STUDY OF THE ACTION OF FOUR AROMATIC CINCHONA DERIVATIVES ON PNEUMOCOCCUS. A COMPARISON WITH OPTOCHIN

It has been shown with one strain of pneumococcus (Type 1, Neufeld), that hydroquinine chloroacetanilide (C 29), hydroquinine p-chloroacetylaminophenol hydrochloride (C 36), hydroquinine m-chloroacetylaminophenol hydrochloride (C 40), and hyroquinine 4-chloroacetylaminopyrocathecol hydrochloride (C 110) have a rapid pneumococcidal activity both in vitro and in the peritoneal cavity of mice, and to a lesser extent in rabbits. In comparison, optochin is slower in action, but its power is not so easily destroyed either in vitro or in vivo. The introduction of the hydroxy group of the benzene nucleus of hydroquinine chloroacetanilide changes the relationship between organotropism and bacteriotropism. In comparing the rapidity of in vitro bactericidal action and intraperitoneal toxicity, C 29 exhibits the most rapid pneumococcidal action and is the most toxic for mice. C 36, the para-hydroxy derivative, is one-fifth as toxic as C 29 and only one-tenth less active bactericidally. C 40 is one-half as toxic and has approximately the same bactericidal power, while C 110 is one-eigth as toxic and one-fifth as pneumococcidal; and optochin is one-sixth as toxic and has one-fifth the bactericidal action. Arranged in the order of their ability to kill pneumococci when injected simultaneously with them into the peritoneal cavity, the drugs are: C 40, C 110, C 36, optochin, and C 29. The chemotherapeutic action of the aromatic compounds is essentially local in character. But by per os therapy there is demonstrated a certain amount of diffusion of this activity, not shown by any other method of administration, C 40 and C 110 having about the same value as optochin. Intravenous injection of the drugs in small doses destroyed to a greater or less extent the natural defenses of the animal, optochin being perhaps less injurious than the aromatic compounds. This same destruction of natural resistance followed intraperitoneal and subcutaneous injections of the chemicals as measured by intravenous injections of the organisms. The maximum tolerant dose in a single injection (intraperitoneal) is not so efficacious as the same dose divided in fifths and injected at hour intervals. Optochin under these conditions is not so active as the aromatic compounds. In general, repeated doses are more curative than single. There is a zone between the therapeutic and toxic doses, both single and repeated, for all these chemicals alike, where the natural resistance of the animal to an infection is reduced. This effect is noted especially with C 29, C 36, and C 40. In the case of optochin the therapeutic dose is nearer the toxic than with C 110, C 36, and C 40. Apparently these chemicals exhibit a variability in in vivo bactericidal activity according to different strains of pneumococci and numerical virulence.