COMBINED DRUG TREATMENT OF TUBERCULOSIS. I. PREVENTION OF EMERGENCE OF MUTANT POPULATIONS OF TUBERCLE BACILLI RESISTANT TO BOTH STREPTOMYCIN AND ISONIAZID IN VITRO

Abstract

The antimicrobial activity of isoniazid combined with streptomycin was tested against large numbers of multiplying tubercle bacilli of the H37Rv and Pearson I strains. A concentration of streptomycin (1.0 [mu]g/ml of transparent Middlebrook 7H-10 solid medium), not quite sufficient alone to inhibit the growth of all streptomycin-susceptible bacterial cells, was remarkably effective in combination with 20 times the minimum antibacterial concentration of isoniazid (1.0 [mu]g/ml) in reducing the emergence of drug-resistant mutants. Low concentrations of isoniazid (0.2 [mu]g/ml to 1.0 [mu]g/ml) combined with streptomycin (2 [mu]g/ml) not only prevented the emergence of any drug-resistant mutants from a large population, but also sterilized all members of such a population within 3 weeks. The prevention of emergence of drug-resistant mutants was attributed to the cross-sterilizing action of the 2 drugs on individual mutants separately resistant to each drug.