About MDR TB

Currently TB is treated with an initial intensive 2-month regime comprising multiple antibiotics—rifampicin ( RIF ), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) or streptomycin (SM)—to ensure that mutants resistant to a single drug do not emerge. The next 4 months, only RIF and INH are administered to eliminate any persisting tubercle bacilli. INH and RIF , the two most potent antituberculous drugs, kill more than 99% of tubercule bacilli within 2 months of initiation of therapy. Along with these two drugs, PZA, with a high sterilizing effect, appears to act on semidormant bacilli not affected by any other antitubercular drugs. Using these drugs in conjunction with each other reduces antitubercular therapy from 18 months to 6 months. Therefore, the emergence of strains resistant to either of these drugs causes major concern, as it leaves only drugs that are far less effective, have more toxic side effects, and result in higher death rates, especially among HIV-infected persons.

The phrase "MDR state" in mycobacteriology refers to simultaneous resistance to at least RIF and INH(with or without resistance to other drugs). Genetic and molecular analysis of drug resistance in MTB suggests that resistance is usually acquired by the bacilli either by alteration of the drug target through mutation or by titration of the drug through overproduction of the target. MDRTB results primarily from accumulation of mutations in individual drug target genes. The probability of resistance is very high for less effective antitubercular drugs such as thiacetazone, ethionamide, capreomycin, cycloserine, and viomycin (10 -3); intermediate for drugs such as INH, SM, EMB, kanamycin, and p-amino salicylic acid (10 -6); and lowest for RIF (10 -8). Consequently, the probability of a mutation is directly proportional to the bacterial load. A bacillary load of 10 9 will contain several mutants resistant to any one antitubercular drug. Because the mutations conferring drug resistance are chromosomal, the likelihood of a mutant being simultaneously resistant to two or more drugs is the product of individual probabilities; thus the probability of MDR is multiplicative. Resistance to a drug does not confer any selective advantage to the bacterium unless it is exposed to that drug. Under such circumstances, the sensitive strains are killed and the drug-resistant mutants flourish. When the patient is exposed to a second course of drug therapy with yet another drug, mutants resistant to the new drug are selected, and the patient may eventually have bacilli resistant to two or more drugs. Serial selection of drug resistance, thus, is the predominant mechanism for the development of MDR strains; the patients with MDR strains constitute a pool of chronic infections, which propagate primary MDR resistance. In addition to accumulation of mutations in the individual drug target genes, the permeability barrier imposed by the MTB cell wall can also contribute to the development of low-level drug resistance. Studies addressing resistance to SM have found evidence of such a two-step mechanism for the development of drug resistance.