Antibiotic Plasma Concentrations During Continuous Renal Replacement Therapy With a High Adsorption Membrane (oXiris®)

Study Overview
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Brief Summary
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Study: Open label, non-randomized, observational, descriptive and prospective pharmacokinetic. Patients: sepsis patients undergoing continuous renal replacement therapy (CRRT) and admitted at the Intensive care unit of Bellvitge University Hospitals. No power calculations needed. Antibiotic treatment: piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin as their standard of care and doses will be at the discretion of the treating physician. CRRT treatment: continuous venovenous hemodiafiltration (CVVHDF) will be performed by using the PrismafleX eXeed™ system with a high adsorbent membrane (oXiris®). Antibiotic concentrations: blood pre and post filter, urine and ultrafiltrate samples will be collected at steady state conditions. Samplig time will depend on dosage regimens of each antibiotic.

Detailed Description
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The study is an open label, non-randomized, observational, descriptive and prospective pharmacokinetic study. Setting: this study will be conducted at the Intensive Care Unit at the Bellvitge University Hospital. Study aims: the primary objective is to determine the PK/PD target attainment of piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin in septic critically ill patients treated with CVVHDF using oXiris® membrane. Secondary aims are: i) to characterize the PK of piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin in critically ill patients under CVVHDF therapy using oXiris® membrane by developing a population PK model; ii) to identify the clinical and demographic sources of PK variability observed in these patient and iii) to develop individualized dosing recommendations based on the PK/PD index associated with therapy success. Recruitment process: patients who meet the inclusion criteria will be enrolled for at least 72 hours (maximum 96 hours). Sample size: no power calculations are required for this study as it aims to investigate the PK of these antibiotics and does not intend to measure the effect of an intervention between two groups. Antibiotic treatment: patients will receive piperacillin, ceftazidime, cefepime, ceftolozane/tazobactam or daptomycin as their standard of care. Doses will be at the discretion of the treating physician. At the same time, patients will be treated under continuous renal replacement techniques (CRRT) with continuous venovenous hemodiafiltration mode (CVVHDF) using PrismafleX eXeed™ system and high adsorbent polyethyleneimide membrane (oXiris®). Filtration parameters will be determined following the local protocol (dose of 25-30 ml/kg/h) CRRT initiation will be determined by the treating physician on charge, according with the current recommendations of clinical practice and prescriptions of CRRT and local management protocols. The decision to stop the treatment will be determined by: Adequate renal recovery status: adequate capacity to effectively maintain fluid and electrolyte homeostasis and urinary output (>450 ml in 24 h) without the use of diuretics. Hemodynamic stability without renal function recovery. Therapy will be continued as intermittent hemodialysis. Antibiotic concentrations: blood, either pre and post filtration through oXiris® membrane, urine and ultrafiltrate samples will be obtained. Samples will be collected at 1) steady state conditions and 2) after minimum 24h from the concomitant administration of CRRT and antibiotic for piperacillin, ceftazidime, cefepime, ceftolozane and 48h for daptomycin. Sampling times will depend on the dosage regimen of each antibiotic therapy. Drug concentrations will be determined using a previously developed and validated measurement procedure based on ultra-high performance liquid chromatography-tandem mass spectrometry.

Official Title
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Antibiotic Plasma Concentrations During Continuous Renal Replacement Therapy With a High Adsorption Membrane (oXiris®)

Conditions
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Hemodiafiltration, Sepsis, Acute Kidney Injury

Intervention / Treatment
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* Device: Continuous venovenous hemodiafiltration with high adsorption membrane (oXiris®)
* Drug: Antibiotics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients in the setting of sepsis and requirements of CRRT with high adsorption membranes for at least 48 h Age >18 years Treatment with piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin prescribed at the discretion of the treating intensive care physician. Written informed consent will be required before the inclusion of a patient whenever possible and will be requested from the nearest relatives in the other cases. Exclusion Criteria: none.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients under CVVHDF with high adsorption membrane<br>Continuous venovenous hemodiafiltration mode (CVVHDF) using PrismafleX eXeed™ system and high adsorbent polyethyleneimide membrane (oXiris®). Filtration parameters will be determined following the local protocol (dose of 25-30 ml/kg/h). | Device: Continuous venovenous hemodiafiltration with high adsorption membrane (oXiris®)<br>* CRRT initiation will be determined by the treating physician on charge, according with the current recommendations of clinical practice and prescriptions of CRRT and local management protocols. The CVVHDF mode will be performed by using PrismafleX eXeed™ system and high adsorbent polyethyleneimide membrane (oXiris®). Filtration parameters will be determined following the local protocol (dose of 25-30 ml/kg/h).<br>Drug: Antibiotics<br>* Antibiotic concentration-time data will be collected and analyzed.<br>* Other names: Ceftolozane/tazobactam;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of individuals attaining a defined pharmacokinetic-pharmacodynamic target for antimicrobial therapy | Time above minimum inhibitory concentration (%fT > k× MIC) for betalactams, and total-drug AUC24/MIC ≥ 666 for daptomycin | 01/08/2019 - 31/12/2021 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibiotic concentration-time data. | Antibiotic concentration-time data will be collected and analysed to characterize the PK profile of piperacillin, ceftazidime, cefepime, ceftolozane and daptomycin in critically ill patients under CRRT therapy using oXiris® membrane and a population PK model will be developed. | 01/08/2019 - 31/12/2021 | 
| Blood flow (mL/min). CRRT covariate that can affect drug exposure and PK parameters. | Effect of CRRT settings, physiopathological and demographic data on drug exposure and PK parameters. | 01/08/2019 - 31/12/2021 | 
| Dialysate flow rate (L/h). | CRRT covariate that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed. | 01/08/2019 - 31/12/2021 | 
| Ultrafiltrate flow rate (L/h). | CRRT covariate that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed. | 01/08/2019 - 31/12/2021 | 
| Replacement fluid (mL/h). | CRRT covariate that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed. | 01/08/2019 - 31/12/2021 | 
| Extraction rate (L/h). | CRRT covariate that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed. | 01/08/2019 - 31/12/2021 | 
| Urine output (mL/day). | Physiopathological variables that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed. | 01/08/2019 - 31/12/2021 | 
| Albumin (g/L). | Physiopathological variables that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed. | 01/08/2019 - 31/12/2021 | 
| Weight (Kg). | Physiopathological variables that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed. | 01/08/2019 - 31/12/2021 | 
| Admission diagnosis: surgical, medical, trauma. | Physiopathological variables that can affect drug exposure and PK parameters. For each antibiotic, a population pharmacokinetic model will be developed. | 01/08/2019 - 31/12/2021 | 
| Dosage (mg, frequency of administration and mode of administration) needed to achieve the PK/PD target. | Monte-Carlo Simulations using the population PK parameters of the final models in order to generate concentration-time profiles of n hypothetical subjects per dosing regimen will be performed. With this data, we will calculate the probability of target attainment of the PK/PD indices associated to antibiotic therapy success, which will translate in the development of individualized dosing recommendations for our patient population. | 01/08/2019 - 31/12/2021 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute kidney Injury, Sepsis, Antibiotic plasma level, CRRT, oXiris®