High-dose gentamicin in newborn infants: is it safe?

Abstract

Dosing regimens often recommend lower gentamicin doses in neonates (3-5 mg/kg) than in older children (7 mg/kg or more) despite the higher volume of distribution in neonates. We studied an extended-interval high-dose (6 mg/kg) gentamicin regimen in a single tertiary neonatal unit from 2004-2012. During the first week of life, dosing interval was 24 h for term infants, 36 h for preterm infants with gestational age (GA) 29-36 weeks and 48 h for preterm infants with GA <29 weeks. After the first week of life, dosing interval was 24 h if corrected age (GA + postnatal age) ≥29 weeks and 36 h if corrected age <29 weeks. Outcome measures were trough plasma concentration (TPC), ototoxicity and prescription errors. In 546 treatment episodes, TPC was measured prior to the third gentamicin dose. There were 37 episodes (6.7 %) of prescription errors, mainly a too long dosing interval. We included 509 treatment episodes (440 infants) in the final analysis. Mean (standard deviation) gentamicin TPC during the first week of life was 1.1 (0.5) mg/L and after the first week of life 0.8 (0.6) mg/L. In 31 (6 %) episodes, TPC was ≥2.0 mg/L, predominantly among term infants with renal impairment. Thirty-eight patients failed the neonatal hearing screening, but only four of these 38 had permanent hearing loss. All four had a TPC <2.0 mg/L. Conclusions: This extended-interval high-dose gentamicin regimen was associated with low numbers of elevated TPCs, low numbers of prescription errors and no evidence for ototoxicity.

Can we optimize antibiotic use in Norwegian neonates? A prospective comparison between a university hospital and a district hospital

“…The difference in the doses of aminoglycosides in term infants is explained by different local guideline recommendations at the hospitals. We did not register any switch of aminoglycoside doses in term infants during the same course, and one study showed that aminoglycosides safely can be dosed 6 mg/kg every 24 h in term born infants (22). The higher number (mean) of daily administrations with ampicillin at the DH may be explained by the recommendation in a commonly used local Norwegian neonatal supervisor to increase the number of administrations from two up to four per day in severe infections/meningitis (23).…”

Stochastic Process Pharmacodynamics: Dose Timing in Neonatal Gentamicin Therapy as an Example

“…Prolonged or repeated concentrations above a certain value (6×MIC is one estimate) are also usually deprecated. However it has been argued that a single high peak which decays rapidly may perhaps not be too dangerous, due to saturation effects in drug uptake for both ear and kidney (4,25,36). Comparing with Tables I and II indicates that the high initial doses needed to achieve high predicted values of E F , especially doses of 6 mg/kg or more which are used only rarely for neonates (36), are as yet neither unambiguously safe nor unambiguously ruled out by toxicity constraints.…”

“…Clinical guidelines for neonates vary (4,25,30,31,35,36). Guidelines often specify that free drug concentration in the central compartment should include frequent or prolonged troughs<MIC (=2 mg/L) during the first week, which our extreme examples (e.g.…”

“…If mathematically predicted concentration troughs<MIC (36) and E F >50% are taken as goals (see caveats above), there are implications for front boosting. Examples of modelpredicted front boosting advantage include many cases like the contrast between the single 5 mg/kg dose in Table I row 14 and higher-total-dose regimens (rows 2, 8-11) which lead to smaller E F , despite also having at least one dose at least as large as 5 mg/kg and having higher concentration troughs.…”

The hearing function in the premature children following their treatment with the use of ototoxic antibiotics

“…Непрохождение скринингового аудиологического теста у недоношенных детей, принимавших ототоксические антибиотики, по данным различных авторов, колеблется от 8 до 22% [3,4]. Значительный разброс в результатах может быть связан как с разницей в выборках, сроках первичного аудиологического обследования, принятых в различных стационарах мира, так и с использованием различных антибактериальных препаратов.…”