Comparison of antibiotic dosing recommendations for neonatal sepsis from established reference sources
Comparison of antibiotic dosing recommendations for neonatal sepsis from established reference sources
T. B. Y. Liem 0 1
E. M. A. Slob 0 1
J. U. M. Termote 0 1
T. F. W. Wolfs 0 1
A. C. G. Egberts 0 1
C. M. A. Rademaker 0 1
0 Department of Pediatrics, Infectious Diseases and Immunology, Wilhelmina Children's Hospital , Lundlaan 6, 3584 EA Utrecht , The Netherlands
1 Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre , Lundlaan 6, 3584 EA Utrecht , The Netherlands
2 T. B. Y. Liem
Background Incorrect dosing is the most frequent prescribing error in neonatology, with antibiotics being the most frequently prescribed medicines. Computer physician order entry and clinical decision support systems can create consistency contributing to a reduction of medication errors. Although evidence-based dosing recommendations should be included in such systems, the evidence is not always available and subsequently, dosing recommendations mentioned in guidelines and textbooks are often based on expert opinion. Objective To compare dosage recommendations for antibiotics in neonates with sepsis provided by eight commonly used and well-established international reference sources. Setting An expert team from our Dutch tertiary care neonatal intensive care unit selected eight well-established international reference sources. Method Daily doses of the seven most frequently used antibiotics in the treatment of neonatal sepsis, classified by categories for birth weight and gestational age, were identified from eight well-respected reference sources in neonatology/pediatric infectious diseases. Main outcome measure Standardized average daily dosage. Results A substantial variation in dosage recommendations of antibiotics for neonatal sepsis between the reference sources was shown. Dosage recommendations of ampicillin, ceftazidime, meropenem and vancomycin varied more than recommendations for benzylpenicillin, cefotaxime and gentamicin. One reference source showed a larger variation in dosage recommendations in comparison to the average recommended daily dosage, compared to the other reference sources. Conclusion Antibiotic dosage recommendations for neonates with sepsis can be derived from important reference sources and guidelines. Further exploration to overcome variation in dosage recommendations is necessary to obtain standardized dosage regimens.
Antibiotics; Dosing recommendations; Dosing variation; Neonatal sepsis; Neonates
Department of Clinical Pharmacy, Wilhelmina Children’s
Hospital, University Medical Centre Utrecht, Lundlaan 6,
3584 EA Utrecht, The Netherlands
Division of Pharmacoepidemiology and Clinical
Pharmacology, Faculty of Science, Utrecht University,
Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
The most common medication error in neonates is incorrect
dosing due to lack of evidence or lack of access to the
available evidence at the moment of prescribing [
physician order entry (CPOE) and clinical decision support
systems can contribute to the reduction of such medication
errors and thereby increase patient safety [
]. To obtain full
benefit of these systems, evidence-based dosing
recommendations should be included, which unfortunately are not
always available for neonates because of the lack of
pharmacokinetic data and clinical efficacy studies in this vulnerable
patient group [
]. As a consequence, dosing in neonates is
often based on clinical experience and expert-opinion. This
is probably one of the reasons for high variability in dosing
of frequently used antibiotics in European neonatal intensive
care units (NICUs) [
Moreover, a multicentre study on paediatric
antimicrobial prescribing in European hospitals demonstrated that the
prescribed daily dose (PDD) in children increased with age
and weight. This advocates the need to define standardized
paediatric daily doses for different paediatric age groups
and neonates separately [
]. In this perspective, a first step
towards uniformity in neonatal antibiotic dosage
recommendations was previously taken by us through the development
of a set of neonatal defined daily doses (nDDDs) [
Among the drugs most frequently used in NICUs
antimicrobial agents rank highest [
], since the multiple risk
factors for infection in preterm immunocompromised infants
result in a low threshold for the initiation of antimicrobial
therapy. Neonatal infections, predominantly sepsis, are a
significant cause of morbidity and mortality in the newborn,
particularly in preterm, low birth weight infants [
Aim of the study
The aim of this study is to compare the dosage
recommendations for commonly used antibiotics in neonatal sepsis
from eight frequently used and well-established international
neonatal/paediatric reference sources.
