title: Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates.
abstract: OBJECTIVE
  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 regimens.
  
  
  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.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: V
authors.initials: V
authors.lastname: Ramos-Martín
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: A
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: J
authors.initials: J
authors.lastname: Livermore
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: L
authors.initials: L
authors.lastname: McEntee
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: J
authors.initials: J
authors.lastname: Goodwin
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: S
authors.initials: S
authors.lastname: Whalley
authors.affiliation: Department of Microbiology, Universidad de Sevilla, Seville, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Docobo-Pérez
authors.affiliation: University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.
authors.forename: T W
authors.initials: TW
authors.lastname: Felton
authors.affiliation: Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France.
authors.forename: W
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Jacqz-Aigrain
authors.affiliation: Paediatric Infectious Diseases Unit, St George's Hospital, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Sharland
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Turner
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK william.hope@liverpool.ac.uk.
authors.forename: W W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D000465:Algorithms; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D009010:Monte Carlo Method; D000071074:Neonatal Sepsis / Q000188:drug therapy* / Q000209:etiology; D011817:Rabbits; D013203:Staphylococcal Infections; D013210:Staphylococcus / Q000187:drug effects / Q000235:genetics; D014640:Vancomycin / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin