Journal of Antimicrobial Chemotherapy (1992) 30, 475-487
© 1992 The British Society for Antimicrobial Chemotherapy
research-article |
Bactericidal activity of cefclidin (E1040) against Pseudomonas aeruginosa under conditions simulating plasma pharmacokinetics: lack of development of chromosomally-mediated resistance to ß-lactams
Department of Microbiology and Infectious Diseases, Tsukuba Research Laboratories, Eisai Co. Ltd 1-3, Tokodai 5-chome, Tsukuba, Ibaraki 300-26, Japan
Received 28 January 1992; returned 5 May 1992; accepted 5 May 1992
The bactericidal activity of cefclidin (El040), 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 pharmaco-kinetics 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 6h 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 ß-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 ß-lactamase produced by P. aeruginosa was much lower than the affinities of other new ß-lactams, and cefclidin was hydrolyzed more slowly than ceftazidime at a low concentration (2 µm). The high activity of cefclidin against P. aeruginosa, which results mainly from the low affinity of cefclidin for the pseudomonal ß-lactamase, and may play a major role in the absence of regrowth and lack of selection of resistant variants.