This article does not contain any studies with human
participants or animals performed by any of the authors.
Selection of antibiotics and reference sources
In this study the focus was on the variation in dosage
recommendations of antibiotics for neonatal sepsis. Based
on a survey on antibiotic use in all ten Dutch tertiary care
neonatal intensive care units (NICUs) [
], the ten most
frequently used antibiotics in neonates in the Netherlands
were selected: ampicillin, amoxicillin,
amoxicillin–clavulanic acid, benzylpenicillin, flucloxacillin, ceftazidime,
cefotaxime, meropenem, gentamicin and vancomycin.
A team of experts from our children’s hospital, including
a paediatric-infectious disease specialist, a neonatologist and
several hospital pharmacists, selected nine commonly used
and well-established international references in neonatology/
paediatrics and paediatric infectious diseases to be evaluated
for dosage recommendations [
], namely: four general
paediatric dosage handbooks, four neonatal/paediatric infectious
diseases handbooks and one paediatric online formulary:
• Dutch Paediatric Formulary (DPF) (Dutch Expertise
Network on Paediatric Pharmacotherapy, NKFK),
online accessible [
• Infectious Diseases of the Fetus and the Newborn
Infant (Remington & Klein), 8th edition, 2016 [
• Micromedex Neofax Online (Neofax) [
• The Harriet Lane Handbook, 20th edition, 2015 [
• Red Book, 2015 [
• Principles and Practices of Paediatric Infectious
Diseases (Long & Pickering), 4th edition, 2012 [
• Nelson’s Pocket Book of Paediatric Antimicrobial
Therapy (Nelson’s), 22nd edition, 2016 [
• Pediatric & Neonatal Dosage Handbook (PDH), 22th
edition, 2015 [
• The British National Formulary for children, 2015–
2016 (BNFC) [
As a primary condition for comparing dosage
recommendations, at least four reference sources had to provide
dosage recommendations for the specific antibiotic agent.
The reference sources referring to other guidance
documents, which were not based on primary literature sources,
Determination of dosage recommendations
All intravenous dosage recommendations [recommended
daily dosage (RDD)] for neonates with sepsis for the selected
antibiotics mentioned in the included reference sources were
collected, as well as any referenced evidence referring to
original clinical studies in neonates.
In addition, to be able to compare the dosage
recommendations, these were converted to the format ‘mg/kg/
day in x divided doses’, if possible. To avoid interpretation
errors, age categories were unambiguously compared, i.e.,
dosage recommendations for different age-categories were
excluded. In case of a dosage recommendation with a
dosage range as well as an interval range (e.g., 10–20 mg/kg/
day every 6–8 h) the limits were mediated as RDD. In the
aforementioned example, the daily dose limits would be
30–80 mg/kg/day and the RDD would be 55 mg/kg/day.
Next, for each antibiotic and age category the average of
the dosage recommendations in the eight reference sources
was calculated and expressed as the aRDD. Subsequently,
to evaluate similarities and differences between the
dosage recommendations and the aRDD, the deviation of each
RDD relative to the aRDD was calculated. The calculation
of the deviation was determined by the formula: deviation
(%) = − (100 − (RDD/aRDD *100%)). In this formula, the
aRDD was seen as 100%.
Characteristics of reference sources
The dosage recommendations of Remington & Klein were
based on those in the Red Book and Neofax. Since these
two latter reference sources were already included in our
comparison, we did not include Remington & Klein for
The BNFC, Neofax and PDH were the only reference
sources that included dosage recommendations for almost
all ten selected antimicrobial agents (nine out of ten).
