title: Simulation of human serum pharmacokinetics of cefazolin, piperacillin, and BRL 42715 in rats and efficacy against experimental intraperitoneal infections.
abstract: Studies were performed to determine the effects of BRL 42715, a potent beta-lactamase inhibitor, on the activity of cefazolin and piperacillin against experimental intraperitoneal infections caused by either Escherichia coli or Serratia marcescens in rats. Compounds were administered to rats as a continuous infusion of an exponentially diluted solution to simulate in rat plasma the concentration-versus-time curves obtained for humans following intravenous bolus administration. A simulated 1-g dose of cefazolin was ineffective in reducing the bacterial counts in blood and peritoneal fluid samples of animals infected with S. marcescens US20, which produced class Ia beta-lactamase, and as a result, mortality was similar to that of infected controls. Similarly, a simulated 2-g dose of piperacillin was ineffective in reducing bacterial numbers and mortality in animals infected with E. coli 41548, producing a TEM-1 beta-lactamase. However, when the antibiotics were coadministered with BRL 42715, bacterial numbers were reduced significantly and all animals survived at least 16 h after infection. These data demonstrate the ability of BRL 42715 to potentiate the activity of cefazolin and piperacillin against beta-lactamase-producing bacteria that would otherwise be resistant to these antibiotics and illustrate the application of a model to simulate human serum concentrations in conscious rats.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Betchworth, Surrey, England.
authors.forename: G
authors.initials: G
authors.lastname: Woodnutt
authors.forename: V
authors.initials: V
authors.lastname: Berry
authors.forename: L
authors.initials: L
authors.lastname: Mizen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002437:Cefazolin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000627:therapeutic use; D004927:Escherichia coli Infections / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D007769:Lactams; D008297:Male; D008826:Microbial Sensitivity Tests; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology; D010878:Piperacillin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D016868:Serratia Infections / Q000188:drug therapy; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D007769:Lactams; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C061593:C6-(N1-methyl-1,2,3-trazolylmethylene)penem; D002437:Cefazolin; D010878:Piperacillin