Download An Evaluation of a Gentamicin Dosing Protocol in the Treatment of

An Evaluation of a Gentamicin Dosing Protocol in the Treatment of Bacterial Infections in
Neonates
Johanna Ponnuthurai BHSc1; Nisha Varughese, PharmD2; Claire Laframboise, Rph3; Lena
Lauzon, Rph2; Annie Pouliot, Ph.D2; Brigitte Lemyre, MD4,5
Affiliations: 1Clinical Research Unit, Children’s Hospital of Eastern Ontario Research Institute,
Ottawa, Canada; 2Department of Pharmacy, Children’s Hospital of Eastern Ontario, Ottawa,
Canada; 3Department of Pharmacy, The Ottawa Hospital, Ottawa, Canada; 4Department of
Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, Canada; 5Department of Obstetrics,
Gynecology and Newborn Care the Ottawa Hospital, Ottawa, Canada
Running Title: Evaluation of a Gentamicin Dosing Protocol
Key Words: gentamicin, newborn
Corresponding author: Brigitte Lemyre, MD, Department of Pediatrics, Children’s Hospital of
Eastern Ontario, 401 Smyth Road, Ottawa, Canada, K1H 8L1
Email: [email protected]
Telephone: +1 (613) 737-8561
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Abstract
Objective: To determine the safety and efficacy of a revised gentamicin dosing regimen.
Study Design: Retrospective study of neonates ≤ 1 month corrected gestational age and admitted
to one of 3 Neonatal Units between June 1and December 31, 2012. The primary outcome was
trough levels ≤2 mg/L.
Result: 151 neonates (mean 33.5 weeks) were included. 80% of patients had a trough level ≤2
mg/L while 94% had peak levels of 5-10 mg/L. The majority of trough levels >2 mg/L were in
infants 29-36 weeks corrected and ≤14 days and in term babies ≤7 days of age. Lower
gestational age and lower 1 and 5 minute Apgar scores were associated with a high trough.
Conclusion: Our gentamicin dosing regimen is suboptimal for moderately preterm neonates who
are ≤14 days and term infants ≤7 days. Further research is needed to determine the most effective
gentamicin dosing regimen, particularly in preterm neonates.
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List of Abbreviations
CHEO – Children’s Hospital of Eastern Ontario
HIE - Hypoxic ischemic encephalopathy
NICU – Neonatal intensive care unit
TOH-CC – The Ottawa Hospital – Civic Campus
TOH-GC – The Ottawa Hospital – General Campus
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Introduction
Gentamicin is an aminoglycoside antibiotic with bactericidal properties that is routinely
used along with beta-lactam antibiotics to treat proven or suspected bacterial infections in term
or preterm neonates.1-4 Gentamicin has concentration dependent bacterial killing and a postantibiotic effect, which can lead to toxicity if trough concentrations are too high.2, 4 To optimize
therapeutic concentrations and to minimize toxicity, gentamicin serum levels are closely
monitored. Low trough concentrations correspond with a reduced risk for toxicity, and a high
peak concentration corresponds with therapeutic efficacy.8
Gentamicin dosing regimens in neonates at our centers are based on traditional dosing
based on weight, gestational or corrected gestational age. The target trough level is ≤ 2mg/L and
the target peak level is 5-10 mg/L, with the ideal peak level between 7 and 10 mg/L. Dosing can
be challenging in neonates due to their increased volume of distribution and decreased renal
clearance, compared to that of adults.2, 6 Factors that have been known to affect clearance and
determine dosing include birth weight, gestational age, and postnatal age which also affect
gentamicin clearance.1 Gentamicin is excreted by the kidneys un-metabolized through
glomerular filtration, which can accumulate in neonates with immature renal function after birth,
including those with hypoxic ischemic encephalopathy (HIE) due to perinatal asphyxia.4, 6, 7
The Pharmacists at our three institutions collectively revised our gentamicin dosing
protocol (Figure 1) recently to optimize peak levels and minimize toxicity for term and preterm
neonates. The objective of this study was to examine the safety and efficacy of the revised
dosing regimen compared to the prior dosing regimen.
Materials and Methods
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A retrospective chart review of neonates admitted to the level 3c neonatal intensive care
unit (NICU) of the Children’s Hospital of Eastern Ontario (CHEO), the level 3a NICU of The
Ottawa Hospital – General Campus (TOH-GC) or the level 2c neonatal unit at The Ottawa
Hospital – Civic Campus (TOH-CC) between June 1, 2012 and December 31, 2012 was
conducted. The study was approved by the Research Ethics Boards at CHEO and TOH. Neonates
up to one month corrected gestational age who had at least one serum gentamicin level measured
were included in the study.
