Severe Sepsis, Carbapenem Resistant Bacterial Infection
Conditions
Keywords
Severe sepsis, Ceftazidime-avibactam, Population pharmacokinetics (PPK), Pharmacokinetic (PK), Critically ill Patients, Pharmacodynamic (PD), Renal replacement therapy
Brief summary
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.
Detailed description
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.
Interventions
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.
Sponsors
First Affiliated Hospital of Zhejiang University
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Critically ill patients with severe sepsis(CRO infections) and treated with CAZ-AVI(culture-confirmed CRO susceptible to CAZ-AVI); * Age ≥ 18 years; * Expected ICU stay ≥48 hours. * Hemoglobin \>70 g/L during the pharmacokinetic blood-sampling period； * The patient or authorized persons agree and sign the informed consent.
Exclusion criteria
* Expected ICU stay \<48 hours. * Pregnant woman.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma drug concentrations of CAZ and AVI after first-dose administration | 0, 1, 2, 4, 6, and 8 hours after the first-dose infusion. | Plasma concentrations of CAZ and AVI will be measured after the first-dose infusion. |
| Plasma drug concentrations of CAZ and AVI at steady state | 0, 1, 2, 4, 6, and 8 hours after the steady-state infusion. | Plasma drug concentrations of CAZ and AVI will be measured after the steady-state infusion |
| Population pharmacokinetic characterization and PK/PD-based dosing evaluation of CAZ-AVI | After completion of pharmacokinetic data collection | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Microbiological clearance | 14 day after the onset of infection | Microbiological clearance assessed based on follow-up microbiological culture results. |
| Infection-related mortality | 14 day after the onset of infection | Infection-related mortality within 14 days after the onset of infection. |
| Treatment outcome | 14 day after the onset of infection | Treatment outcome within 14 days after the onset of infection. |
| all-cause mortality | 30 day after the onset of infection | 30 day all-cause mortality |
| length of stay | Day 1 is defined as the day of confirmed diagnosis, the duration from confirmed diagnosis to ICU discharge will be measured. | Post-infection ICU length of stay |
Countries
China
Contacts
STUDY_CHAIRYongHong Xiao, PhD
First Affiliated Hospital of Zhejiang University
Outcome results
None listed