title: Coagulase negative staphylococcal sepsis in neonates: do we need to adapt vancomycin dose or target?
abstract: Despite differences in types of infection and causative organisms, pharmacokinetic-pharmacodynamic (PKPD) targets of vancomycin therapy derived from adult studies are suggested for neonates. We aimed to identify doses needed for the attainment of AUC/MIC > 400 and AUC/MIC > 300 in neonates with sepsis and correlate these targets with recommended doses and treatment outcome.
  
  
  
  Neonates who had Vancomycin therapeutic drug monitoring (TDM) performed between January 1, 2010 and December 31, 2012 were studied. Clinical characteristics, episodes of Gram-positive sepsis with outcomes and all neonatal blood culture isolates in hospital were collected from medical records. To estimate probability of target attainment of AUC/MIC >400 and AUC/MIC >300 a 1000-subject Monte Carlo simulation was performed by calculating AUC using Anderson's (Anderson et al. 2006) and TDM trough concentrations (Ctrough) based population PK models.
  
  
  
  Final dataset included 76 patients; 57 with confirmed Gram-positive sepsis. TDM was taken after the 1stto 44thdose. 84.1% of Ctroughwere within the range 5-15 mg/L. Currently recommended doses achieved probability of the targets (PTA) of AUC/MIC >400 and AUC/MIC >300 in less than 25% and 40% of cases, respectively. Doses required for 80% PTA of AUC/MIC > 400 for MIC ≥2 mg/L resulted in Ctroughvalues ≥14 mg/L. Mean AUC/MIC values were similar in treatment failure and success groups.
  
  
  
  With currently recommended vancomycin dosing the therapeutic target of AUC/MIC > 400 is achieved only by 25% of neonates. Appropriate PKPD targets and respective dosing regimens need to be defined in prospective clinical studies in this population.
authors.affiliation: Pediatric and Neonatal Intensive Care Unit, Tartu University Hospital, 1a L. Puusepa street, 50406, Tartu, Estonia. helgi.padari@kliinikum.ee.
authors.forename: Helgi
authors.identifier: 0000-0003-4935-2712
authors.initials: H
authors.lastname: Padari
authors.affiliation: Hematology and Oncology Clinic, Tartu University Hospital, Tartu, Estonia.
authors.forename: Kersti
authors.initials: K
authors.lastname: Oselin
authors.affiliation: Institute of Copmuter Science, University of Tartu, Tartu, Estonia.
authors.forename: Tõnis
authors.initials: T
authors.lastname: Tasa
authors.affiliation: Pediatric and Neonatal Intensive Care Unit, Tartu University Hospital, 1a L. Puusepa street, 50406, Tartu, Estonia.
authors.forename: Tuuli
authors.initials: T
authors.lastname: Metsvaht
authors.affiliation: Department of Clinical Microbiology, United Laboratories of Tartu University Hospital, Tartu, Estonia.
authors.forename: Krista
authors.initials: K
authors.lastname: Lõivukene
authors.affiliation: Institute of Microbiology, University of Tartu, Tartu, Estonia.
authors.forename: Irja
authors.initials: I
authors.lastname: Lutsar
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D003030:Coagulase; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D016896:Treatment Outcome; D014640:Vancomycin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D003030:Coagulase; D014640:Vancomycin
keywords: Neonate; Pharmacokinetics; Population pharmacokinetics; Vancomycin