Population Pharmacokinetics of Ceftazidime in Critically Ill Children: Impact of Cystic Fibrosis

Background: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections. Objectives: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens. Methods: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software. Results: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T->MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children. Conclusions: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.