PENICILLIN 179 



Streptothricin. A chemically undefined substance from Actinomyce.s lavendidce. It is 

 an organic base, active in low concentrations against Gram -negative and to a lesser extent 

 Gram-positive bacteria (VVaksman and Woodruff 1942, Kocholaty 1942, Waksman 1943). 

 Doses sufficient to kill Br. abortus infecting a developing chick embryo were not toxic 

 (Metzger et al. 1942). 



Miscellaneous Mould Products. Glister (1941) reports a substance from Aspergillus 

 flavus with a bacteriostatic titre of 1 : 200,000 for Gram-negative bacteria. A citrinin-like 

 substance has been obtained from an Aspergillus of the candidus type (Timonin 1942). 

 McKee and MacPhillamy (1943) and White (1943) report penicillin-like substances from 

 Aspergillus flavus and Aspergillus flavipes, and recently Florey and his colleagues (1944) 

 have obtained penicillin-like substances from five species of penicillia, namely, P. /?Mor- 

 escens, rubens, avellanum, baculatum, and turbalum. 



Penicillin. 



We have already discussed the circumstances that led to Fleming's discovery 

 of this remarkable substance, and his adumbration of its significance in the therapy 

 of infection. Its production in bulk, its concentration in a stable, highly active 

 form, the methods of its assay, and the definition of its powers and limitations 

 in the therapy of animal and human infection, we owe to the work of Florey and 

 his colleagues (Chain et al. 1940, Abraham et al. 1941). In their hands penicillin 

 proved to be outstanding among antibacterial agents. 



It is active in low concentrations, the growth of Staph, aureus being inhibited 

 by 1 part in 50 milUons of a highly purified preparation. It has little toxicity 

 for animal tissue. Mice weighing 25 gm. are unaffected by injection of 20 mgm. 

 of the purified preparation. It is active, as Fleming showed, against a wide range 

 of Gram-positive bacteria, and its in vivo activity parallels its in vitro activity. 

 But for the fact that peniciUin is rapidly eliminated from the animal body, which 

 necessitates frequent administration to maintain therapeutic concentrations in 

 the tissues, the chemotherapeutic index (the ratio of tolerated dose to curing dose) 

 would be enormous. As it is, in vitro ratios of toxic and bacteriostatic concen- 

 trations are very large. For example, human leucocytes will tolerate 250,000 times 

 the concentration of penicillin needed for the total inhibition of Staph, aureus. 

 Florey and his colleagues described penicilUn as a weak acid of low molecular 

 weight, forming stable salts with alkaline earth metals, soluble and stable in organic 

 solvents and in water between pH 5 and 7. They concentrated it from filtrates 

 of cultiires of Penicillium notatum by acidification and extraction with chloroform 

 and amyl acetate, and re-extracted the penicillin into water by adjusting the pH 

 to neutrality. The yield of penicillin is relatively small. For example, 100 litres 

 of culture filtrate yielded 1 gm. of a material inhibiting Staph, aureus in a dilution 

 of 1 in 10^ (Abraham et al. 1941). Crude preparations, containing about 1 per cent, 

 of penicillin, inhibited Gram-positive organisms in low concentrations and were 

 only slightly toxic to animals and man. The chief toxic effect was the induction 

 of rigors in man, and was due to an impurity which was later removed by more 

 elaborate methods of preparation. 



PenicilUn is destroyed by dilute acid and alkali, by heavy metals, by primary 

 amines, primary alcohols, ketonic reagents and oxidising agents. It is most 

 conveniently handled as a salt of sodium, calcium or barium. 



Recent improvements in the production of peniciUin have included methods of counter- 

 acting the accumulation of acid in the growing cultures, for acidity depresses the peniciUin 

 yield. This may be achieved by the use of buffers (Challinor and McNaughtan 1943), 



