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Improved Vancomycin Dosing in Children Using Area Under the Curve Exposure

Le, Jennifer PharmD, MAS, FCCP, BCPS-ID*†; Bradley, John S. MD*‡; Murray, William PharmD; Romanowski, Gale L. PharmD; Tran, Tu T. PharmD; Nguyen, Natalie PharmD*; Cho, Susan PharmD*; Natale, Stephanie PharmD; Bui, Ivilynn BS; Tran, Tri M. BS (Candidate); Capparelli, Edmund V. PharmD*

Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e318286378e
Antimicrobial Reviews
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 * Wt0.75 * (0.48/serum creatinine)0.361 * (ln(age)/7.8)0.995 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.

Author Information

From the *University of California San Diego, La Jolla; Miller Children’s Hospital, Long Beach; and Rady Children’s Hospital of San Diego, San Diego, CA.

Accepted for publication 4, 2013.

This work was presented as an oral presentation at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy on September 20, 2011, in Chicago, IL.

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.

The project described was supported by Grant Number K23AI089978 to J.L. from the National Institute of Allergy And Infectious Diseases; U54HD071600 to E.V.C. from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; T35 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to N.N.; and research stipend from the Skaggs School of Pharmacy and Pharmaceutical Sciences to S.C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health. The authors have no other funding or conflicts of interest to disclose.

Address for correspondence: Jennifer Le, PharmD, MAS, FCCP, BCPS-ID, Associate Professor of Clinical Pharmacy, UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, MC 0714, La Jolla, CA 92093-0714. E-mail: jenle@ucsd.edu.

© 2013 Lippincott Williams & Wilkins, Inc.