The Rate of Bactericidal Action of Penicillin in Vitro as a Function of Its Concentration, and Its Paradoxically Reduced Activity at High Concentrations Against Certain Organisms

Abstract

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

High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation

“…8 As clinical relevance of CAP Eagle effect was not certain, we report no increase in clinical failures associated with HD-CAP therapy, compared with SD therapy. This reversible paradoxical Eagle effect observed in experimental cases of IFI treated with increasing CAP doses perhaps is similar to the Eagle effect initially described with penicillin, 26 which is now regarded as a laboratory epiphenomenon with no detectable clinical impact. In the past decade, a considerable shift has occurred in the fungal species causing disease in immunosuppressed patients.…”

“…8,25 This paradoxical effect is similar to that described for Gram-positive bacteria in response to increasing b-lactam drug concentrations (the 'Eagle effect'). 26,27 Interestingly, this resistance to drug-induced inhibition of growth at higher concentrations of CAP is reversible and is more pronounced among Candida species; 25 the echinocandin-pneumocandin-Eagle effect is less pronounced with filamentous molds, although in experimental animal models of brain zygomycosis lower CAP concentration favorable effect was reversed by increasing the concentration of the drug leading to reduced High-dose caspofungin therapyresponse. 28 This has not been noted in invasive pulmonary aspergillosis, where a modest paradoxical increase in fungal burden with increasing dose can be reversed by continued escalation of the drug concentration.…”

Quantitative Assessment of Bactericidal Activities of β-Lactam Antibiotics by Agar Plate Method

“…The MLCs for some gram-positive strains, however, proved to be extraordinarily high compared with MICs. This disparity between MLCs and MICs among these gram-positive strains would mainly be due to the "Eagle effect" which has been reported to be demonstrated in liquid medium (3,12). In the present study, the concentrations producing complete bactericidal activity (MBCs) were usually higher than the MICs and MLCs.…”

Bactericidal activity of gentamicin againstS. aureus: In vitro study questions value of prolonged high concentrations

“…However, this is of little benefit in case of cell-wall active antibiotics, such as the penicillins and cephalosporins, as they usually show little concentration-dependent bacterial activity (Vogelman and Craig 1986). For concentrations of these antibiotics above 5-10 times MIC, no further increase in kill rates is seen, and even a paradoxical reduction in bacterial killing was observed for some organisms at higher concentrations (Eagle and Musselman 1948).…”