Renal impairment is associated with high cefepime concentrations in critically ill children

Introduction: Studies have associated excessive beta-lactam exposure with toxicity, including cefepime (FEP) and neurotoxicity. It is critical to identify patient factors associated with high FEP exposures that may increase risk of toxicity. Work from our group showed that elevated FEP troughs occur in children with impaired renal function. Here we use modeling to expand our analysis to include patients with samples collected throughout the dosing interval, hypothesizing that patients with acute kidney injury (AKI) have higher risk of elevated FEP exposure. Methods: An IRB approved study was conducted at a tertiary children’s hospital. Patients who received at least 24h of FEP in the pediatric intensive care unit (PICU) and had at least two opportunistic samples collected were eligible for inclusion. Total FEP concentrations were measured using a validated high performance liquid chromatography assay. Concentrations throughout the dosing interval were modeled in MwPharm++ (Mediware, Czech Republic) using a previously established population PK model of cefepime in pediatrics (Shoji, 2016), observed concentrations, and Bayesian estimation. Elevated Cmin were defined as ≥30µg/mL based on adult toxicity studies. AKI was defined by Kidney Disease-Improving Global Outcomes (KDIGO) creatinine criteria. Demographics and clinical characteristics were analyzed using Mann-Whitney rank sum tests and Chi-square analysis. Results: Ninety-two patients were included, of which 18 patients (19.6%) had at least one Cmin ≥30µg/mL. Patients with and without elevated Cmin were similar in age, weight, sex, PICU and hospital length of stays, PRISM III scores, and duration of FEP therapy. Patients with elevated Cmin, compared to patients without elevated Cmin, were more likely to have pre-existing chronic kidney disease (28% vs 3%, p=0.003) and AKI during the study period (89% vs 57%, p=0.01). Mortality at 28 days was significantly higher in patients with elevated Cmin than those without (11% vs 4%, p=0.05). Conclusions: Among critically ill children, impaired renal function either from chronic kidney disease or acute kidney injury increases risk of elevated serum cefepime concentrations. Identifying these high-risk patients is a critical first step toward evaluating clinical consequences of elevated cefepime concentrations.