Clearance of ceftazidime-avibactam in an in vitro continuous venovenous hemodialysis model

Abstract

Abstract Background Optimal dosing of ceftazidime-avibactam (C-A) in critically ill patients on continuous renal replacement therapy (CRRT) is unknown. The objective of this study was to evaluate the adsorption and transmembrane clearance (CLTM) of C-A in an in vitro continuous venovenous hemodialysis (CVVHD) model to guide dosing in the absence of clinical data. Methods CVVHD was simulated with bovine blood (200 mL/minute) on a Prismaflex dialysis unit with polysulfone (HF1400) and AN69 (M150) hemofilters at dialysate flow rates (Qd) of 2 and 4 L/hours. Pre-hemofilter plasma samples were collected at 0, 5, 10, 20, 30, 45, and 60 mins after C-A addition; postfilter and dialysate samples were collected at 10 and 45 mins for saturation coefficient (SA) calculation. Adsorption was determined by total drug recovery in dialysate and plasma after 120 mins of dialysis at 2 L/hours. CLTM was calculated as the product of SA and Qd (CLTM-SA) and by elimination rate constant (CLTM-ke) derived from the slope of log-linear concentration-time plots. Results Mean (± SD) SA and CLTM values for C-A from duplicate experiments are in Table 1. CLTM was not affected by filter type, and increased linearly with Qd when calculated by two different methods. Avibactam CLTM was higher than ceftazidime CLTM with each filter and rate. Adsorption affected 17.3% and 20.2% of C-A for HF1400 and AN69 filters, respectively. Conclusion Significant Qd- dependent clearance of C-A was observed in in vitro CVVHD. CLTM of ceftazidime was slightly higher than previous reports and may reflect the larger surface area of contemporary filters in this study. The more rapid clearance of avibactam, particularly at higher flow rates, suggests that dose adjustments should focus on ensuring adequate avibactam exposure during CVVHD. Disclosures L. H. Danziger, Allergan: Investigator, Research grant.