Gentamicin was administered by intermittent intravenous infusion over 30 minutes. A
trough sample was obtained 30 minutes before administration of the third dose and a peak
sample was obtained 30 minutes after the end of the third infusion. Data was collected using
electronic patient records and individual patient charts. Demographic data collected included
gestational age, postnatal age, gender and birth weight. All data regarding gentamicin
administration (dose, interval, trough and peak levels) were also collected. Apgar scores at 1, 5,
and 10 minutes, admission diagnosis, diagnosis of HIE (defined as a cord pH ≤7.1 and an Apgar
score of ≤5 at 10 minutes) and whether therapeutic hypothermia was received were also
collected. Urine output from 24hrs prior to 72hrs after the first dose of gentamicin, creatinine
and urea levels pre-gentamicin were also collected if available.
Participants were categorized into different age groups according to the gentamicin
dosing protocol: 1) less than 29 weeks and more than 14 days; 2) less than 29 weeks and 0-14
days; 3) 29-36 weeks and more than 14 days; 4) 29-36 weeks and more than 14 days; 5) 37
weeks or more and more than 7 days; and 6) 37 weeks or more and 0-7 days. (Figure 1)
Outcomes
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The primary outcome of the study was the proportion of patients with an acceptable
trough level (≤2 mg/L). Secondary outcomes included the proportion of patients with an
acceptable peak level (5-10 mg/L) and proportions with both acceptable trough and peak by age
group category.
Analysis
Statistical analysis was conducted using SPSS version 20.0. P values <0.05 were
considered significant. Descriptive statistics were used for all categorical variables and
summarized using frequencies and percentages. Normally distributed continuous variables were
summarized using means and standard deviations. Non-normally distributed continuous variables
were summarized using medians and quartiles. Analyses were performed for each of the age
subgroups in the new dosing regimen.
Results
151 neonates were included in the study. Their mean gestational age was 33.5 +/- 5.3
weeks, mean postnatal age was 5.4 +/- 11.9 days and mean birth weight was 2.3 +/- 1.1 kg.
(Table 1) The majority of patients were either 29-36 weeks gestational age and <14 days old or
≥37 weeks in their first week of life. (Table 1)
A trough gentamicin level was measured in 149 neonates. 119 neonates (79.9%) had an
adequate trough level and 30 neonates (20.1%) had an inadequate trough level (Table 2). A peak
gentamicin level was measured in 122 neonates. Target peak levels (5-10 mg/L) were found in
118 neonates (96.7%). Peak levels of 7-10 mg/L were found in 84 neonates (68.9%). Trough
levels were found to be acceptable in all age groups, with the exception of neonates 29-36 weeks
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gestational age and 0-14 days old, where 33.3% had a high trough and term babies 0-7 days old,
where 17.5% had a high trough (Table 2).
We performed exploratory analyses, to identify risk factors that could be associated with trough
levels >2 mg/L in these 2 subgroups. In the 29-36 weeks gestational age and 0-14 days subgroup, the lower the gestational age, the greater the likelihood of a trough level >2mg/L (Pearson
correlation coefficient, 2 tailed, p=0.007) (Table 3). Apgar score at 1 and 5 minutes also
correlated inversely with a high trough level (p=0.05 for Apgar score at 1 minutes and p=0.01 for
Apgar score at 5 minutes). Low urinary output (<2 mL/kg/h) after the first dose of gentamicin or
concomitant treatment with ibuprofen or indomethacin were not associated with a high trough
level.
In the 0-7 day-old term neonate sub-group, a diagnosis of HIE was associated with a
greater risk of having a high gentamicin trough level (p=0.007); 4 out of 6 infants (including 3
out of 4 babies who received therapeutic cooling) with HIE on admission had a high trough
level. Apgar scores at 5 minutes were also inversely correlated with a high trough level (p=0.01).
As well, a higher gestational age in this category was associated with a lower likelihood of a high
trough level (p=0.045). We assessed whether a serum creatinine ≥60 µmol/L was associated with
a higher likelihood of a high trough level, but it was not (p=0.054).
Discussion
Dosing gentamicin in neonates to obtain maximal efficacy with minimal toxicity is
challenging. This study found that our revised gentamicin dosing regimen did not achieve this
goal for moderately preterm infants who are less than 2 weeks old and term babies who are in
their first week of life. Our dosing regimen thus requires adjustment. Our data suggests that
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gestational age as well as postnatal age significantly influence gentamicin clearance, likely due
to delayed kidney maturation. This is consistent with previous studies on gentamicin
pharmacokinetics.1, 2, 7 Overall, babies less than 34 weeks gestational age and less than 2 weeks
of life were more likely to have high trough levels. Currently, the dosing regimen for neonates
between 29-36 weeks gestational age and 0-14 days old is 3-3.5mg/kg/dose every 18h; this may
be too broad in terms of dose and age range, particularly for the moderately preterm neonate.
Consideration should be given as to whether lowering the dose or increasing the interval would
allow maximal efficacy and minimal toxicity.
