Population pharmacokinetics of cefepime in neonates with severe nosocomial infections

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Abstract

Objective

To define the pharmacokinetic behaviour of cefepime in neonates with severe nosocomial infections using a mixed effects model.

Patients and Methods

Thirty-one newborn infants were included in the study; 10 additional infants participated in the validation of the pharmacokinetic model. Cefepime CL and V were determined using an open monocompartmental model with first-order elimination. The influence of demographic and clinical characteristics on the model was evaluated. The non-linear mixed effect model (NONMEM) program was used to determine the pharmacokinetic population model.

Results

The mean corrected gestational age for infants participating in the construction and validation of the model were 35 and 33 weeks, respectively. Factors included in the final pharmacokinetic model were body surface area (BSA) and calculated CLCR. The final population model was CL (L/h) = 0·457 BSA (m2) + 0·243 CLCR (L/h) and V(L) = 4·12 BSA (m2). This model explains 33·3% of the interindividual variability for CL and 12·8% for V. This model was validated in ten neonates with nosocomial infections by assessing the predictive capacity of plasma cefepime concentrations using a priori and Bayesian strategies.

Conclusions

The predictive performance of this population model for cefepime plasma concentrations was adequate for clinical purposes and can be used for individualizing cefepime therapy in newborn infants with severe infections. Cefepime plasma concentrations can be predicted based on BSA and calculated CLCR. Cefepime therapy using a 250 mg/m2 dose administered every 12 h is adequate to achieve plasma concentrations greater than 8 μg/mL during more than 60% of the dosing interval and is expected to be effective in the treatment of bloodstream infections caused by most gram negative organisms in newborn infants. A dose of 550 mg/m2 would be required for the treatment of infections caused by Pseudomonas sp.

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