EARLY BACTERICIDAL ACTIVITY OF ISONIAZID IN PULMONARY TUBERCULOSIS - OPTIMIZATION OF METHODOLOGY

Early bactericidal activity (EBA) of antituberculosis drugs is the rat e of decrease in the concentration of tubercle bacilli sputum during t he initial days of therapy. The study reported here was designed to op timize the methodology for obtaining precise EBA measurements. The stu dy compared the results with two versus five treatment days; overnight sputum collections with early morning collections; and quantitative s mears for acid-fast bacilli (AFB) with quantitative cultures. Isoniazi d (INH) was used as a model drug. Among 28 smear-positive patients enr olled in the study in five cities in the United States, 16 were evalua ble (INH-susceptible tuberculosis [TB] and adequate sputum collections ). The mean baseline bacterial load was 6.69 log(10) cfu/ml (SE = 0.24 ). Quantitative culture of 10- or 12-h sputum collections obtained on two baseline days and treatment Day 5 was the optimal method for EBA m easurement. The mean 5-d EBA was 0.21 log(10) cfu/ml/d (SE = 0.03; p < 0.001), and the EBA appeared to be constant during the first five tre atment days. On the basis of these data, multiarm studies of investiga tional drugs will require 25 evaluable subjects per arm to detect (80% power and two-tailed alpha of 0.05) an EBA at least 50% as large as t he EBA of INH. In countries with a low incidence of TB, the usefulness of this methodology for rapidly assessing new antituberculosis agents may be limited by the relatively large number of subjects required to compare EBA values across treatment arms.