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 AUC(0-24)/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 AUC(0-24)/MIC >400.

Methods: Vancomycin AUC(0-24)/MIC predictions were conducted across a range of dosages (40-70 mg/kg/d) using a Monte Carlo simulation (n = 5000). AUC(0-24) 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% < or =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 AUC(0-24)/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 AUC(0-24)/MIC >400 for invasive MRSA infections. A vancomycin dosage of 60 mg/kg/d was predicted to optimize achievement of this target in children.

Figure 1

Monte Carlo simulation of the effects of vancomycin dosage on the achievement of AUC_0–24/MIC >400 in children receiving vancomycin 40 to 70 mg/kg/d for invasive methicillin-resistant Staphylococcus aureus infection. At each dosage, the percentage of children predicted to achieve AUC_0–24/MIC >400 is reported for 3 separate simulations each using a different vancomycin clearance (CL) estimate from the literature.^– The same MIC distribution was used for each simulation. See the Methods section for model details.

Figure 2

Monte Carlo simulation of the effects of MIC distribution on the achievement of vancomycin AUC_0–24/MIC >400 in children receiving vancomycin 40 or 60 mg/kg/d for invasive methicillin-resistant Staphylococcus aureus infection. (A) The proportion of isolates with a MIC of 1 mg/L varied, while the MIC of 2 mg/L was constant at 1% and the proportion of MIC ≤0.5 mg/L was adjusted so that the overall MIC distribution summed to 100%. (B) The proportion of isolates with a MIC of 2 mg/L was varied, while MIC ≤0.5 mg/L was constant at 40% and the proportion with a MIC of 1 mg/L was adjusted so that the overall MIC distribution summed to 100%. Data points represent the mean (SD) of 3 simulations, each using a different vancomycin clearance estimate.

Figure 3

Percentages of children predicted to achieve vancomycin AUC_0–24/MIC >400 for known MIC at vancomycin dosages of 40 and 60 mg/kg/d for invasive methicillin-resistant Staphylococcus aureus infection. Data points represent the mean (SD) of 3 Monte Carlo simulations, each using a different vancomycin clearance estimate.