Population Pharmacokinetics of Anti-infectives in Critically Ill Children

Study Overview
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Brief Summary
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Concentrations and effects of anti-infectives in critically ill children are unpredictable and the risk of under-exposure may be associated with poor clinical outcomes. In addition, between-subject variability (BSV) is known to be substantial in critically ill children. Rationalisation of anti-infectives in children is therefore desirable. The investigators aim to investigate, using a population approach, the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-infectives including PK/PD targets (fT(%) > minimal inhibitory concentration (MIC)) and PD endpoints (clinical outcomes) in critically ill children. Covariates The effects of covariates on anti-infectives PK and PK/PDs are investigated in order to better explain the BSV and to ultimately suggest individualized dosage regimens. It will be a prospective PK study including 11 anti-infectives antibiotics. Six blood samples were taken from each patient during dosing interval. The primary PK/ PD targets were anti-infectives concentrations above the MIC of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. The investigators used skewed logistic regression to describe the effect of anti-infectives exposure on patient outcome.

Detailed Description
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Background and aims of the study: Recent studies have suggested a risk of under-exposure to anti-infectives in critically ill adults. This under-exposure may be associated with poor clinical outcomes as well as a delay or incomplete clinical resolution of infection; The dosing regimen of anti-infectives in critically ill children is usually based on weight (i.e. mg per Kg). However, between-subject variability is known to be substantial in children and even more so in critical illness; As a result, concentrations and effects of anti-infectives are unpredictable and the risk of under- or over-exposure is thus genuine and considerable. Rationalisation of anti-infectives in children is therefore desirable. The purpose of the present study is to investigate, using a population approach, the pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous anti-infectives including usual PK/PD targets (fT(%) > minimal inhibitory concentration (MIC)) and PD endpoints (clinical outcomes) in critically ill children. The effects of developmental and other factors related to critical illness on anti-infectives PK and PK/PDs are investigated in order to better explain the observed between-subject variabilities and to ultimately suggest individualized dosage regimens. This prospective study will be conducted in six paediatric services of Public Hospitals in Paris, France Intervention: Patient selection will take place in the 6 paediatric services. The senior physician proposes the study to holders of parental authority whose child receives or will receive anti-infectives during its follow-up or hospitalization. The senior physician will give a briefing note to the holders of parental authority, and if the child is able to understand the information. The non-oral opposition for the retrieval and analysis of data will be collected. No intervention or no charge will be made for this study.

Official Title
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Population Pharmacokinetics and Rationalization of Anti-infectives Administration in Critically Ill Children

Conditions
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Pediatric Intensive Care Unit, Pediatric Immuno-hematology Department

Intervention / Treatment
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* Other: Pharmacokinetics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Minor patient requiring the administration of an anti-infective belonging to the following classes : β-lactam antibiotics; aminoglycosides, glycopeptides; fluoroquinolones; other antibiotics (daptomycin, rifampin, trimethoprim, sulfamethoxazole, clarithromycin); fungal; antivirals, during its follow-up or hospitalization Exclusion Criteria: Patient and parents having notified to the doctor that they refuse data recovery.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum 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 |
| --- | --- |
| Anti-infectives<br>Anti-infectives of the following : β-lactam antibiotics, Aminoglycosides, Glycopeptides, Fluoroquinolone, Daptomycin, Rifampin, Trimethoprim, Sulfamethoxazole, Clarithromycin, Fungal, Antiviral Pharmacokinetics | Other: Pharmacokinetics<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| anti-infectives concentration |  | until 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of identified or suspected pathogen |  | until 28 days | 
| composite measure of the health condition | Clinical data: anthropometric characteristics, organs function, severity score, clinical cure | until 28 days | 
| predictive variables of underdosing/overdosing of antiinfectives and biological evolution | Clinical data: anthropometric characteristics, organs function, severity score, clinical cure | until 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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β-lactam antibiotics, Children, Anti-infectives, Aminoglycosides, glycopeptides, Fluoroquinolone, Fungal, Antiviral