title: Cefclidin (E1040), a novel cephalosporin: lack of selection of beta-lactamase overproducing mutants in an in vitro pharmacokinetic model system.
abstract: The bactericidal activity of cefclidin (E1040), a new cephalosporin, against a clinical strain of Citrobacter freundii was compared with that of ceftazidime in a two-compartment in vitro pharmacokinetic model system designed to simulate plasma concentrations in humans for 12 hours after intravenous administration of a 1 g dose. Both cefclidin and ceftazidime showed rapid bactericidal activity against C. freundii. However, during the simulation of ceftazidime treatment, regrowth was observed after two hours and a subpopulation emerged which was resistant to ceftazidime. Neither regrowth nor the emergence of resistant mutants was observed with cefclidin during the 12-hour simulation. The ceftazidime-resistant mutants constitutively overproduced beta-lactamase at levels which were about 500-fold higher than that of the parent wild-type strain. Against this beta-lactamase overproducing mutant, no bactericidal activity of ceftazidime was observed in the in vitro model system, whereas the bactericidal activity of cefclidin was observed during the 12-hour period. The emergence of Enterobacter cloacae mutants derepressed for beta-lactamase production was also observed with ceftazidime but not cefclidin. The affinity of cefclidin for the beta-lactamase isolated from these mutants was lower than that of ceftazidime, and the kinetic parameters of enzymatic hydrolysis showed that cefclidin was hydrolyzed more slowly at a low concentration (0.2 microM) than was ceftazidime. It is suggested that the high activity of cefclidin against strains derepressed for beta-lactamase plays a major role in the absence of emergence of resistant mutants.
authors.affiliation: Department of Microbiology and Infectious Diseases, Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: N A
authors.initials: NA
authors.lastname: Watanabe
authors.forename: K
authors.initials: K
authors.lastname: Katsu
mesh_terms: D001419:Bacteria / Q000187:drug effects; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004790:Enzyme Induction; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D009154:Mutation; D001618:beta-Lactamases / Q000096:biosynthesis*
chemical_list: D002511:Cephalosporins; C056494:cefclidin; D002442:Ceftazidime; D001618:beta-Lactamases