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. FK037had 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,MRSAand 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 μg/ml or lower. Of essential PBPs 3, la and lb of E. coli and P. aeruginosa, FK037 inhibited PBP 3 at the lowest I50 (0.03 and 0.04 μml, respectively) and PBPs la and lb with I50 values of 2.7 μml or lower. FK037, like cefpirome, was highly stable to hydrolysis by various β-actamases except Ic cephalosporinase from Bacteroides fragilis, and had extremely low affinity for β-actamases. Therefore, FK037 was more potent than ceftazidime in activity against β-actamase-producing bacteria except P. aeruginosa and Serratia marcescens. The ability of FK037 to penetrate the outer membraneof E. coli was slightly higher than that of ceftazidime, but slightly lower than that of cefpirome. © 1993, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION. All rights reserved.