Term babies 0-7 days old with high trough levels were of particular interest because they
were all admitted to the 3c NICU at CHEO. This may be explained by higher acuity of illness in
these patients, who were referred from community hospitals; however we were not able to
demonstrate that retrospectively. Many of these term neonates had HIE or were cooled for HIE,
but not all of them, which may be associated with poorer renal function and lower creatinine
clearance. Recent literature has found that therapeutic hypothermia can alter gentamicin
pharmacokinetics, prolonging its half-life.3, 6, 12, 13 Neonates with HIE often have renal
dysfunction, which results in an inability to properly excrete gentamicin.7 Frymoyer et al. noted
that gentamicin clearance was 25-50% lower in term neonates with HIE than their term, nonasphyxiated counterparts.
While our institutions use traditional dosing, there exists debate in the literature that
extended interval dosing may be more effective. Previous studies 8, 9, 10 on term neonates suggest
that extended interval dosing is superior to traditional dosing, in achieving higher peak levels and
lower trough levels. Much of the literature regarding extended interval dosing looks at late
preterm or term neonates.8, 9, 10, 14, 15, 17 A daily dose of 4mg/kg is recommended for term babies
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≥34 weeks gestational age.8, 9, 10, 15, 16, 17 There is limited data available confirming the efficacy
of this regimen in early preterm neonates, born <34 weeks.2, 16, 17 Available dosing
recommendations for preterm neonates states that 3mg/kg is optimal.16 Even less research is
available for early preterm infants as they are often not considered in these studies.
We acknowledge the following limitations for our study: 1) the retrospective nature of
this study has intrinsic limitations, mostly availability of all data; 2) small numbers of some subgroups prevented meaningful analysis and allows for the possibility of type 2 errors; 3) analysis
of the influence of renal function was limited by the age of the majority of infants, as most had
not established good urine output yet.
Due to the above findings, we have used pharmacokinetic modeling to modify the dosing
of gentamicin for these 2 subgroups. (Data not shown) The modifications include a precise dose
(3.5 mg) as opposed to a range of dosing (3.0 to 3.5 mg) and dosing every 24h in infants 29-36
weeks and 0-14 days instead of every 18h. For neonates with a low cord pH and low Apgar
scores or those with risk factors for abnormal renal function, we also recommend obtaining a
serum trough level 24h after the first dose of gentamicin and giving further doses only if the
level is ≤2 mg/L. We are currently evaluating the effects of these revisions in our dosing
regimen.
In conclusion, a dose of 3-3.5mg/kg/dose every 18h was found to be sub-optimal in
neonates 29-36 weeks gestational age and 0-14 days old. Furthermore, a dose of 33.5mg/kg/dose every 18h was also found to be sub-optimal in term neonates 0-7 days old.
Ongoing quality assurance projects to ensure optimal dosing regimens in the neonatal population
are important, particularly after modifications. The literature is inconclusive regarding whether
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extended interval dosing is the best method of gentamicin dosing for preterm neonates, therefore,
further research is warranted.
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Acknowledgements
The authors would like to acknowledge Samantha Somers for editing the manuscript.
Conflict of Interest
The authors declare no conflicts or financial interest in any product or service mentioned in the
manuscript including grants, medications, employment, gifts, and honoraria.
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References
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undergoing therapeutic hypothermia. Ther Drug Monit 2013; 35(2): 217-222.
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and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia.
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Table 1: Demographics of Study Participants
Demographics
n=151
Gender [n (%)]
Male
95 (62.9%)
Female
56 (37.1%)
GA, weeks (mean +/- SD)
33.5 +/- 5.262
BW, kg (mean +/- SD)
2.263 +/- 1.106
Postnatal age, days (mean +/- SD)
5.42 +/- 11.950
Subgroup [n (%)]
≤28 weeks CGA and >14 days
1 (0.7%)
≤28 weeks GA 0-14 days
26 (17.0%)
29-36 weeks CGA and >14 days
14 (9.3%)
29-36 weeks GA and 0-14 days
50 (33.1%)
≥37 weeks and >7 days
3(2.0%)
≥37 weeks and 0-7 days
57 (37.8%)
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Table 2: Gentamicin trough levels by age group
Age Group
Pre-
≤2
≤ 28
≤ 28
29-36
29-36
≥ 37
≥ 37
weeks
weeks
weeks
weeks
weeks
weeks
CGA
GA
CGA
GA
GA
GA
>14 days
0-14 days
>14 days
0-14 days
> 7 days
0-7 days
1
24
12
32
3
47
0
2
2
16
0
10
1
26
14
48
3
57
gentamicin (mg/L)
level
>2
(mg/L)
N (total)
16
Table 3: Gentamicin trough levels in 29-36 weeks and <14 days subgroup
Gestational age in weeks
Pre-
29
30
31
32
33
34
35
36
2
0
3
1
7
9
2
8
5
4
2
1
3
0
1
0
≤2
gentamicin (mg/L)
level
>2
(mg/L)
17
Figure 1: Gentamicin Dosing Protocol
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