Am. J. Respir. Crit. Care Med., Volume 156, Number 3, September 1997, 895-900

The Early Bactericidal Activity of Isoniazid Related to Its Dose Size in Pulmonary Tuberculosis

PETER R. DONALD, FREDERICK A. SIRGEL, FREDERICK J. BOTHA, HEINER I. SEIFART, DONALD P. PARKIN, MICHEL L. VANDENPLAS, BERNARD W. VAN de WAL, JOHANNES S. MARITZ, and DENIS A. MITCHISON

Departments of Paediatrics and Child Health, Pharmacology, Medical Biochemistry, and Internal Medicine, Tygerberg Hospital and the University of Stellenbosch, Cape Town; MRC Centres for Epidemiological Research in South Africa and for Molecular and Cellular Biology, University of Stellenbosch; The South African National Tuberculosis Research Programme Tygerberg, Cape Town, South Africa; and Department of Medical Microbiology, St. George's Hospital Medical School, London, United Kingdom

Collections of sputum from 105 patients with newly diagnosed pulmonary tuberculosis were made before and at 1 and 2 d after the start of chemotherapy with isoniazid (INH) alone given to groups of patients in doses of 600 mg, 300 mg, 150 mg, 75 mg, 37.5 mg, 18.75 mg, and 9 mg daily, as well as from an untreated group. Counts of colony forming units (cfu) of Mycobacterium tuberculosis in the collections were set up on plates of selective 7H10 medium. The early bactericidal activity (EBA) of INH was defined as the decrease in log₁₀ cfu/ml sputum/day during the first 2 d of treatment. A smooth curve relating EBA to log dose was obtained, with 600 mg INH yielding the highest mean EBA of 0.539, and 18.75 mg INH yielding the lowest EBA (0.111) that could be distinguished from the bactericidal activity of the untreated group. The ratio of the usual dose of 300 mg INH to the lowest dose, of 18.75 mg, that produced a detectable EBA, termed the therapeutic margin, was therefore 16, in contrast to the lower therapeutic margin of 4 for rifampin. The EBA was related to the INH acetylator genotype of patients treated with 600 mg or 9 mg INH.

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