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 μg/mL; minimum serum concentration, 1.3 ± 0.5 μg/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 μg/mL, respectively. MICs ranged from 2 to 4, 0.125 to 8, and 2 to 8 μg/mL against P aeruginosa, E cloacae, and S aureus, respectively. For the intermittent regimen, serum inhibitory titers (SITs) at 24 hours were ≥ 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 ≥ 1:2 in all subjects. Conclusions: The intermittent regimen maintained serum concentrations above the MIC for P aeruginosa and E cloacae in ≥ 92% (11/12) of subjects for ≥ 70% of the dosing interval, provided the MIC was ≤ 4 μg/mL. Both continuous infusion regimens provided a C(ss) above the MIC for all organisms. However, the C(ss) was ≥ 4 times the MIC only if the MIC was ≤ 2 μg/mL. Only the 4-g regimen provided such concentrations against isolates with an MIC of 4 μg/mL, and neither regimen provided such concentrations when the MIC was 8 μg/mL. These findings should be applied in comparative clinical studies.
|Number of pages||10|
|State||Published - 2000|
Bibliographical noteFunding Information:
The protocol was approved by the US Food and Drug Administration and by the appropriate institutional review boards at the University of Texas Health Science Center, South Texas Veterans Health Care System, and Frederic C. Bartter General Clinical Research Center, San Antonio, Texas. All subjects provided written informed consent before enrollment.
This study was supported by an un restricted research grant from Bristol-Myers Squibb, Princeton, New Jersey,a nd National Institutes of Health Grant RR-01346. The results were presented at the International Congress on Clinical Pharmacology in Orlando, Florida, on April 12, 1998. The authors acknowledge the nursing and dietetic care provided by the staff of the Frederic C. Bartter GeneralC linical Re-searchC enter at the South Texas Veterans Health Care System in SanA ntonio, Texas.
- Beta- lactams
- Continuous infusion
- Intermittent bolus infusion
ASJC Scopus subject areas
- Pharmacology (medical)