Combined drug treatment of tuberculosis. II. Studies of antimicrobially-active isoniazid and streptomycin serum levels in adult tuberculous patients.

The importance of achieving concentrations of both streptomycin and isoniazid adequate to sterilize all parent drug-susceptible organisms was empasized by in vitro studies on the prevention of emergence of mutants resistant to these drugs (1). Many factors determine the concentrations of these agents to which multiplying tubercle bacilli are exposed in the human subject: dosage; absorption and excretion; metabolic alteration; binding to protein; and diffusion into lesions, tissues and cells. Furthermore, with streptomycin the problem is complicated by the presence of substances in the lesions which antagonize the antibacterial action of the drug. Metabolic alteration of isoniazid has been estimated from serum levels of antimicrobially-active drug collected at intervals following a test dose (2, 3). Isoniazid is altered to derivatives such as acetyl-isoniazid and isonicotinic acid which have little or no antimicrobial activity (4, 5). B6nicke and Reif (6), Cuthbertson, Ireland, Wolff and Kuper (7), and Hughes, Schmidt and Biehl (8) have found that the rate of metabolic alteration of the isoniazid molecule varies widely in different individuals. Mandel, Cohn, Russell and Middlebrook (9) demonstrated a significant relationship between this rate of metabolic alteration of isoniazid and the bacteriologic response in isoniazid-treated tuberculous patients. The chemical methods thus far described for the determination of isoniazid (10-14) are not practical for the antimicrobially-active moiety, as they are neither sufficiently sensitive nor specific to permit measurement of the low concentrations present in the sera of many subjects receiving conventional dosages of this drug. Streptomycin serum concentrations have been investigated, and apparently this drug is not subject to significant metabolic alteration (15). There were differences between the serum concentrations of streptomycin achieved by four different subjects (16). Most studies have tended to emphasize the uniformity of the handling of streptomycin from subject to subject (17-20). However, very few human subjects were used. The purpose of this report (the second of a series) is to present our experiences with specific microbiologic assays for isoniazid and streptomycin performed on sera from isoniazidand streptomycin-treated adult tuberculous patients, and to discuss the clinical significance of the results.