400 ANNUAL REPORT SMITHSONIAN INSTITUTION, 1952 



the antibiotics field during the past 10 years has been such that it is 

 relatively unlikely that in the future we shall be required to determine 

 the pharmacology of, or to use, many new antibiotics which have not 

 been purified. In the following discussion of the pharmacology of 

 antibiotics, only those chemotherapeutic substances that are currently 

 in use will be discussed, keeping in mind that the pharmacology of 

 some was determined on the impure drug, while others were studied in 

 the pure state. 



TYROTHRICIN 



The tyrothricin available commercially consists of an impure de- 

 fatted mixture containing approximately 20 percent gramicidin and 

 80 percent tyrocidine. Tyrothricin, gramicidin, and tyrocidine are 

 highly active poisons. Both tyrothricin and tyrocidine hemolyze 

 erythrocytes. Gramacidin has been shown to be hemolytic as well, 

 but its action is delayed and the lytic activity of tyrothricin is usually 

 ascribed to its tyrocidine content. The lysis caused by tyrocidine is 

 prevented by the presence of serum. Gramicidin is more toxic than 

 tyrocidine for cells in general, and the cytotoxicity of tyrothricin is 

 largely due to its gramicidin content. 



Injection of small amounts of these drugs in animals by the intra- 

 venous, intramuscular, intraperitoneal, or subcutaneous routes invari- 

 ably causes death in a relatively short time. Death is apparently due 

 to respiratory failure since the heart may continue to beat for some 

 time after breathing ceases. Animals dying after lethal doses of 

 these drugs show nonspecific degenerative changes. Acute conges- 

 tion of the lungs and abdominal viscera, petechial hemorrhages of 

 lungs, kidney, and myocardium, and diffuse hemorrhages of the spleen 

 have been reported. Histopathological examination usually shows 

 fatty degeneration of the liver with necrosis, cloudy swelling of the 

 tubular epithelium of the kidney, and hemorrhage of the glomeruli. 

 Orally tyrocidine and gramicidin are of relatively low toxicity. 



In man, no appreciable toxicity of tyrothricin has been reported fol- 

 lowing local application. During the past 2 years, increased com- 

 mercial availability of tyrothricin preparations has emphasized the 

 need for cautious use of this drug. Following its use as nose drops 

 with or without a vasoconstrictor, both parosmia and anosmia may 

 occur. More serious, however, is the possibility of chemical menin- 

 gitis following the use of solutions of tyrothricin for irrigation of 

 cavities near the subarachnoid space. Fatal chemical meningitis has 

 been reported after such use of tyrothricin solutions. Following injec- 

 tion of 1 cc. of 1 : 1,000 tyrothricin in alcohol into the cisterna magna 

 of dogs, death occurred immediately or within a few hours in 50 per- 

 cent of the animals so treated. The pathological process in the surviv- 

 ing animals was consistent with acute purulent chemical meningitis. 