Table 1 shows the characteristics of the eight analysed
reference sources. The Red Book, Nelson’s and Long &
Pickering did not include age-dependent categories for
dosage recommendations. The Dutch Paediatric
Formulary, Harriet and Lane handbook and Nelson’s were based
All reference sources included neonatal dosage
recommendations. Most of the reference sources had dosage
recommendations for preterm infants, but the Red Book,
Long & Pickering and PDH did not. However, all reference
sources used different age categories for both populations
based on birth or current weight, gestational age (GA) or
postmenstrual age (PMA).
All reference sources used literature referencing for their
dosage recommendations. However, only three reference
sources mentioned their literature referencing, i.e., the PDH,
Long & Pickering and the Neofax. The DPF mentioned the
literature references partially, no references were described
for ceftazidime and vancomycin. The Neofax referred to the
Red Book 2009 for the dosage recommendations of
ampicillin and penicillin G. The Red Book 2015 was a literature
reference for dosage recommendations of gentamicin,
ampicillin, ceftazidime, benzylpenicillin and cefotaxime in the
PDH. The highest total number of literature references for
each antibiotic agent was in the Neofax, of which
meropenem had 16 references. Cefotaxime and ceftazidime had the
lowest number of references. Comparison of all available
references illustrated that only a few were cited in common.
In total 309 dosage recommendations were included for
comparison. Flucloxacillin, amoxicillin and
amoxicillin-clavulanic acid were excluded because less than four reference
sources included dosage recommendations for these agents.
Therefore, seven of the initial ten selected antibiotics were
evaluated. Table 2 illustrates the variation in dosage
recommendations between the reference sources for the seven
Figure 1 shows the variation in standardized dosage
recommendations in comparison to the aRDD for each
evaluated reference source. The relative deviation of the RDD
compared to the aRDD is shown for each antibiotic and
reference source. Between the evaluated reference sources
the relative deviation of the RDD compared to the aRDD
for ampicillin, ceftazidime, meropenem and vancomycin is
above 50%, in contrast to benzylpenicillin, cefotaxime and
Long & Pickering showed larger variation in dosage
recommendations in comparison to the aRDD, compared to the
other reference sources. On the other hand, the BNFC
demonstrated the least variation in dosage recommendations in
comparison to the aRDD of all evaluated reference sources.
To our knowledge, this is the first study that reviewed eight
internationally well-respected reference sources for
dosage recommendations of antibiotics for neonatal sepsis and
showed a substantial variation between reference sources
therein. The dosing recommendations of ampicillin,
ceftazidime, meropenem and vancomycin showed a larger
variation compared to those of benzylpenicillin, cefotaxime and
The Summaries of Product Characteristics (SmPCs) of
the concerning antibiotics were evaluated when specific
dosage recommendations for neonatal sepsis were
available. These neonatal dosage recommendations were
explicitly available in the SmPC of cefotaxime and gentamicin
exclusively, which might be an explanation for the smaller
variation in dosage recommendations between the
evaluated reference sources for these two antibiotics compared to
ampicillin, ceftazidime, meropenem and vancomycin.
Furthermore, in comparison with the other seven
evaluated reference sources Long & Pickering demonstrated a
larger variation in its dosage recommendations in
comparison to the aRDD. It is, however, difficult to explain why
this reference source stands out in the comparison of dosage
recommendations. One possible explanation for this
discrepancy could be that Long & Pickering has a focus on
diagnosis and management of paediatric infectious diseases
rather than providing a complete neonatal antibiotic dosage
Overall, there may be several reasons for the
considerable variation between some antibiotic dosage
recommendations. First of all, the lack of clinical efficacy studies in the
neonatal population [
]. Furthermore, large trials are
required to show any differences in clinical efficacy between
dosage recommendations, which are hard to set up in this
vulnerable population in practical and ethical perspective,
let alone excellent pharmacokinetic (PK)-pharmacodynamic
(PD) studies including appropriate biomarkers as endpoint.
