The Combined Action of Penicillin and the Sulfonamides in Vitro : The Nature of the Reaction

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Abstract
The combined in vitro inhibitory action of penicillin and 3 sulfonamides (sulfathi-azole, sulfadiazine and sulfapyrazine) was tested against 18 bacteria. 5 strains were sulfonamide-susceptible strains of Staphylococcus aureus, 5 were sulfonamide-resistant S. aureus, and 8 were Gram-negative rods. If both agents were present in inhibitory concs., synergism resulted. If either one of the agents was not in itself inhibitory no synergism resulted. The degree of synergism obtained was related to the conc. of the two agents and the resistance of the bacteria. The synergistic action is explained as resulting from an initial reduction in the total number of bacteria by the penicillin which permits a conc. of sulfonamide which was only partially inhibitory in the presence of a large number of cells to become completely inhibitory in the presence of a smaller number of cells. A delayed growth of 5. aureus occurring in 48 hrs. in the penicillin control tubes was found to be due to the development of penicillin-resistant bacteria. Inhibition of these penicillin-resistant forms by the added sulfonamide markedly increased the synergistic effect. Sulfathiazole was found to effect a temporary but marked inhibition of penicillin activity when the sulfonamide was present in the cultures 5 hrs. before the addition of the penicillin.