Microbial persistence is the term used to signify the phenomenon whereby microbes that are susceptible to a drug in vitro can nevertheless survive long continued exposure to it in vivo (1, 2).An unusual form of microbial persistence displayed by tubercle bacilli of human origin was described in previous reports from this laboratory (3-5). Relatively large populations of bacilli (one to three million cells) could be made to "vanish" uniformly from the tissues of mice that had received two compounds; the nicotinamide derivative pyrazinamide, and isoniazid, in appropriate time-dose relationships. The criteria for "vanishing" were failure to detect any bacilli by; microscopy, culture, or guinea pig inoculation of the tissues of the infected mice. The "vanishing" did not mean that the bacilli were totally eliminated from the tissues. On the contrary, after a 90 day treatment-free interval, culturable tubercle bacilli could be demonstrated in approximately one-third of the animals. The question immediately arose whether all of the tubercle bacilli had been eradicated in the other two-thirds of the animals in each experiment, or whether the bacilli were still present in them but were in a iatent state.By latent is meant a phase during which the infection is hidden beyond all diagnostic reach. In such a phase, the bacilli conceivably could be present in some altered form or they could be unaltered, but so few in number tl~t they escape detection. In view of the demonstrated sensitivity of the culture techniques employed, it seemed clear that at the most only a very few ~naltered bacilli could be present and escape detection. It was noted (4), however, that if a microbial alteration took the form of sterilization without death, fairly large populations, being nonculturable, might vanish from the tissues because of the insensitivity of microscopy as a detection technique. In the studies reported (3), acid-fast bacilli could not be found with any regularity on microscopy of tissue sections when the organ census was below I × 105 per ml and only
In the preceding paper (1) evidence was presented that the phenomenon whereby large populations of tubercle bacilli can be made to "disappear" from the tissues of mice is produced by an alteration of the bacilli to a sterile ~ state. I t was further shown: that the phenomenon is a specific one produced by the actions of two drugs, pyrazinamide and isoniazid; that it occurs in all or virtually all of the animals in an experimental group; and that once assumed, the sterile state endures for a period measurable in months. Whether the sterile bacilli are morphologically altered cannot be stated from the available evidence. The only indication of a host influence in maintaining the microbial sterility is the increased incidence of microbial revival when large daily doses of cortisone are given in the 3rd or 4th month after sterilization. The present paper is concerned with observations that serve to characterize more sharply this phenomenon of the sterilization of tubercle bacilli in vivo.
The problems of management of tuberculosis in developing nations are studied utilizing the tools of systems analysis. The tuberculosis system consists of interacting components which are the "states of nature" of the disease. The interaction of these components determine the future state of the disease. Controls in the form of therapy, vaccinations or prophylaxis may be superimposed on the natural processes, thus altering the future course of the disease. A descriptive mathematical model describing the flows between the various categories is used to predict the trends both with and without intervention. An optimization model is derived from the descriptive model under the assumption that a program of reduction of active cases has been specified. The optimization model selects the forms of control which achieve the specified reduction program at least cost. Optimization is accomplished via linear programming. The model is general in that the parameters, costs and initial conditions may be varied for different situations. The descriptive mathematical model and the optimization model which determines the most efficient controls are intended to improve decision-making in public health management of tuberculosis.
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