to Ethambutol 1 in 104 organisms. A cavitatory lesion in the lung parenchyma may contain 109 organisms of which few may be resistant to one of the drugs but none of them would be resistant to two or more drugs. This has been the basis of minimum two-drug therapy in tuberculosis(1). Thus such a natural resistance does not come in the way of successful therapy when two or more drugs are employed in the treatment.

The fact that M. tuberculosis may develop acquired resistance to anti-tubercular drugs has been known ever since the introduction of chemotherapy in 1952. The incidence of drug resistance was very low in earlier years. However, with changing epidemiology over the last few years, multidrug resistant strains have emerged increasingly and have posed serious threat in the control of tuberculosis(2).

Multidrug resistant (MDR) tuberculosis refers to disease caused by Mycobacterium tuberculosis organisms resistant to Isoniazid and Rifampicin with or without resistance to other drugs. Drug resistance may be primary or secondary. In primary resistance, patient is infected with drug resistant bacilli without having been exposed to anti-tubercular drugs in the past. Acquired resistance refers to a patient who is initially infected with drug sensitive bacilli but later becomes resistant due to inappropriate therapy.

Genetic Basis of Drug Resistance

Drug resistance appears to be chromosomal in origin caused by specific mutations that occur in independent genes. This resistance is not transferable from one organism to another. However bacilli may show cross-resistance to drugs of similar structure. Unlike in other bacteria, plasmid acquired resistance does not exist in M. tuberculosis. Information exists about 11 genes involved in the genesis of resistance to anti tubercular drug(3).

Factors Contributing to the Development, of MDR Tuberculosis

Poor Patient Compliance is the foremost factor leading to drug resistance. Ignorance and poverty result in frequent defaulting further compounded by substandard quality and irregular supply of drugs. Even with short course chemotherapy, compliance may be as low as 40%. Physicians often contribute to the development of drug resistance by their irrational prescribing practices, which include nonstandard treatment regime, inadequate dosage and duration of therapy and addition of a single drug in case of therapeutic failure. As diagnosis of childhood tuberculosis is often presumptive, over diagnosis is common(4). Many times patients undergo therapeutic trial with anti-tubercular drugs haphazardly. Besides many physicians are too busy to impart health education to their patients and lack ability of proper communication. At times host factors promote drug resistance. Cavitatory lesions with high bacillary load, immunocompromised states such as severe PEM and HIV infection and chronic coexisting diseases such as renal failure or diabetes mellitus are vulnerable situations. Rarely pharmacokinetic variations may lead to poor tissue concentrations of drugs thereby increasing the risk of drug resistance.

MDR Tuberculosis-A Global Threat

The recent report on global surveillance for anti-tubercular drug resistance, 1994- 1997 has the prevalence of resistance to four first-line drugs in 35 countries. The overall prevalence was 12.6% (range, 2.3 to 42.4%) for single drug resistance and 2.2% for multidrug resistance (range, 0 to 22.1 %). Particularly high prevalence of multi- drug resistance was found in Asia, Dominican Republic, former Soviet Union and Argentina(5). The study suggests that there is a serious threat to. the tuberculosis control all over the world. In the developed countries, it is mainly HIV infection that has caused resurgence of MDR tuberculosis(6).

Epidemiology of Drug Resistance in India

Due to lack of adequate culture facilities and poor reporting system, there is no reliable data on MDR tuberculosis in India. The overall prevalence of primary drug resistance in adults is 20-30% for Isoniazid (INH) and 2-3% for Rifampicin (RMP). Acquired drug resistance is much higher to an extent of 50-60% for INH, 20-30% for RMP and 15-20% for Streptomycin. Most of the strains resistant to RMP are invariably resistant to INH also but not vice-a-versa. A study from New Delhi reported primary resistance to INH in 18.5%, and to RMP in 0.6%. Acquired resistance was seen in 50.7% of patients with INH and in 33% with RMP(7). In a study from North Arcot, resistance to INH was seen in 13% and to RMP in 0.07%(8). Data regarding drug resistance in children is scanty. However, it is expected that with a rising prevalence of drug resistance in adults, it will not be too far that we face similar challenges in the pediatric population. It is likely that children will demonstrate more often the primary resistance as a result of contact with an adult suffering from MDR tuberculosis. Children generally suffer from paucibacillary disease with low bacterial load and hence acquired resistance is likely to be less common.

Clinical Application

Physicians must evaluate properly and monitor the progress of every child under treatment for tuberculosis. History of con- tact with an adult suffering from multidrug resistant tuberculosis should make one anticipate primary drug resistance even prior to starting treatment. In such a case, drug regime may be modified suitably. Children suffering from adult type of cavitatory tuberculosis and those who had previous antituberculosis treatment are vulnerable to develop drug resistance and therefore need close supervision and careful assessment. There is no difference between clinical profile of disease caused by drug sensitive and drug resistant bacilli. Absence of symptomatic improvement inspite of adequate compliant treatment, persistent or worsening radiological lesions or persistence of positive smear or culture at the end of 3-4 months of therapy suggests drug resistance. However, lack of bacteriological proof makes diagnosis of MDR tuberculosis rather difficult. It is the poor therapeutic response or delayed or incomplete recovery that should alert the physician to a possibility of drug resistance. Even in the absence of confirmed diagnosis of multidrug resistance, clinical judgment though hypothetical may justify appropriate modification of drug regime. However, poor therapeutic response may be due to several factors other than drug resistance and needs proper evaluation.

