Experimental approach to the problem of treatment failure with penicillin: I. Group a streptococcal infection in mice

Abstract

In an experimental infection of mice with group A beta-hemolytic streptococci the organisms at the site of inoculation remained highly sensitive to the bactericidal action of the drug only as long as they continued to multiply at a rapid rate. When the bacterial population in the muscle focus approached a plateau value, they simultaneously became refractory to the drug and it required days to effect sterilization and cure, instead of as many hours. The refractory state of the organisms was not due simply to the large number of organisms present in the older infection, and there was no evidence that a systemic host factor had been impaired. Further, massive doses of aqueous penicillin which provided concentrations in the muscle 10, 000 times greater than the minimal effective concentration were no more effective than the relatively low concentrations afforded by an injection of procaine penicillin in oil gelled with aluminum monostearate. The proposed explanation for the refractory state of the organisms in the older infection is that in such foci the organisms were no longer multiplying and metabolizing as actively as in the fresh infection, due either to the inadequate diffusion of metabolites into the area of infection or to the local release of toxic products. Possible implications with respect of the therapeutic use of penicillin in man are discussed in the text.