Simulation of human serum pharmacokinetics of cefazolin, piperacillin, and BRL 42715 in rats and efficacy against experimental intraperitoneal infections

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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.