Improved vancomycin dosing in children using area under the curve exposure

Abstract

Background: : Our objectives were to (1) determine the pharmacokinetic indices of vancomycin in pediatric patients; and (2) compare attainment of 2 target exposures: area under curve (AUC) / minimum inhibitory concentration (MIC) ≥400 and trough concentration ≥15 mcg/mL.

Methods: : The population-based pharmacokinetic modeling was performed using NONMEM 7.2 for children ≥3 months old who received vancomycin for ≥48 hours from 2003 to 2011. A 1-compartment model with first-order kinetics was used to estimate clearance, volume of distribution and AUC. Empiric Bayesian post hoc individual parameters and Monte Carlo simulations (N = 11,000) were performed.

Results: : Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range 2.2-13.4) years, weight 22.7 (12.6-46) kg and baseline serum creatinine 0.40 (0.30-0.60) mg/dL. Final model pharmacokinetic indices were clearance (L/h) = 0.248 * Wt * (0.48/serum creatinine) * (ln(age)/7.8) and volume of distribution (L) = 0.636 * Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39-52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects ≥12 years old and 70 mg/kg/day for those <12 years old achieved target AUC/MIC in ~75% and trough concentrations ≥15 in ~45% of virtual subjects. An AUC/MIC ~400 corresponded to trough concentration ~8 to 9 mcg/mL.

Conclusions: : Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.

Conflict of interest statement

Conflict of Interest: J.L. has previously received investigator-initiated grants from Pfizer, Astellas and Cubist and served on the speaker’s bureau for Pfizer. E.V.C. has served as a consultant to Trius, Cerexa and Abbott Pharmaceuticals. All other authors disclose no conflict of interest.

Figures

Figure 1

Exclusion Algorithm.

Figure 2

Effect of Age and Serum Creatinine on Vancomycin Clearance.

Figure 2

Effect of Age and Serum Creatinine on Vancomycin Clearance.

Figure 3

Observed versus Predicted Concentrations based on Individual (a) and Population Parameters (b).

Figure 4

Plots of Residuals in Concentrations.

Figure 5

Methicillin-Resistant Staphylococcus aureus Susceptibility to Vancomycin at Each Minimum Inhibitory Concentration (MIC) by Hospital.

Figure 6

Target Attainment by Area-under-Curve over 24 hours to Minimum Inhibitory Concentration (AUC/MIC) versus Trough (Cmin) using Monte Carlo Simulation (N = 11,000 subjects). *For Hospital A, MIC distribution for methicillin-resistant S. aureus isolates was 85% for ≤ 1 and 15% for > 1 mcg/mL. **For Hospital B, MIC distribution for methicillin-resistant S. aureus isolates was 68% for ≤ 1 and 32% for > 1 mcg/mL.

Figure 7

Probability of Achieving AUC/MIC ≥ 400 based on Serum Creatinine using Monte Carlo Simulation for Vancomycin 60 mg/kg/day. Distribution of minimum inhibitory concentration from Hospital B with 68% of methicillin-resistant S. aureus isolates ≤ 1 and 32% isolates > 1 mcg/mL.

Figure 8

Correlation between Area-under-the-Curve and Minimum Concentration by Monte Carlo Simulation for Vancomycin 60 mg/kg/day.