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

Jon Widding Fjalstad, Einar Laukli, John

N.van den Anker & Claus Klingenberg

European Journal of Pediatrics

ISSN 0340-6199

Eur J Pediatr
DOI 10.1007/s00431-013-2194-1

1 23
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1 23
 Author's personal copy
Eur J Pediatr
DOI 10.1007/s00431-013-2194-1
ORIGINAL ARTICLE
High-dose gentamicin in newborn infants: is it safe?
Jon Widding Fjalstad & Einar Laukli &
John N. van den Anker & Claus Klingenberg
Received: 4 September 2013 / Accepted: 21 October 2013
# Springer-Verlag Berlin Heidelberg 2013
Abstract Dosing regimens often recommend lower gentami-
cin doses in neonates (35 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
20042012. During the first week of life, dosing interval was
24 h for term infants, 36 h for preterm infants with gestational
age (GA) 2936 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 er-
rors. 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
J. W. Fjalstad : C. Klingenberg
Paediatric Research Group, Faculty of Health Sciences,
University of Troms, Troms, Norway
E. Laukli
Department of Ear, Nose and Throat, University Hospital of North
Norway, Troms, Norway
J. N. van den Anker
Division of Paediatric Clinical Pharmacology, Childrens National
Medical Center, Washington, DC, USA
J. N. van den Anker
Intensive Care and Department of Paediatric Surgery, Erasmus
MC-Sophia Childrens Hospital, Rotterdam, The Netherlands
C. Klingenberg (*)
Department of Paediatrics, University Hospital of North Norway,
9038 Troms, Norway
e-mail: claus.klingenberg@unn.no
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.
Keywords Gentamicin . High-dose . Trough plasma
concentration . Ototoxicity . Prescription errors . Neonate
Introduction
Gentamicin, in combination with a beta-lactam antibiotic, is
widely used for treatment of neonatal sepsis [19, 36]. The
bactericidal effect of gentamicin is concentration-dependent.
A high ratio between the peak plasma concentration and the
minimum inhibitory concentration of the infecting microor-
ganism is therefore important for therapeutic response [18,
28]. In contrast, the potential ototoxicity and nephrotoxicity is
thought to be associated with high trough plasma concentra-
tions (TPCs) and a prolonged duration of therapy [3], but
many neonatal studies fail to find proof for this association
[6, 8, 16]. It is commonly suggested for neonates that TPC
should be less than 2 mg/L to minimise potential toxic effects
[24, 25, 33].
Gentamicin is distributed in the extracellular water com-
partment. Neonates, and particularly those born prematurely,
have a proportionally larger volume of distribution than older
children and adults [2, 15, 30]. A higher dose per kilogram is
therefore needed to achieve the same peak concentrations in a
preterm neonate as compared with an older infant or child.
Gentamicin clearance correlates with functional maturation of
the glomerular filtration rate (GFR). The nephrogenesis is
 Author's personal copy
completed by 3435 weeks of gestation, and preterm neonates
have a lower GFR than term neonates [5, 23]. Even in term
neonates, the GFR is low at birth but increases rapidly during
the first week of life with increased renal blood flow and a
decrease in renal vascular resistance [5, 21].
Based on these important pharmacokineticpharmacody-
namic factors, extended-interval gentamicin dosing regimens
for neonates have been developed and are widely used today
[4, 25]. However, many of these dosing regimens do not
differentiate between dosing during the first week of life and
later in the neonatal period. Few studies report ideal adherence
to target TPCs [20]. The British National Formulary for Chil-
dren recommends gentamicin 45 mg/kg every 24 or 36 h for
neonates [24]. However, high TPC (>2 mg/L) is frequently
seen in moderate preterm infants and among infants with
severe perinatal asphyxia when using this dosing regimen
[27]. The Neofax suggests a more complex dosing regimen
with different dosages (45 mg/kg) and intervals depending
on maturation [35]. Complicated dosing regimens may pose a
risk for prescription errors, which again increases the risk of
toxicity [34]. It is also a paradox that most dosing regimens
recommend a lower gentamicin dose per kilogram in neonates
(35 mg/kg) than in older children (7 mg/kg) despite the fact
that neonates have a larger volume of distribution [15].
We previously validated a netilmicin dosing regimen giv-
ing 6 mg/kg every 24 or 36 h, depending on gestational age
(GA) and postnatal age (PNA) [12]. We found mean peak
levels >910 mg/L, but too many potential toxic TPC for
