Comparison of Two Dosage Adjustment Strategies of Vancomycin in Children

Study Overview
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Brief Summary
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Vancomycin is the standard first-line treatment for MRSA infections and a first-line empiric therapy. The relationship between exposure to vancomycin and efficacy is admitted but because of an important intersubject variability, therapeutic exposure isn't usually achieved. The primary aim of this randomized controlled trial is to evaluate a new early dosage adjustment strategy of vancomycin in children, comparing it to the usual treatment strategy. Using a bayesian approach, the purpose is to achieve earlier a therapeutic and non-toxic exposure to vancomycin. The primary hypothesis is that an early dosage adjustment strategy using a bayesian approach will allow patients to achieve the vancomycin pharmacological target faster than with the usual treatment strategy.

Detailed Description
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Introduction/ Clinical significance : Staphylococcus aureus is a common cause of serious infections. Methicillin-resistant Staphylococcus aureus (MRSA) are one of the most common causes of nosocomial antibiotic resistant bacterial infections in the world. According to the last data from the European Antimicrobial Resistance Network, in 2014, 17,4 % of invasive staphylococcal infections are due to MRSA in France, with proportions of up to 56 % in some regions in the European Economic Area (EEA). In the United-States of America, MRSA reach 50 % of Staphylococcus isolates in some studies. Vancomycin is the standard first-line treatment for MRSA infections and a first-line empiric therapy. To optimize good clinical outcomes for invasive MRSA infections using pharmacokinetics-pharmacodynamics of vancomycin, studies support targeting area under the curve (AUC) of the serum concentration versus time over 24 hours to minimum inhibitory concentration (MIC) ratio ≥ 400, which frequently correlates to a trough concentration of 15 - 20 mg/L when the MIC is 1 mg/L. Because of few consensus regarding the dosage to use and high intersubject variability, this pharmacological target is difficult to reach in children, which may lead to a delayed infection control and an increase of vancomycin toxicity-related side effects. Aims : The primary aim is to evaluate an early dosage adjustment strategy of vancomycin in children, comparing it to the usual treatment strategy. Using a bayesian approach, the main purpose is to achieve earlier a therapeutic and non-toxic exposure to vancomycin. The secondary aims are to compare with the usual treatment strategy 1) the proportion of subjects with vancomycin serum concentration within the concentration targets at the 24th hour of treatment, and 2) the clinical (in terms of fever), biological (in terms of CRP) and bacteriological (in terms of blood culture) efficacy of this early dosage adjustment strategy of vancomycin. Hypothesis : This study hypothesizes that early dosage adjustment strategy of vancomycin using a bayesian approach will be superior to usual treatment strategy in achieving the pharmacological target of vancomycin at the 24th hour of treatment in children. Methodology : As part of routine care, a prospective open-label randomized controlled trial will be conducted in a major paediatric hospital in Paris, France. Subjects will be divided into two arms. Each arm will contain 50 subjects. For subjects of the Modeling arm, drug concentration will be measured at the 3rd hour of treatment and dosage adjustment will be done at the 6th hour of treatment using a bayesian approach. Vancomycin serum concentration will be then measured at the 24th hour of treatment. Subjects of the control arm will receive the usual treatment strategy. Vancomycin serum concentration will be measured at the 24th hour of treatment.

Official Title
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Comparison of Two Dosage Adjustment Strategies of Vancomycin in Children

Conditions
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Methicillin-resistant Staphylococcal Infections

Intervention / Treatment
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* Other: Early vancomycin monitoring and bayesian dosage adjustment
* Other: usual vancomycin dose and monitoring strategy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 1 months to 16 years Children for whom a vancomycin treatment is started in the hospital Necker-Enfants Malades in Paris, France No objection of parents and of the child himself if he is able to express it. Exclusion Criteria: Patients undergoing hemodialysis Patients undergoing peritoneal dialysis Newborns less than 1 months old Adolescents more than 16 years old and adults

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 16 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Modeling arm<br>Early vancomycin monitoring and bayesian dosage adjustment | Other: Early vancomycin monitoring and bayesian dosage adjustment<br>* Measure of vancomycin serum concentration at the 3rd hour of treatment and adjustment of vancomycin dosage at the 6th hour of treatment using a bayesian approach. Then measure of vancomycin serum concentration at the 24th hour of treatment.<br>|
| Sham Comparator: Control arm<br>Usual vancomycin dose and monitoring strategy | Other: usual vancomycin dose and monitoring strategy<br>* Vancomycin serum concentration will be measured at the 24th hour of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with vancomycin AUC/MIC ≥ 400 and serum trough concentration ≤ 20 mg/L |  | 24th hour of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vancomycin, Children, Infection, Antibiotic, Methicillin-resistant Staphylococcus aureus (MRSA), Population-based pharmacokinetic modeling, Pharmacokinetics, Pharmacodynamics, Bayesian approach, Therapeutic drug monitoring