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

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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.

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