Population Pharmacokinetic Modeling and Target Attainment of Cefepime in Critically Ill Pediatric Patients

Abstract Background Cefepime dosing guidelines are well defined in healthy populations but have not been studied extensively in critically ill children who often have significant alterations in antibiotic pharmacokinetics (PK) and pharmacodynamics (PD). Cefepime dosing optimization is important for patient outcomes. Method We prospectively enrolled critically ill children receiving cefepime. Plasma samples were collected at opportunistic time points. Cefepime plasma concentrations were measured by liquid-chromatography-tandem mass spectrometry. Population PK (popPK) analysis was conducted with a priori selected covariates. The final covariate model was used to perform probability of target attainment (PTA) analysis. Results Data from 84 participants were analyzed. A 2-compartment with proportional error model was selected as the base model. Inclusion of weight and creatinine clearance (CrCl) improved model fit. Estimated breakpoints—the highest minimum inhibitory concentration with ≥90% pharmacokinetic target attainment—were 2-fold higher for 3-hour compared with 30-minute infusions for q8h dosing regimens. For q12h regimens, 3-hour infusions also yielded 2-fold higher breakpoints for the lowest target. Continuous compared with 3-hour infusions resulted in 4- to 16-fold higher breakpoints at the same daily dose at the higher targets. Increased CrCl led to reduced PTA. Conclusions Given the variability observed in critically ill children, clinicians should consider incorporating therapeutic drug monitoring and popPK models to determine optimal dosing in this population. The use of extended infusions and more frequent or continuous dosing is beneficial for PK/PD target achievement, particularly for Pseudomonas aeruginosa and antimicrobial-resistant pathogens. Use of these strategies should be strongly considered in the pediatric critically ill population.