title: In vitro antibacterial activity of FK037, a novel parenteral broad-spectrum cephalosporin.
abstract: FK037 is a new parenteral cephalosporin, which offers some advantages over the commercially available parenteral cephalosporins. It demonstrated potent broad-spectrum activity against clinical isolates of Gram-positive bacteria including methicillin-resistant staphylococci, and Gram-negative bacteria including Pseudomonas aeruginosa. Against clinical isolates of aerobic Gram-positive bacteria, FK037, like cefpirome, demonstrated more potent activity than ceftazidime, cefoperazone and ceftizoxime. It is noteworthy that FK037, on the basis of the MIC90s, was the most active of all the cephalosporins tested against methicillin-resistant Staphylococcus aureus (MRSA). It was similar in activity to cefpirome against methicillin-sensitive S. aureus (MSSA). Against clinical isolates of aerobic Gram-negative bacteria, FK037, like cefpirome, was superior to cefoperazone, similar to ceftazidime and inferior to ceftizoxime in activity. Against P. aeruginosa, FK037 was superior to cefoperazone, similar or slightly superior to cefpirome and inferior to ceftazidime in activity. However, FK037 exhibited significant activity against Citrobacter and Enterobacter which were highly resistant to ceftazidime, cefoperazone and ceftizoxime. FK037 had an advantage in that its bactericidal activity against S. aureus, Escherichia coli and P. aeruginosa at sub-MICs (1/2 or 1/4 the MIC) was much stronger than those of cefpirome and ceftazidime. Moreover, it exhibited potent bactericidal activity against MSSA, MRSA and P. aeruginosa in a pharmacokinetic in vitro model simulating human plasma concentrations after intravenous dosage of 0.125, 1.0 and 1.0 g, respectively. FK037 inhibited essential penicillin-binding proteins (PBPs), 1, 2 and 3 of S. aureus with a 50% inhibitory concentration (I50) of 0.58 micrograms/ml or lower. Of essential PBPs 3, 1a and 1b of E. coli and P. aeruginosa, FK037 inhibited PBP 3 at the lowest I50 (0.03 and 0.04 micrograms/ml, respectively) and PBPs 1a and 1b with I50 values of 2.7 micrograms/ml or lower. FK037, like cefpirome, was highly stable to hydrolysis by various beta-lactamases except Ic cephalosporinase from Bacteroides fragilis, and had extremely low affinity for beta-lactamases. Therefore, FK037 was more potent than ceftazidime in activity against beta-lactamase-producing bacteria except P. aeruginosa and Serratia marcescens. The ability of FK037 to penetrate the outer membrane of E. coli was slightly higher than that of ceftazidime, but slightly lower than that of cefpirome.
authors.affiliation: Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Mine
authors.forename: Y
authors.initials: Y
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Sakamoto
authors.forename: K
authors.initials: K
authors.lastname: Hatano
authors.forename: K
authors.initials: K
authors.lastname: Kuno
authors.forename: Y
authors.initials: Y
authors.lastname: Higashi
authors.forename: T
authors.initials: T
authors.lastname: Kamimura
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: S
authors.initials: S
authors.lastname: Tawara
authors.forename: F
authors.initials: F
authors.lastname: Matsumoto
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D002442:Ceftazidime / Q000494:pharmacology; D015296:Ceftizoxime / Q000031:analogs & derivatives* / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D002511:Cephalosporins / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D001618:beta-Lactamases / Q000378:metabolism; D000097572:Cefpirome
chemical_list: D000900:Anti-Bacterial Agents; D002442:Ceftazidime; D015296:Ceftizoxime; D002511:Cephalosporins; D001618:beta-Lactamases; D000097572:Cefpirome; C079769:cefoselis