Interventions for Tuberculosis Control and Elimination 2002

Effective or functional monotherapy
The first clinical trial in tuberculosis was by necessity limited to the first
drug developed against tuberculosis, streptomycin. In the trial conducted
by the British Medical Research Council, a total of 109 patients were admitted
to the streptomycin arm. 465 Serial susceptibility testing results were
available among 41 of these patients, 35 of whom acquired streptomycin
resistance (figure 35). As the testing interval between susceptible and resis-
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Figure 35. Emergence of streptomycin resistance during monotherapy in the British
Medical Research Council trial. 465
tant cultures varied to a considerable extent among individual patients, the
point in time when resistance emerged cannot be known precisely. For
this reason, the event was estimated to have occurred at the mid-point
between the time the last susceptible and the first resistant culture was
obtained. Resistance had already started to emerge after three weeks of
treatment. By the time a patient had received two months of streptomycin
monotherapy, the probability that drug resistance had been acquired exceeded
60%.
The explanation for this phenomenon is that among the many susceptible
bacilli present in cavitary disease, spontaneous mutations occur at a
given probability for each drug that convey resistance to that drug. The
bacterial populations found in cavitary lesions obtained from resected lung
tissue of patients were of the order of 10 7 to 10 9 bacilli, whereas those
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