Pharmackinetics/pharmacodynamics of ceftazidime-avibactam in adult critically ill 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 (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 minimum inhibitory concentration, 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 venovenous hemodialysis (CVVHD) and continuous
venovenous 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.