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Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients

Cheatham, S. Christian, Shea, Katherine M., Healy, Daniel P., Humphrey, Melissa L., Fleming, Megan R., Wack, Matthew F., Smith, David W., Sowinski, Kevin M., Kays, Michael B.
International journal of antimicrobial agents 2011 v.37 no.1 pp. 46-50
Monte Carlo method, Pseudomonas aeruginosa, anti-infective agents, blood serum, drug therapy, half life, minimum inhibitory concentration, pathogens, patients, pharmacokinetics, probability, United States
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 0.06μg/mL to 32μg/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±13.5μg/mL, 9.5±5.2μg/mL, 2.4±0.7h, 0.316±0.116h⁻¹, 21.3±6.5L and 6.6±3.6L/h, respectively. At the susceptibility breakpoint of 8μg/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≤8μg/mL.