Cytochemical Interpretation of the Mechanism of Penicillin Action.

According to current usage, the term antibiotic designates a product of the metabolism of one micro6rganism that is antagonistic to the continuation of the normal life activities of another micro6rganism when present even in very low concentrations. Since the early literature on antibiosis has been covered extensively (4, 7, 29, 70, 71, 145, 190), we shall dispense with this phase of the subject. The penicillins owe their outstanding therapeutic position to the fact that they exert a strong selective action against certain types of bacteria in concentrations far below those required to produce appreciable effects on animal tissues. They may be considered virtually non-toxic. The activity, A, of an antiseptic may be expressed in terms of the maximum volume (in ml) of broth in which 1 gram of compound will inhibit the growth of a test organism; and the toxicity, T, may be expressed as the maximum weight (in g) of some suitable laboratory animal that can be killed by injection of a like quantity of the same compound. The ratio, A/T, may be used as an index of relative activity and toxicity. According to this system, a large number indicates relatively low toxicity and a small number relatively high toxicity in comparison with activity. Using Staphylococcus aureu as the test pathogen and adult mice (20 g each, injected intraperitoneally) as test animals, the A/T ratio has been found to be 3 for anemonin, a very toxic compound, 100 for sulfathiazole, and greater than 100,000 for penicillin (28). The virtual lack of toxicity of penicillin was recognized at an early date when it was shown in 1944 that any toxicity of purified penicillin salts could very likely be attributed to the cation. It was found that the toxicity of the sodium, ammonium, strontium, calcium, magnesium and potassium salts of penicillin ranked in the same order as that of the acetates, which have a non-toxic anion (198). The only unfavorable physiological effects that have been reported, apart from the urticaria that occasionally develops in sensitive individuals, are delayed clotting of blood (69a, 123), the precipitation of convulsions following intrathecal injection (192), and partial inhibition of phagocytosis (197). With regard to the first of these observations, however, it should be pointed out that a contradictory report has been published, i.e., that penicillin accelerates clotting