Effect of Avibactam on Ceftazidime Clearance and Volume of Distribution in Patients Undergoing Continuous Renal Replacement Therapy
Start Date
April 2026
Location
3rd floor - Library
Abstract
Ceftazidime-avibactam (CZA) is a novel last resort antibiotic for the treatment of multidrug-resistant MDR gram negative infections. The current FDA recommended dosing regimen is 2 g ceftazidime / 0.5 g avibactam intravenously every 8 hours. This dosing regimen was derived from studies predominantly composed of patients with mildly impaired renal function. In critically ill patients CRRT is commonly being performed which is shown to be associated with supratherapeutic ceftazidime concentrations that carry an enhanced risk of neurotoxic effects. Simultaneously, the variable and often unpredictable impact CRRT has on drug clearance can result in underdosing, and treatment failure. There is an urgent need for better individualized dosing strategies based upon pharmacokinetic/pharmacodynamic (PK/PD) models. The objectives of this study were to develop a sound population pharmacokinetic model for CZA in critically Ill patients undergoing CRRT using nonlinear mixed-effects (NLME) modeling and to characterize the effect on CAZ clearance by AVI exposure. In the fitted model, exposure to Avibactam was identified as a significantly influencing covariate to the pharmacokinetics of Ceftazidime. Exposure to AVI was seen to have an inverse relationship to the volume of distribution of CAZ. The underlying mechanism driving this discovered relationship remains unclear and warrants further investigation. These findings suggest a previously unknown interaction between AVI and CAZ, which may have important implications on dosing regiments for patients.
Effect of Avibactam on Ceftazidime Clearance and Volume of Distribution in Patients Undergoing Continuous Renal Replacement Therapy
3rd floor - Library
Ceftazidime-avibactam (CZA) is a novel last resort antibiotic for the treatment of multidrug-resistant MDR gram negative infections. The current FDA recommended dosing regimen is 2 g ceftazidime / 0.5 g avibactam intravenously every 8 hours. This dosing regimen was derived from studies predominantly composed of patients with mildly impaired renal function. In critically ill patients CRRT is commonly being performed which is shown to be associated with supratherapeutic ceftazidime concentrations that carry an enhanced risk of neurotoxic effects. Simultaneously, the variable and often unpredictable impact CRRT has on drug clearance can result in underdosing, and treatment failure. There is an urgent need for better individualized dosing strategies based upon pharmacokinetic/pharmacodynamic (PK/PD) models. The objectives of this study were to develop a sound population pharmacokinetic model for CZA in critically Ill patients undergoing CRRT using nonlinear mixed-effects (NLME) modeling and to characterize the effect on CAZ clearance by AVI exposure. In the fitted model, exposure to Avibactam was identified as a significantly influencing covariate to the pharmacokinetics of Ceftazidime. Exposure to AVI was seen to have an inverse relationship to the volume of distribution of CAZ. The underlying mechanism driving this discovered relationship remains unclear and warrants further investigation. These findings suggest a previously unknown interaction between AVI and CAZ, which may have important implications on dosing regiments for patients.
