Studies of bacillary populations in experimental tuberculosis of mice treated by isoniazid.

Abstract

When mice are infected with a large dose of virulent tubercle bacilli and treated with isoniazid alone after an interval of fifteen days, resistant populations emerge very frequently. This fact, noted by Grumbach, is not confined to isoniazid, but is produced with many other antibacillary agents (1-3). Treatment of established murine tuberculosis under certain conditions thus furnishes a useful experimental model for the quantitative study of resistant populations appearing in m:vo. Similar populations have been observed in vivo in other experimental circumstances (4-8); but up to now precise quantitative studies on their conditions of emergence and their composition arc lacking. Even in man such studies are rare (9, 10). The fact that it is necessary to administer a single antituberculous agent to obtain experimentally resistant populations, when the treatment of human tuberculosis is usually with multiple-drug regimens, does not detract from the utility of ElIch studies, as resistant populations appearing in these two circumstances only differ in one single character, their frequency. The present work is a quantitative and qualitative study of populations of tubercle bacilli founel in the lungs of mice during delayed treatment with isoniazid. Two different doses have been used, one large, the other small, and the evolution of baeillary populations has been studied in relation to the active isoniazid concentration found in blood serum with these two doses of isoniazid. The administration of large doses of isoniazid is of topical interest. The study of the concentration of active isoniazid in blood serum has given rise to much work, and will give rise to more. Although the prineipal aim of the present work is to draw attention to certain fundamental obscurities which persist in our knowledge of the mechanisms of appearance of great resistant populations, the practical implications will also be considereq.