moderate preterm infants [12]. In 2004, we changed our
standard aminoglycoside from netilmicin to gentamicin and
developed a new high-dose extended-interval regimen. We
continued using the same aminoglycoside dose (6 mg/kg) as
pharmacokinetic parameters for netilmicin and gentamicin are
similar [35], but we increased the dosing interval for the more
preterm infants to 48 h. The three major aims for this study
were, based on the 8-year experience with this dosing regi-
men, (1) to evaluate gentamicin TPCs to assess pharmacoki-
netic safety, (2) to assess the potential ototoxicity and (3) to
evaluate the number of prescription errors.
Material and methods
Study design and patients
This is a retrospective single-centre cohort study. The neonatal
intensive care unit at the University Hospital of Northern
Norway in Troms is the only tertiary neonatal unit in the
two most northern counties in Norway covering a population
of 230,000 with around 3,000 births per year. All infants
<34 weeks gestation and all infants receiving mechanical
ventilation in the catchment area are treated in this unit, so
for these infants, our data are population-based. Eligible
Eur J Pediatr
patients, identified from the hospital laboratory database, were
neonates up to 50 weeks of corrected age (GA + PNA) that
had received gentamicin treatment for suspected or proven
infection and had one or more TPCs measured from January
2004 through May 2012. The regional ethical committee
approved the study.
Gentamicin dosing regimen and monitoring
We administered 6 mg/kg gentamicin as a 30-min infusion,
irrespective of GA and PNA. The dosing intervals during the
first week of life were 24 h if GA was 37 weeks (group A),
36 h if GA was 2936 weeks (group B) and 48 h if GA was
<29 weeks (group C). After the first week of life, dosing
intervals were 24 h if corrected age (GA + PNA) was
29 weeks (group D) and 36 h if corrected age was <29 weeks
(group E). TPCs were obtained right before the third dose.
During the study period, two different immunoassays with a
lower limit of detection <0.3 mg/L were used to analyse
gentamicin plasma concentration (2004-09: GENT2, Roche,
Mannheim, Germany, 20102012: CEDIA Gentamicin II
Assay, Microgenics, Passau, Germany). An internal validation
showed a good correlation between both methods.
Data collection
Two of the authors (JF and CK) reviewed the medical records
of all patients. We registered background data (sex, age,
weight, diagnoses and complications incl. acute renal failure)
and gentamicin TPC. We took extra care to assess medical
staff prescription and evaluated whether dosing (milligrams
per kilogram) and dosing intervals were in line with dosing
protocol. We evaluated nursing staff administration, and for
this study, we defined that a dose given >3 h earlier or later
than scheduled was an administration error.
Audiology assessment
Before discharge, all infants were screened for ototoxicity by a
transient-evoked otoacoustic emission (OAE) test (Madsen,
AccuScreen, GN Otometrics, Denmark). Prior to 2007, a risk-
based screening approach was used, including all neonates
treated with gentamicin. Since January 2007, OAE has been
implemented as a universal screening test of all newborn
infants. Patients who failed OAE screening had an automatic
auditory brainstem response test as first follow-up test. Further
follow-up was then individualised in the audiology unit. We
carefully reviewed data on hearing for all patients referred for
follow-up. An experienced audiologist (EL) reassessed all
cases with possible persistent hearing problems. To ensure
that no patients with severe ototoxicity were missed, the
audiologist also identified all children who went on to have
hearing aids or cochlear implants and were born during the
 Author's personal copy
Eur J Pediatr
audit period. Furthermore, all patient at risk for neurological
sequelae (GA <32 weeks/birth weight <1,500 g and severe
perinatal asphyxia) were seen at regular intervals in the out-
patient clinic up to 2 years of age, and sensory impairment was
recorded.
Statistics
Data were analysed using IBM-SPSS (version 20.0) statistical
software. Gentamicin TPCs <0.3 mg/L were assigned a value
of 0.2 mg/L. Descriptive results are expressed as mean (stan-
dard deviation (SD)) or median (interquartile range (IQR)), as
appropriate. A p value<0.05 was considered significant.
Results
There were 2,247 infants admitted to the neonatal unit during
the 8-year study period, and 315 infants were discharged with
a diagnosis of culture-positive (n =55) or culture-negative
(n =260) neonatal sepsis. We identified 546 treatment epi-
sodes from 457 neonates who had one or more gentamicin
