Comparison of Two Dosage Adjustment Strategies of Vancomycin in Children
Condition: Methicillin-resistant Staphylococcal Infections
MeSH terms: Staphylococcal Infections
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): Early vancomycin monitoring and bayesian dosage adjustment; usual vancomycin dose and monitoring strategy
Intervention type(s): Other; Other
Intervention description(s): 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.; Vancomycin serum concentration will be measured at the 24th hour of treatment.
Intervention MeSH terms: Vancomycin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Vancomycin; Children; Infection; Antibiotic; Methicillin-resistant Staphylococcus aureus (MRSA); Population-based pharmacokinetic modeling; Pharmacokinetics; Pharmacodynamics; Bayesian approach; Therapeutic drug monitoring