Pharmacokinetics and Pharmacodynamics of Cefepime in Patients with Various Degrees of Renal Function

Abstract

This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CL CR ) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (C min ). C min in this group was found to be 3.3 ؎ 3.6 mg/liter (mean and standard deviation), compared to 19.5 ؎ 21.5 mg/liter in patients with a CL CR of between 60 and 100 ml/min (P ‫؍‬ 0.025) and 14.0 ؎ 11.5 mg/liter in patients with a CL CR of <60 ml/min (P ‫؍‬ 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CL CR were highly correlated (P ‫؍‬ 0.00033) according to the equation CL‫؍‬ 0.324 liters/h ؉ (0.0551 ؋ CL CR ). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h ؊1 , respectively. The time-concentration profiles for 1,000 patients (CL CR s, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a C min that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs <2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are >4 mg/liter), particularly when CL CR exceeds 120 ml/min.Cefepime is a parenteral fourth-generation cephalosporin antibiotic with an extended spectrum of antimicrobial activity. It is active against many gram-positive and gram-negative bacteria, including most members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus (12,13). It is excreted primarily unchanged in the urine. The terminal half-life (t 1/2 ) in plasma is approximately 2 h in normal renal function and increases proportionately to 13.5 h as renal function declines toward anuria. A good correlation has been demonstrated between cefepime clearance (CL) and creatinine clearance (CL CR ) in healthy volunteers with various degrees of renal function (1-4). Dosage adjustment for renal insufficiency has been recommended in order to prevent drug accumulation, which may result in a higher incidence of adverse drug events and/or an unnecessary increase in drug costs (9).The dosage adjustment recommended is primarily based on the proportional decrease in the rate of elimination and healthy volunteer data. However, modification of the dosing regimen based on renal impairment should also take into consideration pharmacodynamic parameters predicting clinical outcome (17). In vitro data have suggested that the bactericidal activity of ␤-lactams is generally concentration independent and that there is a lack of a postantibiotic effect against gramnegative bacteria (8,19). Time abov...

Population Pharmacokinetics of Cefepime in the Neonate

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Clinical Pharmacodynamics of Antipseudomonal Cephalosporins in Patients with Ventilator-Associated Pneumonia

“…Target pharmacodynamic exposures are traditionally derived from in vitro and in vivo animal infections models, with limited human data to validate these findings. Human studies with cephalosporins have produced variable % ƒT Ͼ MIC exposure data for microbiological success (12,13,37). Others have suggested enhanced ␤-lactam activity by maintaining a ƒC min / MIC Ͼ 4 to 6 (37,38).…”

Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

“…Even the NCCLS frequently relies on healthy-subject data to assess the viability of MIC breakpoints. When possible, PK data should be derived from the population of interest (1,12,22,30,32,33). In summary, 3.375 g of piperacillin-tazobactam given intravenously every 6 h performed well, achieving excellent target attainment rates for MICs of Յ8 (piperacillin) and 4 (tazobactam) mg/liter.…”

“…Monte Carlo simulation has been integrated with accepted pharmacodynamic models to compare antimicrobials and determine their abilities to achieve critical dynamic endpoints (1,12,13,15,(20)(21)(22)32). It is a mathematical technique in which parameter values are randomly drawn from a multivariate distribution.…”