Pharmacokinetics of Antibiotics in Critically Ill Patients Receiving CVVHF

Study Overview
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Brief Summary
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The mortality in patients with sepsis and severe acute kidney injury requiring continuous renal replacement therapy (CRRT) remains high. Antibiotic therapy is a key treatment of these patients and in recent years new antibiotics have been licensed. However, data is lacking to determine the optimal dosing regimens of these antibiotics for high (Australia and other countries) and low intensity (Japan) of CRRT. Aim To establish the appropriate dosing regimens of newly available antibiotics during CRRT can applied globally.

Official Title
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Pharmacokinetics of New Licensed Antibiotics in Critically Ill Patients Receiving Continuous Venovenous Haemofiltration: An International Collaborative Study

Conditions
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Sepsis, Acute Kidney Injury

Intervention / Treatment
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* Other: blood samples and filtered fluid will be collected.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (age ≥18 years or older) Sepsis (Sepsis-3 criteria) Acute kidney injury requiring CRRT (KDIGO criteria) Eligible for intensive care without restrictions or limitations Exclusion Criteria: Chronic renal failure Obvious or suspected pregnancy Intracranial bleeding

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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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: To establish the appropriate dosing regimens of newly available antibiotics during CRRT<br>High dose (world standard dose) and low dose CRRT (Japan local) CRRT protocol Vascular access will be obtained by inserting a double-lumen dialysis catheter into the internal jugular or femoral veins. High dose CRRT in Australia, Blood flow through the extracorporeal circuit will be maintained at 150 ml/min. The CVVHF replacement volume will be set at 25ml/kg/hour and bicarbonate-buffered replacement fluids will be added in post-dilutional mode. Low dose CRRT in Japan, Blood flow through the extracorporeal circuit will be maintained at 80 ml/min. CVVHF replacement volume will be set at 15ml/kg/hour and bicarbonate-buffered replacement fluids will be added in the post-dilutional mode. Fluid balance, volume removal and the duration of CVVHF will be determined by the ICU physician based on the patient's individual clinical status. | Other: blood samples and filtered fluid will be collected.<br>* Arterial blood samples will be collected just before the commencement of continuous venovenous haemofiltration (CVVHF) and 1 h after the termination of CVVHF. Prefilter and post-filter venous blood samples and filtered fluid will be collected 1 and 3 h after the commencement of CVVHF and at the end of CVVHF.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma new antibiotics concentration during continuous venovenous haemofiltration (CVVHF) in critically ill patients receiving infusion of these drugs. | New drugs are Tedizolid, Daptomycin (anti-MRSA), Tazobactam/ Ceftolozane (anti-gram negative), Metronidazole (Anti-anaerobic). Plasma antibiotics concentrations will be measured at 5 time-points and prefilter and postfilter plasma and filtered-fluid antibiotics levels will be measured at 3 time-points during CVVHF. | 72 hours | 
| Calculated clearances of new antibiotics during continuous venovenous haemofiltration (CVVHF) in critically ill patients receiving infusion of these drugs. | New drugs are Tedizolid, Daptomycin (anti-MRSA), Tazobactam/ Ceftolozane (anti-gram negative), Metronidazole (Anti-anaerobic). Total clearance by CVVHF: (Cltotal) = (Cpre - Cpost / Cpre) × Blood flow (ml/min), Clearance by filtration: (Clfil) = (Clfil / Cpre)× replacement volume (ml/min), Clearance by absorption of the filter: (Clab) = (Cltotal) - (Clfil) (ml/min). | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of serum creatinine | Concentration of serum creatinine | through study completion, an average of 1 year | 
| length of stay in the hospital | length of stay in the hospital | up to 30 days, length of stay in the hospital will be calculated using the earliest of date that the subject is medically ready for discharge when captured, the date of discharge | 
| ICU Mortality | Mortality at ICU discharge | at ICU discharge assessed up to 30 days | 
| Hospital Mortality | Mortality at hospital discharge | at hospital discharge assessed up to 30 days |