Intermittent treatment of pulmonary tuberculosis : A concurrent comparison of twice-weekly isoniazid plus streptomycin and daily isoniazid plus p-aminosalicyclic acid in domiciliary treatment.
Tuberculosis Chemotherapy Centre.
Lancet; 1963; 1078-1080 and Indian Journal of Tuberculosis; 1963; 10; 117-122.
Domiciliary chemotherapy of tuberculosis has become accepted practice in developing countries, but the best method of administering the drugs is still in question. Self-medication for long periods may result in irregularities, and although fully supervised daily chemotherapy has been used to avoid these, it imposes a considerable strain on clinic and patients, and is hardly practicable in developing countries (see review by Fox). If, instead, supervised therapy could be given intermittently - e.g., twice a week - the method could become more generally applicable.
A rational basis for intermittent chemotherapy was suggested by previous studies at this Centre. In a comparison of three regimens of isoniazid alone with a regimen of isoniazid plus p-aminosalicyclic acid (PAS) it had been found that a daily dosage of isoniazid(7.8-9.6 mg per kg. body-weight) was more effective when given in one dose than when given in two doses. There was evidence that this was because a high peak concentration of isoniazid in the serum played a more important role in the response to treatment than the maintenance of a continuous inhibitory level of the drug. It was therefore reasonable to study regimens in which the interval between suitable high doses of isoniazid was extended. It seemed unlikely that efficacy would be seriously diminished by a limited degree of intermittency, in view of our observation that patients who showed irregularity (on the evidence of urine tests) in taking isoniazid in a large dosage every day responded to treatment as well as those who were completely regular.
There is relevant experimental evidence that a high dosage of streptomycin or isoniazid given at intervals of five or seven days is effective in suppressing the development of tuberculosis in the guinea pig. There is similar evidence, in tuberculosis of the mouse, of the effectiveness of isoniazid every seven days, and of isoniazid plus streptomycin every three days.
In view of our finding and the experimental evidence, we decided to test the effectiveness of a combination of the two most potent standard anti-tuberculosis drugs - namely, isoniazid and streptomycin - given twice-weekly under supervision, the minimum interval considered to offer substantial practical advantages over a daily regimen. Isoniazid was to be given in high dosage and streptomycin was to be administered in doses of 1g. which, in view of the light weight of our patients, is a higher dosage than is usual.
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