# Pharmacokinetics/pharmacodynamics of ceftazidime-avibactam in critically ill adult patients receiving continuous renal replacement therapy

## TL;DR

This study examines how the antibiotic ceftazidime-avibactam behaves in critically ill patients on kidney replacement therapy, finding that standard doses may be too high and cause toxicity.

## Contribution

The study provides new pharmacokinetic/pharmacodynamic data for ceftazidime-avibactam in critically ill patients undergoing CRRT.

## Key findings

- Drug exposure was significantly increased in CRRT patients compared to healthy subjects.
- 90.48% of patients had ceftazidime concentrations exceeding the neurotoxicity threshold.
- CVVH showed higher clearance of the drug compared to CVVHD.

## Abstract

Ceftazidime-avibactam (CAZ-AVI), a novel antibiotic, is effective in treating infections caused by carbapenem-resistant Gram-negative bacteria. However, in patients receiving continuous renal replacement therapy (CRRT), both the pharmacokinetics (PK) and pharmacodynamics (PD) of the drugs can be significantly altered. Currently, there remains a lack of clear guidelines regarding optimal dosing regimens for CAZ-AVI during CRRT. Prospectively, this study evaluated the PK/PD of CAZ-AVI in 21 critically ill patients receiving CRRT. We collected blood samples at 5–7 sampling points within one administration cycle and then determined the total plasma drug concentrations. Phoenix was used to calculate the PK parameters. The clearance at steady state (CLSS) of patients receiving CRRT was significantly reduced, and drug exposure was also significantly increased compared to healthy subjects. Notably, four patients demonstrated the free minimum plasma concentrations (fCmin) of CAZ exceeding eight times the MIC, and 90.48% (19 cases) of the patients exhibited CAZ plasma concentrations exceeding the neurotoxicity threshold of 104 mg/L. PK/PD analysis indicated that the standard dosing regimen of 2.5 g every 8 hours of CAZ-AVI may pose a risk of excessive drug exposure. In addition, CRRT was the primary elimination pathway for CAZ-AVI in critically ill patients with acute kidney injury receiving CRRT. Significant differences in extracorporeal clearance were observed between continuous veno-venous hemodialysis (CVVHD) and continuous veno-venous hemofiltration (CVVH) for both CAZ and AVI; CVVH demonstrated higher clearance for CAZ and AVI compared to CVVHD. To prevent potential toxic reactions, it is urgent to establish a safer and more rational dosing regimen for patients receiving CRRT.