Non Response Without Drug Resistance

Therapeutic failure may not necessarily suggest drug resistance. Most common cause of poor response in our setting is patient non-compliance. As Direct Observed Therapy is difficult to implement, not more than 40% of patients complete the entire treatment regularly. If the default period is less than a week, same treatment plan may be continued. If the default period is between a week and a month, treatment period may be extended for a month more. However, if default period is more than a month, it is necessary to employ the entire treatment again. Unfavourable pathology such as fibrocaseous cavitatory lesions responds poorly and leaves behind permanent damage. These patients continue to remain symptomatic even after completion of standard therapy and are difficult to evaluate in terms of persistence of infection. Immunocompromised hosts do not respond well to conventional drug regime even with drug sensitive infection. At times immune-mediated newer lesions may develop in spite of successful treatment(9). It is obviously not due to drug resistance but may confuse the issue. In case of therapeutic failure, it is most vital to confirm that the primary diagnosis is not a wrong diagnosis which is being perceived as drug resistance. Thus in a clinical setting, in absence of bacteriological proof, possibility of drug resistance must be considered after proper evaluation of various factors mentioned above.

Laboratory Proof

In routine clinical practice it is difficult to obtain proof of drug resistance. Children with cavitatory lesions often demonstrate culture positivity in sputum samples. In other types of lung lesions, bronchoalvelolar lavage should be considered for proper diagnosis, whenever feasible. It is likely to be positive even after 4-6 weeks of treatment in drug sensitive infection as well. Persistence of bacteria after 3-4 months of therapy suggests drug resistance. Besides routine culture methods.

Bactec radiometric method and PCR may be used for bacteriological diagnosis and drug sensitivity tests. It is possible to assess drug resistance by special methods such as Phage reporter assay(10) and Mycobacterial growth indicator tubes.

Management

Therapy of MDR tuberculosis is expensive and frustrating because of poor out- come. In absence of bacteriological proof, atleast two drugs are added to the existing regime. Thus, a patient is treated with 5-6 anti-tubercular drugs simultaneously. The Consensus Statement of lAP working Group has suggested the drug regime as 2SHRZE/1HRZE/6HRE in case of suspected drug resistance. Therapy may have to be modified or extended as per the response. If bacteriological proof exists, a suitable drug regime is chosen to include atleast three sensitive drugs and the treatment is continued for 18-24 months(11). Tuberculosis resistant to three or more. drugs requires use of second-line drugs such as Ethionamide, Cycloserine, Amino-glycosides, Quinolones, Macrolides, etc. Ciproflaxacin alters pharmacokinetics of Rifampicin significantly to lower the serum concentration and hence Ofloxacin is preferred over Ciprofloxacin. Since medical treatment is often not successful and at times is accompanied with significant side-effects, surgery has a role in management of MDR tuberculosis. Resection of diseased tissue reduces bacterial load and improves chances of cure with medical treatment(12).

Chemoprophylaxis

A minimum of two drugs are used in primary chemoprophylaxis and may include Ethambutol and Pyrizinamide for a period of 12 months. Children who are infected with drug resistant bacilli, though without disease, should receive full treatment(13). There is a renewed interest in the use of BCG vaccine for health professionals and others at risk of getting exposed to MDR tuberculosis(14).

Prevention

Concern about the increasing prevalence of multidrug resistant potentially in- curable tuberculosis should enthuse commitment to make the National Tubeculosis Control Program more effective. It is important to evolve proper surveillance and reporting system and protocol for diagnosis. Fortunately there is a way to prevent drug resistance. Patients must have an access to the program. which should ensure that the drugs are available and the patients adhere to the suitable drug regime. Direct observed therapy improves patient compliance. Individual physicians should exercise adequate caution in the diagnosis of tuberculosis and choose the correct drug regime. Every effort must be made to ensure .patient compliance. Contacts must be traced and managed appropriately.

Multidrug resistant tuberculosis is a serious problem and along with HIV infection poses a great danger to the mankind at the turn of the century. Worst may be feared in our country unless everyone concerned does his or her bit to contribute to the control measures and contain the epidemic.
 

Y.K. Amdekar,
Honorary Professor of Pediatrics,
Institute of Child Health,
J.J. Hospital and Grant Medical College,
 Mumbai, India.

9. Ajay SK, Lakhkar BB, Bhaskarnand N. Intracranial tuberculoma manifesting during treatment. Indian Pediatr 1996; 33: 231-233.

10. Jacobs WR Jr, Barletta RG, Udani R. Rapid assessment of drug susceptibilities of M. tuberculosis by means of luciferase reporter phages. Science 1993; 260: 819-822.

11. Treatment of Childhood Tuberculosis: Consensus Statement of lAP Working Group Indian Pediatr. 1997; 34: 1093- 1096.

12. Pomerantz M, Brown JM. Surgery in the treatment of multidrug resistant tuberculosis. Clin Chest Med 1997; 18: 123-130.

13. Swanson DS, Jeffrey RS. Drug resistant tuberculosis in pediatrics. Pediatr Clin North Am 1995; 42: 553-569.

14. Swaminathan S. Multidrug resistant tuberculosis. Pematr Pulmonology Update 1997; 9: 7-11.