M. tuberculosis becomes resistant to antibiotics through spontaneous mutations in the chromosome. INH resistance is associated with deletions or mutations in the katG gene. This gene encodes a catalase-peroxidase enzyme, which activates INH (17). The inhA gene also may be involved with resistance to INH as well as to ethionamide (17). The exact mechanism of resistance with the inhA gene has not been described. Substitution of leucine for serine at position 531 in the rpoB gene confers resistance to rifampin. This mutation is also associated with high-level rifabutin resistance (18). Resistance to fluoroquinolones is due to point mutations in the gyrA gene (19). None of the known genes are linked, so resistance to one antibiotic usually does not confer resistance to another unrelated drug (20).

Mutations leading to rifampin resistance occur at a rate of approx 10-8. Mutations leading to INH, streptomycin, ethambutol, kanamycin, or aminosalicylic acid (PAS) resistance occur at a rate of approx 10-6 and mutations to ethionamide, capreomycin, cycloserine, or thiacetazone occur at a rate of approx 10-3 (21). Resistance to fluro-quinolones occurs with a frequency of 10-8 (19). Resistance to two antibiotics, such as rifampin and INH, would be expected to occur at the multiplicand of the two resistance frequencies (i.e., 10-8 x 10-6 or 10-14). Because tuberculous cavities may contain 109 organisms (36), any patient with cavitary TB carries approx 1000 organisms with primary resistance to INH and 10 organisms with primary resistance to rifampin before any therapy. Since few, if any, bacteria are resistant to both drugs, however, the proba bility of cure using both drugs is high because INH would kill the rifampin-resistant bacteria and rifampin would kill the INH-resistant bacteria. If, however, the patient were infected with INH-resistant M. tuberculosis, the majority of organisms in the cavity would be resistant to INH, and a regimen of INH and rifampin would, in effect, be single-drug therapy with rifampin alone. Rifampin resistance would develop among the INH-resistant population at a frequency of 10-8. The patient might improve initially while rifampin kills the majority of the bacteria, but then strains resistant to both drugs would emerge, and the patient would relapse.

Physician behavior can lead to drug resistance (22). In 1977, Byrd and co-workers assessed the management of TB by nonpulmonary physicians and concluded that 73% of the patients had been treated inappropriately (23). The most common errors were the use of inadequate or excessive drug doses and the use of a single drug to treat bacterio-logically proven disease. In 1993, similar problems were noted in an analysis of the previous management of patients with MDR-TB referred to the National Jewish Medical and Research Center in Denver. In this study, common errors leading to MDR-TB included (1) failure to obtain susceptibility testing, (2) failure to start an adequate initial regimen, (3) failure to modify the regimen when the susceptibility of the organism changed, and (4) failure to use directly observed therapy (DOT) (24). In a recent survey of TB management practices in Kentucky, investigators found that TB was diagnosed by culture in only 66% of patients (thus, no susceptibility data were obtained in the remaining 34% of patients), 12 different regimens were used to treat the patients, monitoring of bacteriologic cure was appropriate in fewer than 65% of cases, and DOT was used in only 38% of patients (25). Reports from other countries have documented similar problems.

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