Penicillin has been shown to be directly and rapidly bactericidal (1-9), and not merely bacteriostatic. Whether that direct action is augmented in vi~o by the natural defense mechanisms of the body has not yet been conclusively determined; but in any case, it is a reasonable surmise that the concentration of penicillin which is most rapidly effective against a given organism in vitro may also be the most effective in vivo. Further, if different organisms vary not only with respect to the effective concentrations of penicillin, but also in the maximal rate at which they can be killed by the drug, there may be a corresponding variation in the time for which treatment with penicillin must be continued in order to effect cure.The present paper will describe experiments relating to the effect of the concentration of penicillin on the rate of its bactericidal action in vitro against a number of bacteria. As had previously been indicated by Hobby, Meyer, Dawson, and Chaffee (1, 2), Eagle and Musselman (6), and Demerec (7), the rate at which the bacteria were killed by penicillin in vitro was found to vary strikingly within relatively narrow zones of concentration. For every organism here studied, one could define (1) a concentration at which the net rate of multiplication was significantly reduced, (2) a somewhat higher concentration at which the organisms were killed faster than they multiplied, so that the net number of viable organisms slowly decreased, and (3) a maximally effective concentration, at which the organisms died at a maximum rate which was not further increased even by a 32,000-fold increase in penicillin concentration (cf. references 1, 2, 6, 7). However, the several bacterial species differed not only with respect to the magnitude of this maximally effective concentration of penicillin, but also with respect to the maximal rate at which they could be killed by the drug; and there was no necessary relationship between the two values. Finally, with many bacterial species there was a sharply defined concentration of penicillin,at which it was optimally effective, and in excess of 99 on

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In the therapeutic use of penicillin, the question as to whether the minimum effective concentration in vivo is the same, greater, or less than that necessary to kill the same organ'sm in vitro is of obvious importance. Data are here reported with respect to the minimal effective serum concentrations of penicillin in a number of experimental infections in mice and rabbits. As will be shown, these serum levels were usually 2 to 5 times higher than those necessary to kill the same organism in vitro. However, in view of the known concentration differential between the serum and tissue fluids, this suggests that the effective concentration of penicillin at the actual site of infection is in most instances the same as that effective in vitro. METHODS AND MATERIALS The use of procaine penicillin to provide reasonably stable serum concentrations of penicillin. In order to obtain a reliable measure of the effective serum concentrations of penicillin, it was necessary to keep these levels reasonably constant for the time that the drug was acting on the organisms. This was accomplished by the use of procaine penicillin G suspended in peanut oil, gelled by the addition of 2 per cent aluminum monostearate (Buckwalter and Dickison, 1948). A series of such suspensions were prepared, varying in penicillin content in approximately 2-fold steps from 320,000 down to 80 units per ml. The cooperation of the staff of the Bristol Laboratories, by whom these penicillin suspensions were prepared, is gratefully acknowledged. The various suspensions were injected intramuscularly in a fixed volume of 0.1 ml in mice weighing 17.5 to 22.5 grams. In rabbits (2.5 to 3.5 kg) the dosage volume in ml was one-fifth of the body weight in kilograms. The serum concentrations of penicillin at varying intervals thereafter are summarized in table 1. The relatively slow rate at which the penicillin concentration fell, reflecting its slow and continuing absorption from the intramuscular depot, is evident from the table. For purposes of interpolation, lines were fitted to the experimental data by the least squares method. Penicillin assays. Serum penicillin assays were carried out by a serial dilution technique previously described (Eagle and Newman, 1947). Ten-ml specimens were obtained from rabbits by cardiac puncture, and mice were exsanguinated from the exposed heart. Horse blood was used as the hemolytic indicator in assaying the mouse sera, and rabbit blood for the rabbit sera. The results shown in the tables have been corrected for the inhibitory effect of serum in the assay (Eagle and Tucker, 1948). These corrective factors in the case of mouse serum were found to be 1.9 for whole serum, 1.3 for 1:2 serum, and 1.15 for 1:4 serum.

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