Pharmacokinetics and pharmacodynamics of cefepime administered by intermittent and continuous infusion

Objective: This study assessed the pharmacokinetics and pharmacodynamics of cefepime administered by intermittent and continuous infusion against clinical isolates of Pseudomonas aeruginosa, Enterobacter cloacae, and Staphylococcus aureus. Background: Because beta-lactam antibiotics exhibit time-dependent bactericidal activity and lack prolonged postantibiotic effects against many bacteria, the goal of therapy is to maintain serum drug concentrations above the minimum inhibitory concentration (MIC) for the relevant pathogen over most of the dosing interval. Continuous infusion is a mode of drug administration that can provide serum drug concentrations continuously above the MIC for most bacterial pathogens. Methods: Twelve healthy volunteers were enrolled. Each received cefepime 2 g by intermittent bolus q12h and, on another day, was randomly assigned to receive 4 or 3 g administered by continuous infusion over 24 hours. Results: For the intermittent regimen, the mean (+/- SD) pharmacokinetic findings were: maximum serum concentration, 112.9 +/- 21.1 mu g/mL; minimum serum concentration, 1.3 +/- 0.5 mu g/mL; and half-life, 2.6 +/- 0.4 hours. For the 3- and 4-g continuous infusion regimens, steady-state serum concentrations (C-ss) were 13.9 +/- 3.8 and 20.3 +/- 3.3 mu g/mL,, respectively. MICs ranged from 2 to 4, 0.125 to 8, and 2 to 8 mu g/mL against P aeruginosa, E cloacae, and S aureus, respectively. For the intermittent regimen, serum inhibitory titers (SITs) at 24 hours were greater than or equal to 1:2 in 46% of subjects against P aeruginosa, 48% against E cloacae, and 2% against S aureus. For both continuous infusion regimens, SITs for each organism were greater than or equal to 1:2 in all subjects. Conclusions: The intermittent regimen maintained serum concentrations above the MIC for P aeruginosa and E cloacae in greater than or equal to 92% (11/12) of subjects for greater than or equal to 70% of the dosing interval, provided the MIC was less than or equal to 4 mu g/mL. Both continuous infusion regimens provided a C-ss above the MIC for all organisms. However, the C-ss was greater than or equal to 4 times the MIC only if the MIC was less than or equal to 2 mu g/mL. Only the 4-g regimen provided such concentrations against isolates with an MIC of 4 mu g/mL, and neither regimen provided such concentrations when the MIC was 8 mu g/mL. These findings should be applied in comparative clinical studies.