This prospective observational study is conducted at the First Affiliated Hospital of Zhejiang University School of Medicine from June 1, 2021 to January 1, 2024. The study aims to characterize the population pharmacokinetics of ceftazidime (CAZ) and avibactam (AVI) in critically ill patients receiving ceftazidime-avibactam (CAZ-AVI), including patients with and without renal replacement therapy (RRT). Plasma concentrations of CAZ and AVI will be measured after the first-dose and steady-state administrations. Population pharmacokinetic and pharmacokinetic/pharmacodynamic target-attainment analyses will be performed to explore dosing strategies according to renal function and RRT status.
This is a prospective, single-center observational cohort study of critically ill adult patients receiving CAZ-AVI for carbapenem-resistant organism (CRO) infections. Arterial blood samples (3 mL) will be collected at 0, 1, 2, 4, 6, and 8 hours after the first-dose and steady-state CAZ-AVI infusions. Blood samples will be centrifuged at 4°C and 4000 rpm for 10 min, and the separated plasma will be stored at -80°C until measurement of ceftazidime (CAZ) and avibactam (AVI) concentrations. Plasma concentrations of CAZ and AVI will be quantified using ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF). Clinical and laboratory characteristics will be recorded, together with RRT-related treatment parameters in patients receiving RRT. Population pharmacokinetic(PPK) models of CAZ and AVI will be developed using the collected concentration and clinical data.The resulting PPK models will subsequently be used in Monte Carlo simulations (MCSs) to identify candidate model-informed dosing regimens across renal-function and RRT strata.
Study Type
OBSERVATIONAL
Enrollment
33
Critically ill adult patients (≥18 years) receiving intravenous CAZ-AVI for carbapenem-resistant organism (CRO) infections will be enrolled. Arterial blood samples (3 mL) will be collected at 0, 1, 2, 4, 6, and 8 hours after the first-dose and steady-state CAZ-AVI infusions for measurement of plasma CAZ and AVI concentrations.
The First Affiliated Hospital,College of Medicine,Zhejiang University
Hangzhou, Zhejiang, China
Plasma drug concentrations of CAZ and AVI after first-dose administration
Plasma concentrations of CAZ and AVI will be measured after the first-dose infusion.
Time frame: 0, 1, 2, 4, 6, and 8 hours after the first-dose infusion.
Plasma drug concentrations of CAZ and AVI at steady state
Plasma drug concentrations of CAZ and AVI will be measured after the steady-state infusion
Time frame: 0, 1, 2, 4, 6, and 8 hours after the steady-state infusion.
Population pharmacokinetic characterization and PK/PD-based dosing evaluation of CAZ-AVI
Population pharmacokinetic models of ceftazidime and avibactam will be developed using plasma concentration and clinical data from critically ill patients. Pharmacokinetic/pharmacodynamic analyses will be performed to evaluate dosing regimens across different levels of renal function, including patients receiving renal replacement therapy (RRT).
Time frame: After completion of pharmacokinetic data collection
Microbiological clearance
Microbiological clearance assessed based on follow-up microbiological culture results.
Time frame: 14 day after the onset of infection
Infection-related mortality
Infection-related mortality within 14 days after the onset of infection.
Time frame: 14 day after the onset of infection
Treatment outcome
Treatment outcome within 14 days after the onset of infection.
Time frame: 14 day after the onset of infection
all-cause mortality
30 day all-cause mortality
Time frame: 30 day after the onset of infection
length of stay
Post-infection ICU length of stay
Time frame: Day 1 is defined as the day of confirmed diagnosis, the duration from confirmed diagnosis to ICU discharge will be measured.
length of stay
Total ICU length of stay.
Time frame: From ICU admission to ICU discharge will be measured(assessed up to 120 days).
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