Factors involved in the enhanced efficacy against Gram-negative bacteria of fourth generation cephalosporins

Abstract

The fourth generation cephalosporins, cefpirome and cefepime, demonstrate better activity against strains of Enterobacter cloacae with derepressed β -lactamase than the third generation compounds cefotaxime and ceftriaxone. Several methodological refinements were used to measure the parameters, predicted by the Zimmermann-Rosselet equation to be important in the efficacy of β -lactams. Outer membrane permeability was measured by a novel HPLC method. The kinetics of interaction of purified β -lactamase with β -lactams were estimated to calculate the inhibition and catalytic constants. The periplasmic concentration of β -lactams leading to growth inhibition of cells was determined by substituting the above parameters into the Zimmermann-Rosselet equation. Consideration of these three factors allowed accurate prediction of MICs in isogenic E. cloacae strains with differing porin or β -lactamase contents. The fourth generation cephalosporins had markedly reduced affinity for β -lactamase and increased outer membrane permeability when compared to the third generation cephalosporins. Such advantages were only partly offset by a lower stability of complexes with β -lactamase and reduced affinity for their targets.