TPC registered. There were 37 episodes (37/546; 6.7 %) of
incorrect medical staff prescription, which were excluded
from final analyses on TPC and ototoxicity. We included a
total of 509 treatment episodes (three doses gentamicin)
belonging to 440 patients; 395 patients received one, 36
patients received two and 9 patients received 3 separate treat-
ment episodes. For the whole study population, the mean (SD)
GA was 36.4 (5.3)weeks and the mean (SD) birth weight was
2,739 (1,326)gram. There were 85 (19 %) patients with a very
low birth weight (<1,500 g) and 61 patients (14 %) with GA
<29 weeks.
Table 1 shows population and outcome data among the
different treatment groups. Patients in groups D and E were
predominantly preterm infants with suspected or proven epi-
sodes of late onset sepsis. Many of these patients had already
received gentamicin treatment during the first week of life. We
decided to include these patients when describing population
data of infants treated after first week of life clearly aware of
the fact that 33 of 118 patients in groups D and E were already
included in groups AC.
The mean (SD) gentamicin TPC for all treatment episodes
during the first week of life was 1.1 (0.5)mg/L and after first
week of life 0.8 (0.6)mg/L. Table 2 and Fig. 1 show pharma-
cokinetic data on all 509 treatment episodes, divided by the
five treatment groups. We observed a potential toxic TPC
(2.0 mg/L) in 31/509 (6.1 %) treatment episodes. Of these,
22 were observed in group A and predominantly in children
with perinatal asphyxia (n =13) or renal failure of other rea-
sons including congenital renal malformations (n =4).
Thirty-eight of 440 patients (8.6 %) failed the OAE screen-
ing before discharge and were referred for follow-up in the
audiology unit. Seventeen had normal hearing on the first
follow-up. Another 17 patients were diagnosed with middle
ear problems but did not have any confirmed sensorineural
hearing loss later. Four patients who failed their OAE test were
suspected to have permanent hearing loss, and one additional
patient who passed the OAE test later received a cochlear
implant. Two of these five patients probably have small uni-
lateral hearing losses, two received hearing aids and one
received a cochlear implant (Table 3). Only 1 out of 31
patients with a TPC 2.0 mg/L suffered a permanent hearing
loss. This patient, diagnosed with a congenital cytomegalovi-
rus (CMV) infection, was the one who initially passed the
OAE test but later developed severe hearing loss and received
a cochlear implant.
Thirty-one of 37 treatment episodes with medical staff
prescription errors involved ordering a 12-h too long interval.
Mean (SD) TPC among these was 0.6 (0.4)mg/L, and none
had a TPC 2.0 mg/L. Six treatment episodes were prescribed
with too short intervals (12 h). Mean (SD) among these was
1.5 (0.9)mg/L, and in two episodes, TPC was 2.0 mg/L
(33 %). Due to obviously lower/higher TPCs in episodes with
wrong dosing intervals compared to those with correct dosing
interval, we found it correct to exclude these 37 episodes in the
final analyses.
We identified 81/509 (16 %) episodes with nursing staff
errors regarding timing of administration. Gentamicin was
administered too late in 59 episodes (mean (SD) TPC, 0.9
(0.4)mg/L) and too early in 22 episodes (mean (SD) TPC, 1.0
(0.5)mg/L). The TPCs in these 81 episodes were within the
range and not statistically different than the other 428 episodes
(mean (SD) TPC, 1.0 (0.6)mg/L). We decided to include these
81 episodes in the final analyses as we considered they reflect
normal deviations in a busy neonatal unit.
Discussion
This clinical study is to our knowledge the largest study ever
to analyse an extended-interval gentamicin dosing regimen in
neonates over a wide range of GA, including a large number
of patients after the first week of life. All infants included
received at least two doses of gentamicin. We found that 6 %
of all treatment episodes had a TPC 2 mg/l, a proportion
similar or lower than most comparable studies [11, 14, 20, 27].
Two studies report even lower rates of potential toxic TPCs
[10, 29]. Hansen and co-workers administered gentamicin
every 24 h and gave a lower dose to preterm infants <35 weeks
(3 mg/kg) than to term and near-term infants (4 mg/kg) [9]. In
their study, no patients had a TPC >2.0 mg/L, but >20 % of the
preterm infants had peak levels <6 mg/L. The Christchurch
dosing protocol [4, 29] has complex dosing equations based
on birth weight, leading to higher dose (milligrams per kilo-
gram) and longer intervals (up to 60 h) for infants with the
 Author's personal copy
Eur J Pediatr

