061: Cefazolin Removal Via Pediatric Continuous Renal Replacement Therapy: An Ex-vivo Analysis

Statement of Purpose: Cefazolin, a first-generation cephalosporin is frequently prescribed to critically ill patients requiring continuous renal replacement therapy (CRRT) due to its high activity against many gram-positive bacteria. Recent evidence has demonstrated that cefazolin remains one of the most frequently prescribed antibiotics amongst pediatric patients receiving CRRT however there are currently no pediatric-specific CRRT dosing recommendations to guide its use. Therefore a lack of informative pharmacokinetic data to guide safe and effective dosing regimens may increase the risk of treatment failure or adverse effects in this population. The objectives of this study were to investigate the cefazolin-circuit interaction and quantify the rate of removal within a pediatric CRRT circuit.

Description of Methods & Materials: The cefazolin-circuit interaction was evaluated using a closed loop ex vivo CRRT circuit with the PRISMAX System and HF1000 filter set. CRRT was performed utilizing continuous veno-venous hemodiafiltration (CVVHDF) with blood flow rate of 80 mL/min, dialysis fluid rate of 400 mL/h, pre-filter replacement fluid rate of 300 mL/h and a post-filter replacement fluid rate of 100 mL/h. Three standard control samples of cefazolin were included in each phase to assess drug degradation. Cefazolin was administered to the CRRT circuit to achieve a concentration of 250 mg/L. Serial pre-filter blood samples were collected along with time matched control and dialysate samples. The CVVHDF circuit was run in triplicate to assess inter-run variability. Cefazolin recovery in plasma was determined at time = 5 minutes. An unpaired t test was used to analyze the effect of CVVHDF on the recovery of cefazolin in plasma. Drug passage (dialysate saturation constant) was determined by the ratio cefazolin concentration in dialysate to plasma. Transmembrane filter clearance was estimated by the product of the dialysate saturation constant and circuit flow rates.

Data & Results: A total of 48 samples were analyzed for cefazolin concentrations in plasma and dialysate. Concentrations at time = 1 minute were dropped from the analysis as they were below the limit of quantification. Average recovery (standard deviation) of cefazolin in plasma at time = 15 minutes was 63.12% (12) and 10.35% (2.6) at 4 hours. The recovery of cefazolin in plasma was significantly different compared to the standard control at the completion of the experiment (p = < 0.001). The average dialysate saturation constant over the course of the experiment was 0.31 (0.11), resulting in an estimated transmembrane clearance of 6.12 (2.12) mL/min. The resulting dialysate saturation constant and transmembrane clearance indicate cefazolin is adequately filtered within a pediatric CVVHDF circuit.

Interpretation, Conclusion or Significance: Current dosing recommendations for use of cefazolin in pediatric patients receiving CRRT are largely extrapolated from adult data. Cefazolin is frequently administered to pediatric patients receiving CRRT, however there are currently no specific pediatric pharmacokinetic data to guide dosing recommendations within this patient population. The results of this study are the first to analyze the cefazolin-CRRT circuit interaction when pediatric CRRT settings are applied. Incorporating the results of this study within physiologically-based pharmacokinetic models has the potential to optimize safe and effective dosing regimens for cefazolin and improve clinical trial planning within this patient population.

Disclosures: