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Evaluation of Vancomycin Use in Late-Onset Neonatal Sepsis Using the Area Under the Concentration–Time Curve to the Minimum Inhibitory Concentration ≥400 Target

Bhongsatiern (JJ), Jiraganya MSc (Pharm)*; Stockmann, Chris MSc†,‡; Roberts, Jessica K. PhD, MSCI; Yu, Tian PhD; Korgenski, Kent E. MS, MT (ASCP)§; Spigarelli, Michael G. MD, PhD†,‡; Desai, Pankaj B. PhD*; Sherwin, Catherine M. T. PhD, FCP

doi: 10.1097/FTD.0000000000000216
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Aim: To develop a vancomycin population pharmacokinetic model and assess the probability of attaining a pharmacodynamic target associated with clinical and microbiological success, a ratio of the 24-hour area under the concentration–time curve to the minimum inhibitory concentration (MIC) ≥ 400, in a 5-year clinical cohort of preterm and term neonatal patients with late-onset staphylococcal sepsis.

Methods: Therapeutic drug monitoring data were obtained from septic neonates with ≥1 vancomycin concentration(s) from January 2006 to September 2011. Only neonates with a postnatal age of >72 hours and a positive microbiological culture were included. Population pharmacokinetic model was developed using nonlinear mixed effects modeling (NONMEM 7.2). Eleven demographic characteristics were evaluated as covariates. Probabilities of achieving the pharmacodynamic target were evaluated.

Results: A 1-compartment model with first-order elimination was constructed from 528 vancomycin concentrations collected from 152 preterm and term neonates. Body weight, creatinine clearance (CL), and postmenstrual age were identified as significant covariates. Estimated vancomycin CL and volume of distribution for typical neonates were 0.068 ± 0.03 L·h−1·kg−1 and 0.62 ± 0.13 L/kg, respectively. Coagulase-negative staphylococci (85.5%) and Staphylococcus aureus (14.5%) were the common pathogenic organisms. The distribution of vancomycin MIC breakpoints was composed of approximately 70% MIC breakpoint of ≤2 mcg/mL. Approximately 54% of neonates, with a median serum creatinine concentration of 0.44 mg/dL, achieved the target ratio of 24-hour area under the concentration–time curve to the MIC ≥ 400 with a median daily dose of 30 (interquartile range, 21–42) mg/kg.

Conclusions: Body weight, creatinine CL, and postmenstrual age significantly influenced vancomycin CL. The current vancomycin doses are acceptable at MICs ≤1 mcg/mL because they are likely to achieve the pharmacodynamic target in the majority of neonatal patients, although higher doses may be considered for more resistant staphylococcal infections.

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*Department of Pharmaceutical Sciences, The James L. Winkle College of Pharmacy, University of Cincinnati, Ohio;

Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine;

Department of Pharmacology and Toxicology, University of Utah College of Pharmacy; and

§Intermountain Healthcare, Pediatric Clinical Program, Salt Lake City, Utah.

Correspondence: Catherine M. T. Sherwin, PhD, FCP, Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT 84108 (e-mail: Catherine.sherwin@hsc.utah.edu).

All authors have completed the Authorship Responsibility, Financial Disclosure, and Copyright Transfer form at http://edmgr.ovid.com/tdm/accounts/copyrightTransfer.pdf and declare: J. J. J. Bhongsatiern was supported by the William J. Fulbright Scholarship Board; the International Fulbright Science and Technology Award; C. Stockmann is supported by the American Foundation for Pharmaceutical Education; J. K. Roberts is supported by the Pharmacotherapy Subspecialty Award from the Primary Children's Hospital Foundation. No financial relationships with any organization that might have an interest in the submitted work. No other relationships or activities that could appear to have influenced the submitted work. No funding was provided to assist in the preparation of this research article.

The authors declare no conflict of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com).

Received February 12, 2015

Accepted April 18, 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.