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

The fourth generation cephalosporins, cefpirome and cefepime, demonstrate better activity against strains of Enterobacter cloacae with derepressed /Mactamase than the third generation compounds ccfotaxime and ceftriaxonc. Several methodological refinements were used to measure the parameters, predicted by the Zimmermann-Rosselet equation to be important in the efficacy of /Mactams. Outer membrane permeability was measured by a novel HPLC method. The kinetics of interaction of purified /Mactamase with /Mactams were estimated to calculate the inhibition and catalytic constants. The periplasmic concentration of /Mactams 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 /Mactamase contents. The fourth generation cephalosporins had markedly reduced affinity for /Mactamase and increased outer membrane perme-ability when compared to the third generation cephalosporins. Such advantages were only partly offset by a lower stability of complexes with /Mactamase and reduced affinity for their targets