Pharmacodynamics of vancomycin in children
Frank Kloprogge(1,2), Louise Hill(2,3), John Booth(2,4), Adam Irwin(2,4), Garth Dixon(2,4) and Joseph Standing(2,4)
(1) UCL School of Pharmacy, London, UK (2) UCL Institute of Child Health, London, UK (3) Division of Medicine, St Georges Hospital, London, UK (4) Great Ormond Street Hospital, London, UK
Objectives: The European Medicines Agency is currently updating product information of vancomycin, including investigating its appropriate dosing and monitoring in children [1]. Vancomycin is used to treat serious Gram-positive infections resistant to other antibiotics. It is a narrow therapeutic index drug requiring therapeutic drug monitoring after intravenous administration. Initial paediatric dosing schedules are based on extrapolations from adults which might result in sub-optimal exposures (AUC's). The aim of this study was to explore pharmacodynamic targets for vancomycin in a paediatric population.
Methods: Using a nonlinear mixed-effects model vancomycin plasma concentration-time profiles from a large retrospective database were analysed. The vancomycin exposure threshold (unbound vancomycin AUC/MIC at day one) associated with an increased chance of treatment failure was identified using Classification And Regression Tree (CART) analysis, which was a similar procedure as previously performed in an adult population [2]. Moreover, an investigation into whether unbound vancomycin exposure at day one was correlated with c-reactive protein (CRP) levels was undertaken.
Results: The pharmacokinetic model was developed using data from 596 patients (age range: 0.03-255 months body-weight range: 1.75-95.0 kg) and adequately described Vancomycin exposure. For 72 of the patients (age range: 0.32-205 months body-weight range: 0.742 - 76 kg) also clinical MIC's of invasive blood stream isolates were available from a variety of Gram-positive bacteria. The CART analysis indicated that children below 1.7 years of age had an increased risk (RR: 0.61 [0.426-0.885] treatment failure. Children younger than 1.7 years of age required a non-significant 10% higher dose as compared to children above 1.7 years of age. Serial CRP data were available for 139 patient. Among these patients six patients also had MIC data, which made it impossible to perform hypothesis testing on the correlation between vancomycin exposure and CRP.
Conclusions: Approximately 10 percent had a blood isolate highlighting the difficulty of running clinical pharmacokinetic-pharmacodynamic trials in children. The sample size will be increased by inclusion of data from other hospitals in order to determine a robust pharmacodynamic threshold. In parallel, the most clinically relevant endpoint is being defined in collaboration with clinicians to produce meaningful in-silico dose optimizations.
References:
[1] EMA/222696/2016, Review of vancomycin-containing medicines started, 1 April 2016 (http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Vancomycin_31/WC500204131.pdf)
[2] Lodise et al, Vancomycin Exposure in Patients With Methicillin-Resistant Staphylococcus aureus Bloodstream Infections: How Much Is Enough?, 2014, CID, 2014:59