Abstract
BackgroundAlthough aminoglycosides are routinely used in neonates, controversy exists regarding empiric dosing regimens. The objectives were to determine gentamicin pharmacokinetics in neonates, and develop initial mg/kg dosing recommendations that optimized target peak and trough concentration attainment for conventional and extended-interval dosing (EID) regimens.MethodsPatient demographics and steady-state gentamicin concentration data were retrospectively collected for 60 neonates with no renal impairment admitted to a level III neonatal intensive care unit. Mean pharmacokinetics were calculated and multiple linear regression was performed to determine significant covariates of clearance (L/h) and volume of distribution (L). Classification and regression tree (CART) analysis identified breakpoints for significant covariates. Monte Carlo Simulation (MCS) was used to determine optimal dosing recommendations for each CART-identified sub-group.ResultsGentamicin clearance and volume of distribution were significantly associated with weight at gentamicin initiation. CART-identified breakpoints for weight at gentamicin initiation were: ≤ 850 g, 851-1200 g, and > 1200 g. MCS identified that a conventional dose of gentamicin 3.5 mg/kg given every 48 h or an EID of 8-9 mg/kg administered every 72 h in neonates weighing ≤ 850 g, and every 24 and 48 h, respectively, in neonates weighing 851-1200 g, provided the best probability of attaining conventional (peak: 5-10 mg/L and trough: ≤ 2 mg/L) and EID targets (peak:12-20 mg/L, trough:≤ 0.5 mg/L). Insufficient sample size in the > 1200 g neonatal group precluded further investigation of this weight category.ConclusionsThis study provides initial gentamicin dosing recommendations that optimize target attainment for conventional and EID regimens in neonates weighing ≤ 1200 g. Prospective validation and empiric dose optimization for neonates > 1200 g is needed.
Highlights
Aminoglycosides are routinely used in neonates, controversy exists regarding empiric dosing regimens
Neonates were excluded if they developed acute renal failure before or during gentamicin therapy, had an increase in Serum creatinine (sCr) > 25% from baseline during treatment, or had a calculated gentamicin half-life > two standard deviations (SDs) from the mean half-life observed in the study population following data analysis, without the availability of an additional set of serum concentrations to confirm the accuracy of this calculated half-life
Gentamicin was most commonly used for the treatment of culture negative sepsis (30/60; 50%)
Summary
Aminoglycosides are routinely used in neonates, controversy exists regarding empiric dosing regimens. In adult and older pediatric populations, EID regimens targeting peak concentrations of ≥ 20 mg/L are routinely recommended based on data suggesting that aminoglycoside activity is optimized with peak: minimum inhibitory concentration (MIC) ratios of 8–10:1 [3,4,5]. For these patient populations, EID has consistently demonstrated equal efficacy, and equal or reduced toxicity versus conventional dosing [1, 6,7,8,9,10]. Since aminoglycoside pharmacokinetic (PK) parameters in neonates may be influenced by weight [15, 18,19,20, 28, 29], gestational age [15, 28, 29] and postnatal age [19, 28, 29], further research is required in this unique population in order to optimize target attainment and thereby, maximize the probability of efficacy of the antibiotic while minimizing the risk of nephrotoxicity
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