Beta-Lactams Dosing In Pneumonia in ICU in Patients Treated by Continuous Renal Replacement Therapy: the BLIPIC Study

Study Overview
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Brief Summary
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Pneumonia are the most frequent infections in ICU. Little is known about beta-lactam doses necessary for this infection for patients treated with continuous veino-veinous hemodialysis. The pharmacokinetic variability expose to over and underdosage leading to toxicity or therapeutic failure. The aim of this study is to define if beta-lactams doses used in pneumonia for patients with acute kidney injury treated with our hemodialysis conditions lead to beta-lactam therapeutic plasma levels.

Detailed Description
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Pneumonia are the most frequent infections in ICU. Little is known about beta-lactam doses necessary for this infection for patients treated with continuous veino-veinous hemodialysis. The pharmacokinetic variability expose to over and underdosage leading to toxicity or therapeutic failure. The aim of this study is to define if beta-lactams doses used in pneumonia for patients with acute kidney injury treated with our hemodialysis conditions lead to beta-lactam therapeutic plasma levels. This prospective observational multicenter study will include all patients with pneumonia treated by beta-lactam and continuous veino-veinous hemodialysis in 5 ICU. Blood sampling will be done at assumed pharmacokinetic steady state. Protocol sample concentrations of beta-lactams immediately prior to re-dosing, after 24 hours of association of intraveinous beta-lactam and continuous veino-veinous hemodialysis. Another sample will be done after 48 hours. The ICU measured bacterial MICs routinely when the pathogen will be determined. Surveyed ICUs will adopt SFM-EUCAST breakpoints for the targeted (or suspected) bacteria to determine pharmacokinetic/pharmacodynamic targets when a mesured MIC (Minimum inhibitory concentration) is not available. Local hospital antibiogram data can also be used to describe likely pathogen susceptibility. Target attainment is defined as 100% fT> 5 MIC. Due to the long delay to receive therapeutic drug monitoring results, doses could not be ajusted. Factors which could cause concentrations variations will be registered. When neurotoxicity is suspected, a sample will be realized to know beta-lactam concentration and the adverse event will be notified.

Official Title
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Beta-Lactams Dosing In Pneumonia in ICU in Patients Treated by Continuous Renal Replacement Therapy

Conditions
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Beta-lactam, Continuous Renal Replacement Therapy, Pneumonia, Antibiotic

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years Receiving intraveinous beta-lactam : amoxicillin, amoxicillin-clavulanic acid, piperacillin-tazobactam, cefotaxime, ceftazidime, cefepime, meropenem, imipenem With AKI defined as any of the following, and treated with Multifiltrate Ci-Ca CVVHD 1000® kit with a dialysis dose of 25 ml/kg/h : Increase in creatininemia ≥ 0.3 mg/dl (≥ 26.5 µmol/l) within 48 hours Increase in creatininemia ≥ 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days Urine volume < 0.5 ml/kg/h for 6 hours Hospitalized in ICU Presence of a catheter to facilitate sample collection With pneumonia defined as any of the following : Chest X-ray pneumonia : opacities, new or progressive infiltrates AND at least one of the following : hyperthermia > 38°C or hypothermia < 36°C with no other explanation ; leukopenia < 4 G/L ou leukocytosis > 12G/L AND at least one of the following : new onset purulent sputum or change in sputum character, new onset or worsening cough or dyspnea or tachypnea, rales or bronchial breathing, lower oxygen saturation/hypoxemia or increase of oxygen needs or respiratory assistance Treated within 24 hours by citrate hemodialysis AND beta-lactam respecting dose and administration conditions of the study : Amoxicillin : loading dose followed immediately by 2g by extended infusion for 4 hours every 8 hours Amoxicillin-clavulanic acid : 2g every 8 hours by intermittent bolus Piperacillin-tazobactam: loading dose followed immediately by 4g/0.5g by continuous infusion every 8 hours (< 80 kg) ou 6 hours (> 80 kg) Cefotaxime: loading dose followed immediately by 2g by continuous infusion every 8 hours Ceftazidime : loading dose followed immediately by 2g by continuous infusion every 8 hours Cefepime: loading dose followed immediately by 2g by continuous infusion every 8 hours Meropenem : loading dose followed immediately by 2g (> 60 kg) ou 1,33g (< 60 kg) by extended infusion for 4 hours every 8 hours Imipenem : loading dose followed immediately by 750 mg (< 80 kg) ou 1g (> 80 kg) by extended infusion for 4 hours every 6 hours In case of extrem weight, dose will be on investigator's discretion but administration conditions have be to respected. No objection has been obtained from the patient or their legally authorised representative Exclusion Criteria: Aged < 18 years ECMO Cystic fibrosis Burn victim Pregnant woman Any rapidly-progressing disease or immediately life-threatening illness Objection from the patients or their legally authorised representative No social security scheme Interruption of antibiotic before samples Patient in prison

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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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of beta-lactams concentrations above plasma therapeutic levels | We aimed to obtain concentrations over 5 MIC (Minimum inhibitory concentration) for at least 80% of patients. | Day 3 after start of antibiotic and continuous veino-veinous hemodialysis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution of steady state beta-lactam concentrations and their variability | Description of beta-lactam concentration | Day 3 after start of antibiotic and continuous veino-veinous hemodialysis | 
| Incidence of neurotoxicity | Percentage of neurotoxicity | Day 7 after start of antibiotic and continuous veino-veinous hemodialysis | 
| Trends in beta-lactam concentrations between 2 days | Comparaison between 24 hours and 48 hours samples | At Day 1 and Day 2 | 
| Clinical response observed when beta-lactam concentrations achieved 5 MIC | Survival at Day 28 and Day 90 | At Day 28 and day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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amoxicillin, amoxicillin-clavulanic acid, piperacillin-tazobactam, cefotaxime, ceftazidime, cefepime, meropenem, imipenem, multifiltrate, citrate, CVVHD, extended and continuous infusion, TDM, Therapeutic Drug Monitoring