A previously reported form of microbial persistence whereby large populations of tubercle bacilli can be made to "vanish" uniformly from the tissues of mice has been shown to occur generally throughout each group of animals subjected to the experimental procedure; it does not reflect the eradication of the bacilli in the majority of animals with their persistence and ultimate revival in only a minority. The one demonstrable alteration of the tubercle bacilli while "vanished" is that they are sterile. Thus, they are undetectable by cell-free culture, tissue culture, and blind animal passage, i.e. by any method based on microbial multiplication. Whether they have also undergone alteration in morphology and persist in some unconventional form cannot be stated. Acid-fast forms similar to tubercle bacilli can be detected in small numbers by intensified microscopic search of tissue homogenates but the relationship of these forms to the sterile bacilli that ultimately revive is unclear. Thus, the persisting tubercle bacilli are more correctly designated as being in a "sterile state" than one of true latency. The uniform induction of the sterile state is a specific phenomenon requiring the participation of both the nicotinamide derivative, pyrazinamide, and isoniazid. Once assumed, this sterile state is relatively stable and the time required for revival of the tubercle bacilli in the spleens in one-half the animals is seven months. This process can be speeded up by the administration of large doses of cortisone in the third or fourth month after sterilization but revival is not significantly affected by the administration of cortisone earlier.

Animals↗

PubMed1966

Microbial persistence. II. Characteristics of the sterile state of tubercle bacilli.

The capability of tubercle bacilli to assume a long continued sterile state in the tissues when exposed to pyrazinamide and isoniazid is a highly specific drug-microbe phenomenon in which host participation is not critical. Although it is the pyrazinamide that possesses the sterilizing type of action, the role of the isoniazid is specific and essential. The isoniazid serves to convert a phenomenon that occurs irregularly with pyrazinamide alone into one that occurs with a high degree of uniformity. The observations suggest a competition between isoniazid and the pyrazinamide (or its parent nicotinamide) for a site or entrance in or on the tubercle bacilli and for sterilization, the isoniazid apparently must reach the site first. The rare failures to attain complete sterilization, appear to depend on the emergence of pyrazinamide-resistance which prevents the necessary dependent action of the two drugs. Populations already in the sterile state are nevertheless subject to a continued drug influence. Whether this represents a direct action on the sterile bacilli or an indirect effect produced by making the environment hostile to microbial revival, cannot be determined from the present observations.

Animals↗

PubMed1966