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 1 g every 8 h (q8h), infused over 4 h, 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 ± 0.7 h, 0.316 ± 0.116 h −1, 21.3 ± 6.5 L and 6.6 ± 3.6 L/h, respectively. At the susceptibility breakpoint of 8 μg/mL, the PTA was >90% for 1 g and 2 g q8h (4-h infusion) and 1 g and 2 g every 6 h (q6h) (3-h infusion). For Pseudomonas aeruginosa, the CFR was 88.6% for 1 g q8h (4-h infusion) and ≥92.7% for 2 g q8h (4-h infusion) and 1 g and 2 g q6h (3-h infusion). Cefepime 1 g q8h infused over 4 h provides excellent target attainment for susceptible bacterial pathogens with MICs ≤ 8 μg/mL.