Prediction of vancomycin pharmacodynamics in children with invasive methicillin-resistant Staphylococcus aureus infections: A Monte Carlo simulation

Abstract

Background Due to the emergence of community-associated strains, the prevalence of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections has increased substantially in pediatric patients. A vancomycin AUC0–24/MIC index >400 best predicts treatment outcomes for invasive MRSA infection in adults. Data on whether recommended vancomycin doses in children achieve this break point are lacking. Objective This study aimed to assess the likelihood that currently recommended vancomycin doses in children achieve AUC0–24/MIC >400. Methods Vancomycin AUC0–24/MIC predictions were conducted across a range of dosages (40–70 mg/kg/d) using a Monte Carlo simulation (n = 5000). AUC0–24 was calculated as daily dose divided by vancomycin clearance, and daily dose was fixed for a given simulation. Three literature-reported estimates in children were used to define vancomycin clearance and its variance. For the MIC distribution of MRSA isolates, susceptibility data were obtained from the University of California, San Francisco Children’s Hospital, San Francisco, California (n = 180; 40% ≤0.5 mg/L; 59% = 1 mg/L; and 1% = 2 mg/L). Results Using the recommended empiric dosage of 40 mg/kg/d, 58% to 66% of children were predicted to achieve AUC0–24/MIC >400. Increasing the vancomycin dosage to 60 mg/kg/d substantially increased the likelihood (88%–98%) of achieving this pharmacodynamic target. On sensitivity analysis, a dosage of 40 mg/kg/d was more strongly influenced by small changes in MIC compared with 60 mg/kg/d. Conclusions Recommended empiric vancomycin dosing in children (40 mg/kg/d) was not predicted to consistently achieve the pharmacodynamic target of AUC0–24/MIC >400 for invasive MRSA infections. A vancomycin dosage of 60 mg/kg/d was predicted to optimize achievement of this target in children.

An Evaluation of Vancomycin Dosing for Complicated Infections in Pediatric Patients

“…21 A second study showed that vancomycin troughs of 7 to 10 mg/L are likely predictive of AUC:MIC >400 when using a dosing regimen of 15 mg/kg per dose every 6 hours. 22 Based on this modeling, it may not be necessary to achieve troughs of 15 to 20 mg/L to achieve an AUC:MIC >400 in pediatric patients.…”

Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

“…For neonates, lower targets may suffice as most of the identified infectious organisms are coagulase-negative staphylococci instead of MRSA (11,12). It has been reported that if the MIC is Ͻ1 mg/ liter, 60 mg/kg/day seems necessary to reach an AUC 24 /MIC of Ͼ400 in children (20,(60)(61)(62).…”

Achieving Therapeutic Vancomycin Levels in Pediatric Patients

“…2 Many studies 7,14,17 have used AUC/MIC greater than or equal to 400 as a target for pediatric patients; however, in parallel with target serum trough levels, AUC/MIC has not been studied or verified in pediatric populations to correlate particular ratios with clinical outcomes. In their retrospective cohort study, Le and others 14 examined achievement of AUC/MIC in pediatric patients and highlighted that clinicians may be achieving target AUC/MIC of 400 or greater, despite apparently subtherapeutic trough levels.…”