Fate and Distribution of Penicillin in the Body. II. Duration of Blood Concentration and Chemotherapeutic Effectiveness.

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Abstract
Conclusions It may be concluded that our present bacteriological methods cannot give the value of the minimal penicillin concentrations required for therapeutic activity. It is certain that this concentration in the heavy bacterial infection used is below 0.015-0.03 u/cc serum, which is the sensitivity of the bacteriological method. Our present finding explains only in part the well-documented opinion of other authors that it is not necessary to maintain continuous penicillin blood levels for the whole period of treatment. A more important factor responsible for this is probably the additive chemotherapeutic effect of repeated doses. This effect is obvious from the experiments reported in the literature indicating that fractions of the curative dose, repeated at such intervals as to leave the organism without penicillin for the greatest part of the treatment period, result in cure. This is the case in spirochetal11 as well as in bacterial3 infections. The additive effect might depend on biological changes induced by sub-curative doses on the microorganism, on reduction of the bacterial population, and on the immunological response of the host. The experiments of Kelly and Schnitzer12 would suggest furthermore that the immunological response might influence the susceptibility of the micro-organism to chemotherapy. The immunological response itself can be influenced by the treatment schedule, according to the recent observations of Kil-bourne and Loge.13 In hemolytic streptococcal pharyngitis, the antistreptolysin titer is higher with intermittent penicillin injections than it is with continuously sustained blood levels. Another phenomenon which accounts for the independence of therapeutic effect duration from blood level is revealed in the experiments of Grunberg, Schnitzer, and Unger.14 Penicillinase injected after the total disappearance of penicillin from the host tissue still blocks the therapeutic effect in the local streptococcal infection of mice.