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Evaluation of an empirical dosing schedule for gentamicin in neonates
M R Bloome1, A J Warren, L Ringer
1Department of Pharmacy Services, Henry Ford Hospital, Detroit, MI 48202.
Abstract:
The standard gentamicin dosing recommendations for neonates appear to be inappropriate because they fail to consider the influence of neonatal development on gentamicin pharmacokinetics. Recent reports have emphasized that the standard regimens of 2.5 mg/kg q8-12h produce steady-state trough serum concentrations greater than 2 micrograms/ml in up to 91 percent of preterm infants of less than 35 weeks' gestation. A new dosing schedule based on postconceptional age (PCA) was developed to provide a better guideline for initiating and maintaining gentamicin therapy in neonates: PCA greater than 34 weeks, 2.5 mg/kg iv q12h; PCA 28-34 weeks, 2.5 mg/kg iv q16h; PCA less than 28 weeks, 2.5 mg/kg iv q24h. The new dosing schedule reduced the number of neonates with elevated trough concentrations (greater than 2 micrograms/ml) from 68.4 percent to 33-40 percent. Pharmacokinetic parameters for gentamicin in the various PCA groups were determined. Volume of distribution was constant across age groups (0.5 +/- 0.09 L/kg). Elimination rate constants (kel), half-lives, and clearance rates (Cl) ranged from 0.069 +/- 0.02 to 0.14 +/- 0.04 h-1, 10.71 +/- 2.92 to 6.04 +/- 1.24 h, and 0.58 +/- 0.25 to 0.93 +/- 0.24 ml/kg/min, respectively. Significant relationships were found between kel and Cl and patient age and weight; significant correlations were found between actual and estimated (based on PCA and weight) kel and Cl. Variability in kel and Cl estimated was considerable in spite of the correlations. The observed variability stresses again the need for pharmacokinetic monitoring of gentamicin therapy in neonates.
Insights
Standard gentamicin dosing for neonates is often too high, leading to toxicity. A new schedule based on postconceptional age (PCA) significantly reduces elevated drug levels in preterm infants, improving safety.
Area of Science:
- Neonatal Pharmacology
- Pediatric Infectious Diseases
Background:
- Standard gentamicin dosing regimens in neonates may be inappropriate due to developmental changes affecting pharmacokinetics.
- High trough serum concentrations (greater than 2 micrograms/ml) are observed in up to 91% of preterm infants (<35 weeks' gestation) with current standard regimens.
Purpose of the Study:
- To evaluate a new gentamicin dosing schedule for neonates based on postconceptional age (PCA).
- To determine if the new schedule reduces the incidence of elevated gentamicin trough concentrations.
Main Methods:
- A new dosing schedule was developed: PCA >34 weeks (2.5 mg/kg q12h), PCA 28-34 weeks (2.5 mg/kg q16h), PCA <28 weeks (2.5 mg/kg q24h).
- Pharmacokinetic parameters (volume of distribution, elimination rate constants, half-lives, clearance rates) were determined for different PCA groups.
- Correlations between estimated and actual pharmacokinetic parameters based on PCA and weight were analyzed.
Main Results:
- The new PCA-based dosing schedule reduced elevated trough concentrations from 68.4% to 33-40%.
- Volume of distribution remained constant across age groups (0.5 +/- 0.09 L/kg).
- Elimination rate constants, half-lives, and clearance rates varied significantly with PCA and weight, showing correlations with estimated values but considerable variability.
Conclusions:
- A gentamicin dosing schedule adjusted for postconceptional age improves therapeutic drug monitoring in neonates.
- Despite correlations, significant variability in gentamicin pharmacokinetics necessitates ongoing therapeutic drug monitoring in neonates.