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J Exp Med. 1966 Mar 1;123(3):469-86.

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.

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