BACTERICIDAL EFFECT OF ISONIAZID AS A FUNCTION OF TIME.

Abstract

Isoniazid is the most effective drug in the treatment of tuberculosis and the only drug deemed satisfactory for prophylactic use against this disease. Extensive laboratory and clinical studies have not, however, clarified all the factors that govern the effectiveness of this drug. The metabolic state of the organism, the drug concentration, and the duration of drug exposure play important but uncertain roles in the action of isoniazid. Studies with C-labeled isoniazid (1, 2) have revealed a very rapid uptake of the drug by susceptible bacteria in both a growing and a dormant state. The amount of isoniazid bound was a function of drug concentration, extending well beyond the concentration required to inhibit growth completely. Thus, saturation of the bacterial cell's potential to bind isoniazid is not essential for a growth-inhibiting effect. The in vivo studies of Nouffiard and Berteaux (3) and the in vitro studies of Peizer, Widelock, and Klein (4) have suggested that high concentrations of isoniazid are more lethal than low concentrations. Armstrong's in vitro experiments (5) have demonstrated bacteriostasis by short exposures to low drug concentrations at repeated daily intervals, and Gangadharam (6)' has confirmed the observation that sustained drug concentrations are not essential to isoniazid effectiveness. This point of view has clinical support in the fact that little or no difference exists in the therapeutic response to isoniazid of rapid and of slow inactivators of the drug. Intermittent doses of isoniazid are effective in suppressing experimentally induced tuberculosis in animals (7) . In humans, a single daily dose · of isoniazid that establishes an effective serum concentration for only a brief period of time seems to be therapeutically effective (8). Therefore, it seems important to try to define more precisely the rela-