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

Robert E.W. Hancock, Francis Bellido

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117 Citations (Scopus)


The fourth generation cephalosporins, cefpirome and cefepime, demonstrate better activity against strains of Enterobacter cloacae with derepressed ß-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 ß-lactams. Outer membrane permeability was measured by a novel HPLC method. The kinetics of interaction of purified ß-lactamase with ß-lactams were estimated to calculate the inhibition and catalytic constants. The periplasmic concentration of ß-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 ß-lactamase contents. The fourth generation cephalosporins had markedly reduced affinity for ß-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 ß-lactamase and reduced affinity for their targets.

Original languageEnglish
Pages (from-to)1-6
Number of pages6
JournalJournal of Antimicrobial Chemotherapy
Publication statusPublished or Issued - 1992
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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