Over the last few years some new PK-PD studies have been
carried out [
], but only a few studies published before
2010 are included as a literature reference in the investigated
reference sources. Second, due to geographical regional
variation in antimicrobial susceptibility patterns, empirical
therapy should be guided by local susceptibility patterns
resulting in variation in dosage recommendations [
problems in adoption and dissemination of evidence based
knowledge can cause high dosing variability [
example, the BNFC recommended to double the dose in severe
infections/meningitis. This might be an explanation for some
differences in dosing recommendations. Finally, one could
hypothesize that the variation might be explained by the
differences in the procedure of establishing the dosing
recommendations between the reference sources, e.g., composition
of editorial board, availability of references or frequency
of updating. Regarding the latter, an additional remarkable
finding was that five out of eight reference sources
evaluated in our study were paper ones. In our opinion, the era of
using reference sources in book form has come to an end.
One should henceforth give higher preference to available
online (electronic) information of antibiotic dosage
recommendations as these can be updated regularly.
The variation between recommendations from different
sources was also seen recently by systematically comparing
different sources of drug information regarding dose
adjustment for renal function [
] and those on safety in lactation
]. These inconsistencies in reference sources, guidelines
and drug management programmes might not encourage
adherence to the recommendations from these sources and
subsequently might lead to more experience-based instead
of evidence-based medicine [
This study had the aim to map differences in
dosage recommendations. It was therefore not intended as a
qualitative judgement about the appropriateness of dosage
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recommendations nor intended to judge the quality of the
Inconsistencies in neonatal dosage recommendations
for antibiotics from these common reference sources might
indirectly contribute to the difficulty in clinical practice in
determining an appropriate neonatal dosage [
standardization of neonatal antibiotic dosing schemes is
desirable, which potentially may lead to better outcome and
less toxicity. Moreover, a standardized dosing regimen and
therapeutic drug monitoring (TDM) would help reduce
medication errors as the National Patient Safety Agency (NPSA)
report (Review of Patient Safety for Children and Young
People, June 2009) concluded [
]. However, it is generally
known from several recent PK-PD studies that routine TDM
for exclusively gentamicin and vancomycin in neonates was
strongly recommended in contrast to penicillins and
cephalosporins, since both antibiotics have a small therapeutic
window and overdosing can lead to severe toxicity [
Uniformity in neonatal dosage recommendations of
antibiotics should be achieved and also evidence based.
Evidence should be derived from established international
reference sources, guidelines and corresponding SmPCs. In
addition, not only prospective validation of neonatal dosing
regimens of antibiotics, but also further exploration of
pharmacokinetic and pharmacodynamic aspects of antibiotics in
neonates is therefore essential [
Expert committees should take a lead in interpreting the
existing evidence and in establishing uniform dosage
recommendations, adopting the Grading of Recommendations
Assessment, Development and Evaluation (GRADE)
system preferably [
]. In this context, the development and
implementation of a national knowledge-based formulary
for children in the Netherlands may serve as an successful
]. International consensus is required to
harmonize the way existing data is presented and to develop
better dosage regimens. Ideally, dosage recommendations
for neonatal sepsis should be included in the SmPCs in case
these are not mentioned herein.
Our comparison of dosage recommendations in eight
internationally well-respected reference sources led to the
conclusion that the dosage recommendations for
ampicillin, ceftazidime, meropenem and vancomycin for neonatal
sepsis varied considerably. Further exploration to overcome
variation in dosage recommendations is necessary to obtain
established dosage regimens and thus full benefit of CPOE
and clinical decision support systems in neonatology.
≥ 1 week, ≥ 2000 g
≥ 1 week,
≥ 1 week, ≥ 2000 g
≥ 1 week,
≥ 1 week, ≤ 1200 g
< 7 days, > 2000 g
< 7 days, ≤ 2000 g
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