Bactericidal activity of cefclidin (E1040) against Pseudomonas aeruginosa under conditions simulating plasma pharmacokinetics: lack of development of chromosomally-mediated resistance to beta-lactams

Abstract

The bactericidal activity of cefclidin (E1040), a new cephalosporin, against Pseudomonas aeruginosa was compared with that of ceftazidime and imipenem in an in-vitro model in which antibiotic concentration was varied continuously. A two-compartment open in-vitro model was used to simulate the plasma pharmacokinetics of each antibiotic in man for 12 h after a 1 h infusion of 1 g iv. The bactericidal activity of each antibiotic was observed for 6 h; however, it was diminished or absent after 6 h when the antibiotic concentration fell near to the MIC. With ceftazidime and imipenem, marked regrowth was observed after 6 h. Moreover, selection of resistant variants was observed with ceftazidime, and these variants produced 200 to 500 times more beta-lactamase than the corresponding wild-type strains. With cefclidin neither marked regrowth nor emergence of resistant variants was observed. The affinity of cefclidin for the chromosomal beta-lactamase produced by P. aeruginosa was much lower than the affinities of other new beta-lactams, and cefclidin was hydrolyzed more slowly than ceftazidime at a low concentration (2 microM). The high activity of cefclidin against P. aeruginosa, which results mainly from the low affinity of cefclidin for the pseudomonal beta-lactamase, and may play a major role in the absence of regrowth and lack of selection of resistant variants.