Table 1 Gentamicin treatment groups, population data and audiology assessment

Group A Group B Group C Group D Group E

PNA 07 days PNA 07 days PNA 07 days PNA >7 days PNA >7 days
GA >36 weeks GA 2936 weeks GA <29 weeks CA 29 weeks CA <29 weeks

Dosing intervals Every 24 h Every 36 h Every 48 h Every 24 h Every 36 h

Treatment episodes (n) 250 61 48 138 12
First treatment in this treatment group 247 60 48 107 11
Patients (n) 247 60 48 83 2
GA (weeks) 39.9 (1.3) 32.6 (2.3) 26.0 (1.5) 33.9 (5.7) 24.1 (1.0)
CA (weeks) 38.0 (5.6) 26.5 (1.2)
BW (g) 3668 (630) 2087 (751) 790 (196) 2403 (1301) 661 (140)
Failed OAE 7 (3 %) 8 (13 %) 11 (23 %) 12 (15 %)
Confirmed hearing impairment 1 (0 %) 2 (3 %) 0 (0 %) 2 (3 %)

Values are presented as mean (SD)

GA gestational age, PNA postnatal age, CA corrected age (PNA + GA), BW birth weight, OAE otoacoustic emission test

lowest body weight [4, 29]. In their evaluation of more than 1,
000 TPCs, they reported high peak levels and low TPCs, but
87 % of all patients had only received one dose of gentamicin
[4, 29].
Impaired renal function and high plasma creatinine values
are well-known risk factors for high aminoglycoside TPC [12,
14]. Accordingly, we found that most term infants in the first
week of life with a TPC >2 mg/L had perinatal asphyxia and
renal impairment. When renal failure is likely, it may be
advisable to either check TPC before the second dose of
gentamicin, to routinely increase dosing intervals to 36 h or
to use a different empiric antibiotic until renal function is
clarified. In our unit, we routinely use cefotaxime for empiric
treatment of infants with severe perinatal asphyxia, in partic-
ular infants undergoing hypothermia who already are at high
risk for later hearing impairment [12].
Our dosing regimen has a higher gentamicin dosage (mil-
ligrams per kilogram) than what is commonly recommended
for neonates. Higher peak levels most likely optimise the
efficacy of gentamicin treatment. There is little support in
the literature for an association between high peak levels and
toxicity in neonates [6, 16, 26]. Based on our previous results
using the same dose (milligrams per kilogram) for netilmicin
[12] and other studies using gentamicin 45 mg/kg [10, 11,
20, 27], we would expect that the majority of peak levels with
our dosing regimen are >10 mg/L.
Newborn infants treated with aminoglycosides are at risk
of developing hearing impairment. However, there are many
other potential risk factors for hearing impairment including
perinatal asphyxia, CMV infections, intracranial complica-
tions, prematurity and treatment with loop diuretics [7, 13,
26]. A combination of more than one risk factor is often found
in children who later develop hearing impairment. In one
recent study, gentamicin did not seem to induce any ototoxic-
ity, and in fact, a protective effect against ototoxicity was
proposed [33]. OAE is considered an effective screening test
for detecting aminoglycoside-induced cochlear ototoxicity,
but positive predictive value is low (67 %) [31]. In our study,
38 (8.6 %) infants failed the OAE test. Only 4 out of 38
patients who failed the OAE tests were later diagnosed having

Table 2 Gentamicin trough plasma concentrations (TPCs) from 509 treatment episodes

Group A Group B Group C Group D Group E

PNA 07 days PNA 07 days PNA 07 days PNA >7 days PNA >7 days
GA >36 weeks GA 2936 weeks GA <29 weeks CA 29 weeks CA <29 weeks

Treatment episodes (n) 250 61 48 138 12

TPC, mean (SD) 1.2 (0.6) 0.9 (0.4) 0.9 (0.5) 0.8 (0.6) 1.1 (0.7)
TPC, median (IQR) 1.1 (0.81.4) 0.9 (0.61.1) 0.9 (0.61.3) 0.6 (0.40.9) 0.9 (0.61.7)
TPC 2.0 mg/L 22 (9 %) 1 (2 %) 1 (2 %) 5 (4 %) 2 (17 %)
TPC 1.5 mg/L 60 (24 %) 5 (8 %) 6 (13 %) 13 (9 %) 3 (25 %)
TPC <0.3 mg/La 5 (2 %) 0 1 (2 %) 10 (7 %) 0

