Dose derivation of once-daily dosing guidelines for gentamicin in critically ill pediatric patients.
OBJECTIVE
To determine dose and eligibility criteria for once-daily dosing (ODD) of gentamicin in critically ill pediatric patients.


METHODS
Retrospective chart review of patients admitted to the Pediatric Intensive Care Unit or Cardiac Critical Care Unit at The Hospital for Sick Children (SickKids) who received traditionally dosed intravenous (IV) gentamicin (January 2008 to June 2010). Statistically significant patient characteristics associated with gentamicin pharmacokinetic (PK) parameters were determined by multiple linear regression. Binary partitioning was used to set critical values for these characteristics to derive dose for ODD of gentamicin. Feasibility of implementing ODD of gentamicin in critically ill children was assessed using individualized PK parameters to simulate area under the concentration-time curves and drug-free intervals while targeting a maximum concentration (C(max)) of 16-20 mg/L. Eligibility criteria were determined by patient characteristics that had a statistically significant impact on gentamicin PK.


RESULTS
Volume of distribution (V(d)) and elimination rate constant (k(e)) were calculated for 140 patients. Weight and admission unit were significantly associated with weight-normalized V(d) (Vd/kg), whereas age and serum creatinine (SCr) were significantly associated with k(e). Weight <5 kg and SCr ≥20% over age-specific upper normal limit before gentamicin initiation were associated with prolonged gentamicin elimination. Gentamicin 6 mg/kg IV every 24 hours, the dose at which the highest percentage of patients achieved C(max), area under the curve, and drug-free interval within target ranges simultaneously, was selected as the proposed ODD regimen.


CONCLUSIONS
A regimen of gentamicin 6 mg/kg IV every 24 hours for Pediatric Intensive Care Unit/Cardiac Critical Care Unit patients at SickKids weighing ≥5 kg with SCr <20% above age-specific upper normal limit before initiation of gentamicin is proposed.
*Division of Oncology and Hematology, Department of Pharmacy, and †Critical Care Unit, Department of Pharmacy, The Hospital for Sick Children; ‡Biostatistics Department, Princess Margaret Cancer Program, University Health Network; and §Department of Communication Disorders, ¶Division of Infectious Diseases, Department of Infectious Diseases, ‖Department of Pediatric Laboratory Medicine, **Department of Critical Care Medicine, and ††Child Health Evaluative Services, Department of Critical Care Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
Maria
M
Zakova
Sandra
S
Pong
Angela
A
Trope
Eshetu G
EG
Atenafu
Vicky
V
Papaioannou
Sean Ari
SA
Bitnun
Susan
S
Richardson
Steven
S
Schwartz
Peter
P
Cox
Christopher
C
Parshuram
Winnie
W
Seto
D061605:Administration, Intravenous; D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D004334:Drug Administration Schedule; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006776:Hospitals, Pediatric; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D012189:Retrospective Studies; D055815:Young Adult
D000900:Anti-Bacterial Agents; D005839:Gentamicins