Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates
Authors: Ramos-Martin R , Johnson A, Livermore J, et al.
Published in: J Antimicrob Ther 2016;71(4):992-1002
Objectives CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin
pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin
pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage
Methods A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS
infections were developed. The results were then bridged to neonates by use of population pharmacokinetic
techniques and Monte Carlo simulations.
Results There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels.
The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg.h/L. Simulations predicted that neonates, 29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups.
Conclusions The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and
resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical
use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance.
This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to
take into a randomized controlled trial