In vitro and in vivo activities of LB10522, a new catecholic cephalosporin

Abstract

In vitro activity of LB10522 was compared with those of cefpirome, ceftazidime, ceftriaxone, and cefoperazone against clinical isolates. Against gram-positive bacteria, LB10522 was most active among the compounds tested. It was fourfold more active than cefpirome against methicillin-susceptible Staphylococcus aureus and Enterococcus faecalis. LB10522 was highly effective against most members of the family Enterobacteriaceae tested. Ninety percent of isolates of Escherichia coli, Klebsiella oxytoca, Proteus vulgaris, Proteus mirabilis, and Salmonella spp. were inhibited at a concentration of ≤0.5 μg/ml. These activities were comparable to those of cefpirome. Against Pseudomonas aeruginosa, LB10522 with a MIC at which 90% of the isolates are inhibited of 2 μg/ml was 16- and 32-fold more active than ceftazidime and cefpirome, respectively. LB10522 exhibited excellent protective effects against bacterial infections in mice, as reflected by its in vitro activity. The 50% effective doses of LB10522 were lower than those of cefpirome and ceftazidime against systemic infections caused by Staphylococcus aureus giorgio, Streptococcus pneumoniae III, Pseudomonas aeruginosa 1912E, Escherichia coli 851E, Proteus mirabilis 1315E, Serratia marcescens 1826E, and Acinetobacter calcoaceticus Ac-54. LB10522 was very resistant to hydrolysis by various β-lactamases such as TEM-3, TEM-7, SHV-1, FEC-1, and P-99. LB10522 did not induce β-lactamase in Enterobacter cloacae 1194E, although most of the reference cephalosporins acted as inducers of β- lactamase in this strain. Time-kill study showed that LB10522, at concentrations of two or four times the MIC, had a rapid bactericidal activity against Staphylococcus aureus 6538p, Escherichia coli 851E, and Pseudomonas aeruginosa 1912E.