THE BACTERICIDAL ACTION OF PENICILLIN IN VIVO: THE PARTICIPATION OF THE HOST, AND THE SLOW RECOVERY OF THE SURVIVING ORGANISMS

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Abstract
The rate at which streptococci and pneumococci were killed by penicillin in vivo approximated their rate of death in vitro. A zone-type organism which in vitro was killed more slowly at high concns. of the drug than at lower concns. was killed in mice at the slow zonal rate. With 3 of the 4 spp. studied (type I and type III pneumococci, and a group A streptococcus), the rapid bactericidal action stopped abruptly as soon as the serum penicillin fell to ineffective levels. However, the surviving organisms did not resume multiplication for a no. of hrs. thereafter. This recovery period in vivo was usually longer than that observed in vitro, and with these 3 strains varied from 2 to 5 hrs. The maximum damage to the organisms (i.e., maximum recovery period) was accomplished by exposure to the effective concn. of penicillin for a period of approx. 1 hr.; and longer exposure, or exposure to much higher concns., did not significantly prolong the time required for the bacteria to recover and resume multiplication. During the recovery period, a small but significant proportion of the surviving organisms was disposed of by the host in the absence of penicillin. This increased vulnerability of the penicillin-damaged organisms was also observed when bacteria previously exposed to penicillin in vitro were inoculated intramusc. in mice. With the 4th species (a group B streptococcus), the continuing action of the host on the penicillin-damaged bacteria was quantitatively far more important than the direct bactericidal action of the drug. After a dose which provided effective levels of penicillin for only 30 min. to 1 hr., the bacteria continued to die for periods of 24-48 hrs., and at a rate comparable to that observed during the initial period of drug action. The strikingly enhanced susceptibility of these penicillin-damaged organisms to the host was confirmed when bacteria were exposed to penicillin in vitro and then inoculated. The minimal infectious dose was then several hundred times greater than normal, and 98 to 99% of the organisms were rendered non-viable before they had recovered sufficiently to regain their normal resistance. The implications of these observations with respect to the therapeutic use of penicillin are discussed.