title: Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients.
abstract: The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients requiring antimicrobial therapy. Nine patients received 1g every 8h (q8h), infused over 4h, and steady-state pharmacokinetic parameters were determined by non-compartmental and compartmental methods. Using these pharmacokinetic parameters, 5000-patient Monte Carlo simulations were performed to estimate the pharmacokinetic profiles for six prolonged-infusion dosing regimens. The probability of target attainment (PTA) was calculated at minimum inhibitory concentrations (MICs) ranging from 0.06 μg/mL to 32 μg/mL, and the cumulative fraction of response (CFR) was calculated for six Gram-negative pathogens using MIC data from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) (2005-2007, USA). The pharmacodynamic target was free cefepime concentrations remaining above the MIC for 60% of the dosing interval (60% fT>MIC). Mean ± standard deviation maximum and minimum serum concentrations, terminal elimination half-life, elimination rate constant, volume of distribution and systemic clearance of cefepime were 32.5 ± 13.5 μg/mL, 9.5 ± 5.2 μg/mL, 2.4 ± 0.7h, 0.316 ± 0.116 h(-1), 21.3 ± 6.5L and 6.6 ± 3.6L/h, respectively. At the susceptibility breakpoint of 8 μg/mL, the PTA was >90% for 1g and 2g q8h (4-h infusion) and 1g and 2g every 6h (q6h) (3-h infusion). For Pseudomonas aeruginosa, the CFR was 88.6% for 1g q8h (4-h infusion) and ≥ 92.7% for 2g q8h (4-h infusion) and 1g and 2g q6h (3-h infusion). Cefepime 1g q8h infused over 4h provides excellent target attainment for susceptible bacterial pathogens with MICs ≤8 μg/mL.
authors.affiliation: St Francis Hospital, Department of Pharmacy, Beech Grove, IN, USA.
authors.forename: S Christian
authors.initials: SC
authors.lastname: Cheatham
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Shea
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Healy
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Humphrey
authors.forename: Megan R
authors.initials: MR
authors.lastname: Fleming
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Wack
authors.forename: David W
authors.initials: DW
authors.lastname: Smith
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Sowinski
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kays
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006761:Hospitals; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015233:Models, Statistical; D009010:Monte Carlo Method; D010949:Plasma / Q000737:chemistry; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000077723:Cefepime