Dose derivation of once-daily dosing guidelines for gentamicin in critically ill pediatric patients
Maria Zakova1, Sandra Pong, Angela Trope
1*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.
Insights
A new gentamicin dosing strategy of 6 mg/kg intravenously every 24 hours is proposed for critically ill pediatric patients. This regimen aims to optimize gentamicin therapy and improve patient outcomes in intensive care settings.
Area of Science:
- Pediatric Critical Care Medicine
- Pharmacokinetics and Pharmacodynamics
- Antibiotic Dosing Optimization
Background:
- Critically ill pediatric patients require optimized gentamicin dosing for effective treatment and reduced toxicity.
- Traditional gentamicin dosing may not be suitable for all critically ill children due to variable pharmacokinetic parameters.
Purpose of the Study:
- To establish an appropriate dose and eligibility criteria for once-daily dosing (ODD) of gentamicin in critically ill pediatric patients.
- To ensure therapeutic gentamicin concentrations and minimize adverse effects through optimized dosing.
Main Methods:
- Retrospective chart review of 140 pediatric patients in intensive care units receiving intravenous gentamicin.
- Multiple linear regression and binary partitioning to identify patient characteristics influencing gentamicin pharmacokinetics (Vd, ke).
- Simulation of area under the concentration-time curves and drug-free intervals to determine optimal ODD regimen and eligibility criteria.
Main Results:
- Weight and admission unit significantly impacted gentamicin volume of distribution (Vd/kg).
- Age and serum creatinine (SCr) significantly influenced gentamicin elimination rate constant (ke).
- A gentamicin dose of 6 mg/kg IV every 24 hours was identified as the optimal ODD regimen, achieving target pharmacokinetic goals in the highest percentage of patients.
Conclusions:
- A gentamicin regimen of 6 mg/kg IV every 24 hours is proposed for critically ill pediatric patients.
- Eligibility criteria include a weight of ≥5 kg and SCr <20% above the age-specific upper normal limit prior to gentamicin initiation.
- This ODD regimen aims to improve gentamicin efficacy and safety in the Pediatric Intensive Care Unit and Cardiac Critical Care Unit settings.
Objectives:
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.
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