Monotherapy with either streptomycin or para-amino salicylic acid led to rapid emergence of resistance in a large fraction of patients.  Combining the two drugs, overcame this problem.

If mutations conferring resistance to one drug occur at a frequency of 1 in 1 million then the joint probability of a mutant simultaneously resistant to both drugs is 1 in 10¹².  As the number of bacilli in a cavitary lesion may be 10⁸ to 10⁹, it is an unlikely event that such a mutant is occurring.

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