184 ANTIBACTERIAL SUBSTANCES FOR TREATMENT OF INFECTIONS 



lytic enzyme that is released from penicillin-inhibited cells. Smith and Hay 

 observed that swelling and lysis were associated with active growth, since fully 

 grown suspensions showed neither effect. Eantz and Kirby suggest that staphylo- 

 cocci must divide if penicillin is to be effective, a suggestion also made by Rammel- 

 kamp and Keefer (19436) to explain the prolonged survival of a few bacteria in 

 cultures exposed to inhibitory concentrations of penicillin. Bigger (19446) con- 

 cluded from a study of the death rate of large inocula of Staph, aureus in penicillin 

 broth that growing organisms were killed even by low concentrations of the drug. 

 A few cocci, however, survived prolonged exposure to penicillin, but on removal 

 to penicillin-free broth grew freely, and in this state proved to be fully susceptible 

 to the lethal action of penicillin. Bigger suggests that penicillin is bactericidal 

 only for growing organisms ; on organisms in the lag phase of growth, it may 

 have a purely bacteriostatic action, which, by preventing growth, renders the 

 organisms insusceptible to the lethal effect of the drug. 



In the absence of more extensive data, it is unprofitable to speculate on the 

 mode of action of penicillin in vitro. If it is generally confirmed that only dividing 

 bacteria are susceptible, it is possible that penicillin may act directly on an essential 

 part of the mechanism of fission ; but it is equally possible that it interferes with 

 the metabolism of a substance essential for fission, but one of which the bacterium 

 possesses a reserve, the reserve not being used up until the bacterium has multiplied 

 for a few generations. 



Little work has been made public on the constitution of penicillin. The earlier 

 reports (Abraham, Chain and Holiday 1942, Catch et al. 1942, Meyer et al. 1942) 

 deal with the analysis of impure preparations. More recently, two breakdown 

 products of highly active preparations have been described ; penicillamine, an 

 amino-acid accounting for over half the total nitrogen of penicillin (Abraham 

 et al. 1943) and penillic acid, produced on acid-inactivation of penicillin (Duffin 

 and Smith 1943). Meyer, Hobby and Dawson (1943) have prepared methyl, 

 ethyl and N-butyl esters of penicillin in the hope of obtaining products more 

 stable and less rapidly excreted than penicillin. The esters were less active than 

 penicillin in vitro, but were active in experimental streptococcal infection in mice 

 both by the subcutaneous and oral routes. They were more toxic than penicillin, 

 and presumably owed their activity to hydrolysis in the animal body, with libera- 

 tion of penicillin. 



Action in the Animal Body. The toxicity of penicillin in therapeutic concen- 

 trations appears to be due to impurities, since it varies inversely as the number 

 of arbitrary units per milligram of preparation (Robinson 1943, Hamre et al. 1943) 

 (see also Hobby et al. 1942c, Herrell and Heilman 1943). The mode of adminis- 

 tration to man and animals, and the absorption, distribution and excretion have 

 been studied in some detail. PenicilUn is ineffective by mouth and jper rectum ; 

 it is inactivated by the acid of the gastric juice, and by the bacteria of the rectal 

 contents. Given parenterally, it is rapidly excreted and a variable amount, some- 

 times up to 75 per cent., is found in the urine. It is not clear whether the remainder 

 is destroyed in the body. Penicillin does not pass easily between the blood stream 

 and serous cavities, and for treating infections of the meninges, pleural cavity, 

 peritoneum and joints, it must be introduced directly (Fleming 1943, Florey and 

 Florey 1943, Pilcher and Meacham 1943). 



Like that of sulphonamides, the therapeutic action of penicilUn is apparently 

 purely antibacterial, serving to increase the eflQ.cacy of the natural defence mechan- 