GA gestational age, PNA postnatal age, CA corrected age (PNA + GA), TPC trough plasma concentration
a
TPCs below the lower limit of detection (<0.3 mg/L) were assigned a value of 0.2 mg/L
 Author's personal copy
Eur J Pediatr

Fig. 1 Gentamicin trough plasma

concentrations (TPCs) for each
treatment group. Box plots show
median values (solid bar),
interquartile range (margins of
box) and 5 and 95 percentile
(whiskers). Created using IBM-
SPSS (version 20.0)

permanent hearing impairment, and none of these four had
TPC >2 mg/L. The only child who had a TPC >2 mg/L and
acquired a hearing impairment passed the OAE test but grad-
ually evolved hearing impairment due to a congenital CMV
infection. The low rate of hearing impairment among our
high-risk intensive care infants, and in particular among pa-
tients with potential toxic TPCs, is a strong indication that
gentamicin treatment is safe. Long-term follow-up studies
with detailed hearing evaluation are still needed to confirm
this.
Gentamicin is one of the drugs most commonly associated
with prescription errors in the paediatric setting [22]. Simpler
dosing protocols are associated with less prescription errors
[34]. In our study, 93 % of all treatment episodes were cor-
rectly prescribed. Among the cases were we detected prescrip-
tion errors, almost 2/3 were made in preterm infants after the
first week of life, leading to a too large dosing interval and less
potential toxicity. It is likely that medical staff only considered
the low GA and failed to recognise and assess the PNA.
Improvements in education of medical staff may reduce such
errors.
Our study has limitations. First, a lack of data on peak
gentamicin levels diminishes our ability to fully assess the
pharmacokinetic efficacy of our dosage regimen. However,
we felt it unethical to continue measuring peak levels in this
high-dose regimen after having evaluated this dose in our
previous study. Therapeutic drug monitoring increases the
patient's pain and may cause clinically important blood loss.
Furthermore, 75 % of the cost of gentamicin therapy is due to
therapeutic drug monitoring [32]. For these reasons, it is
important that a dosing regimen achieve the targeted peak
and trough concentrations without requiring additional dosage
adjustment. A second limitation is that the retrospective nature
of our study makes it difficult to fully assess all levels of
ototoxicity. Infants with severe hearing impairment are iden-
tified, but we may have missed less severe ototoxicity in the
neonates who were born towards the end of our study with less
than 21 months of observation. To overcome these problems,

Table 3 Characteristics of five patients with confirmed hearing impairment in this study cohort

Patient TPC gentamicin (mg/L) GA Asphyxia Otofacial malformation CMV infection Neuro-development Hearing intervention

1 2.5 38 Yes No Yes Delayed CI

2 0.5 38 No No No Delayed HA
3 1.8 40 No Yesa No Delayed HA
4 0.8 31 Maybe No No Normal None
5 0.3 35 No No No Normal None

TPC through plasma concentration, GA gestational age, CMV cytomegalovirus, HA hearing aids, CI cochlear implant
a
Chromosomal abnormality
 Author's personal copy
we are planning a prospective long-term follow-up with a
complete audiological assessment. Finally, we did not perform
serial creatinine measurement or analysed urinary biomarkers
[17] for detailed assessment of potential gentamicin nephro-
toxicity. Gentamicin nephrotoxicity, however, is challenging
to assess in the first week of life when plasma creatinine
values are unstable and influenced by renal maturity and
changes in systemic circulation of sick neonates [1]. Further-
more, it seems that in neonates aminoglycosides rarely induce
clinically relevant renal failure in a normal course of treatment
when TPC is in a safe range [9, 25]. In contrast, when infants
have high TPCs, gentamicin is often discontinued, as these
infants usually already have an impaired renal function and
one does not want to further exaggerate this with gentamicin.
Conclusions
This simplified gentamicin high-dose (6 mg/kg) regimen was
associated with a low number of elevated TPCs (>2 mg/L) and
a low number of prescription errors, and we found no evi-
dence for ototoxicity.
Acknowledgments JWF receives financial support from the University
of Troms as a medical research student.
Conflict of interest None.
Ethics approval The study was approved by the Regional Ethics
Committee of North Norway.
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