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

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 (CL_SS) 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 (fC_min) 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.