Gentamicin is commonly used in neonates with hypoxic ischemic enchepalopathy (HIE) for
the empiric treatment of presumed infection. The drug displays concentration-dependent
killing and clinical response is associated with the ratio of the peak concentration over the
MIC (peak/MIC).1,2 However, prolonged high drug concentrations are associated with
nephrotoxicity and therapeutic drug monitoring (TDM) is routinely performed to document
drug clearance. Every 24-hour dosing of gentamicin in full-term neonates takes advantage of
these drug properties and is superior to multiple-daily dosing in terms of achievement of
higher peak concentrations and lower trough concentrations.3
In neonates with HIE, gentamicin pharmacokinetics may be altered. Gentamicin is
eliminated almost exclusively by glomerular filtration4 and neonates with HIE often have
acute kidney dysfunction.5–9 In addition, hypothermia—an effective treatment modality for
HIE10—may cause additional alterations in organ physiology and blood flow that impact
drug pharmacokinetics.11 But, in a recent clinical study of hypothermic versus
normothermic neonates with HIE, both groups had similar trough concentrations, suggesting
little effect of hypothermia on gentamicin pharmacokinetics. However, both groups
frequently had elevated trough concentrations >2 mg/L when receiving gentamicin 4-5 mg/
kg every 24 hours (44% of normothermic and 36% of hypothermic).12 This highlights the
need for a potential alternative dosing of gentamicin in the neonate with HIE. Given that
hypothermia is now recommended as the standard of care for moderate to severe HIE,13 an
understanding of gentamicin pharmacokinetics in the clinical context of hypothermia will be
necessary to help guide dose selection in this population. The objectives of this study were
1) to evaluate the pharmacokinetics of gentamicin in neonates with HIE receiving
hypothermia using a population-based approach and 2) to identify an empiric gentamicin
dosing strategy that optimizes achievement of target peak and trough drug concentrations.
Gentamicin is commonly used in neonates with hypoxic ischemic enchepalopathy (HIE) forthe empiric treatment of presumed infection. The drug displays concentration-dependentkilling and clinical response is associated with the ratio of the peak concentration over theMIC (peak/MIC).1,2 However, prolonged high drug concentrations are associated withnephrotoxicity and therapeutic drug monitoring (TDM) is routinely performed to documentdrug clearance. Every 24-hour dosing of gentamicin in full-term neonates takes advantage ofthese drug properties and is superior to multiple-daily dosing in terms of achievement ofhigher peak concentrations and lower trough concentrations.3In neonates with HIE, gentamicin pharmacokinetics may be altered. Gentamicin iseliminated almost exclusively by glomerular filtration4 and neonates with HIE often haveacute kidney dysfunction.5–9 In addition, hypothermia—an effective treatment modality forHIE10—may cause additional alterations in organ physiology and blood flow that impactdrug pharmacokinetics.11 But, in a recent clinical study of hypothermic versusnormothermic neonates with HIE, both groups had similar trough concentrations, suggestinglittle effect of hypothermia on gentamicin pharmacokinetics. However, both groupsfrequently had elevated trough concentrations >2 mg/L when receiving gentamicin 4-5 mg/kg every 24 hours (44% of normothermic and 36% of hypothermic).12 This highlights theneed for a potential alternative dosing of gentamicin in the neonate with HIE. Given thathypothermia is now recommended as the standard of care for moderate to severe HIE,13 anunderstanding of gentamicin pharmacokinetics in the clinical context of hypothermia will benecessary to help guide dose selection in this population. The objectives of this study were1) to evaluate the pharmacokinetics of gentamicin in neonates with HIE receivinghypothermia using a population-based approach and 2) to identify an empiric gentamicindosing strategy that optimizes achievement of target peak and trough drug concentrations.
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