Expert Review of Clinical Pharmacology

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Antimicrobial dosing in neonates

Aggeliki Kontou, Kosmas Sarafidis & Emmanuel Roilides

To cite this article: Aggeliki Kontou, Kosmas Sarafidis & Emmanuel Roilides (2017)
Antimicrobial dosing in neonates, Expert Review of Clinical Pharmacology, 10:3, 239-242, DOI:
10.1080/17512433.2017.1279968

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EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2017
VOL. 10, NO. 3, 239–242
http://dx.doi.org/10.1080/17512433.2017.1279968
EDITORIAL
Antimicrobial dosing in neonates
Aggeliki Kontoua,b, Kosmas Sarafidisb and Emmanuel Roilides
a
Infectious Diseases Unit, 3rd Department of Paediatrics, Aristotle University School of Health Sciences, Thessaloniki, Greece; b1st Department of
Neonatology, Faculty of Medicine, Aristotle University School of Health Sciences, Thessaloniki, Greece
ARTICLE HISTORY Received 8 October 2016; Accepted 5 January 2017
KEYWORDS Neonates; antibiotics; pharmacokinetics; pharmacodynamics; clinical trials
Neonatal sepsis still remains a significant cause of morbidity
and mortality, prolonged hospitalization, and increased med-
ical costs. Early- and late-onset sepsis often presents with
subtle and nonspecific clinical signs and, if not promptly
treated, may have detrimental consequences including survi-
val with neurodevelopmental deficits or even death [1–3].
Εmpiric antimicrobial therapy is an undeniable part of treat-
ment in neonates with suspected sepsis. Beta-lactams, amino-
glycosides and glycopeptides are among the most commonly
prescribed drugs in neonates, while antifungal and antiviral
agents are used much less frequently.
Recently, data on antibiotic prescription in pediatric popu-
lation from the Antibiotic Resistance and Prescribing in
European Children project were published (www.arpecpro
ject.eu). In the latter study involving 240 neonatal intensive
care units (NICU) from 41 countries, antibiotics were pre-
scribed in 89.2% out of the 3515 neonates evaluated followed
by antifungals (8.8%) and antivirals (1.9%). Of note, gentamicin
combined with ampicillin/amoxicillin or benzylpenicillin were
by far the most frequently used regimens [4]. Moreover, ther-
apeutic administration was recorded in 75% of the antibiotics
prescribed in neonates, for reasons like sepsis, central line-
associated blood stream infections, central nervous system
and skin/soft tissue infections, surgical disease, whereas pro-
phylactic administration (25%) was given for maternal and
newborn risk factors, for medical problems and surgical dis-
ease [4]. Treatment strategies for neonatal sepsis significantly
vary in terms of antibiotic choice and therapy duration among
neonatal centers. As documented in a cross-sectional survey in
19 European countries, 20 different antibiotic combinations
were recorded, with median therapy duration for suspected
sepsis of 7 (IQR 3–10) days [5]. A wide variation in antibiotic
prescribing practices among NICUs was also revealed in a
large antibiotic use cohort study in California (127 NICUs,
52,061 infants and 746,051 patient-days) [6].
1. Off-label use of antibiotics
Lack of evidence-based data is the main cause for the off-
label/unlicensed antibiotic use in neonates. Limited knowl-
edge exists in (a) pharmacokinetics (PK) and safety, (b) route
(continuous or intermittent), dose and duration of
CONTACT Emmanuel Roilides roilides@med.auth.gr 3rd Department of Pediatrics, Hippokration Hospital, Konstantinoupoleos 49, 54642 Thessaloniki,
Greece
© 2017 Informa UK Limited, trading as Taylor & Francis Group
a
administration, and (c) guidelines of using specific antibiotic
(s). A recent prospective cross-sectional study conducted in 36
Italian NICUs confirmed the high prevalence of off-label/unli-
censed drug use in neonates. Anti-infective agents were pre-
scribed off-label in 75% of cases and the reasons of off-label
use were age, dose, dosing frequency, and formulation [7]. In a
Portuguese NICU, although ampicillin and gentamicin were
the most frequently prescribed antibiotics, drug doses and/or
frequencies used were clearly different from those specified in
the Summary of Product Characteristics [8]. This finding is in
line with the results of a previous survey involving 3 European
neonatal centers in which an unregistered dose use of anti-
biotics was recorded in 37.8-51.7% of the prescriptions [8,9].
2. High variability in antibiotic dosing
Due to the lack of evidence-based data, the dosing of com-
monly used antibiotics exhibits high inter-NICU variability.
Guidelines are mainly based on small studies and personal
opinion rather than on randomized clinical trials (RCTs), lead-
ing to broad variability in dosing recommendations among
hospitals. Dosing guidelines are inconsistent and incomplete
resulting in inappropriate prescription of the majority of anti-
biotics given to critically ill neonates. High variability in dosing
of the most frequently prescribed antibiotics has been docu-
mented in 92% of the prescriptions of 89 NICUs in 21
European countries [10]. In a recent French national survey, a
significant inter-NICU variability was also identified as a total
of 444 dosage regimens were administered for 41 antibiotics
[11]. Slow and not generalized implementation of evidence-
based data in the various neonatal centers is a crucial reason
of the high variability in dosing.
This heterogeneity in clinical practice is also depicted in
dosage recommendations by reference books commonly used
by neonatologists, such as Neofax, Red Book, Blue Book, and
British National Formulary for children (BNFC). For example,
BNFC 2015–2016 recommends that amikacin be administered
in neonates in a multiple daily regimen (loading dose 10 mg/
kg, then 7.5 mg/kg every 12 h) or in extended interval dose
regimen (15 mg/kg every 24 h) [12]; in contrast, Neofax recom-
mends that daily dosage and intervals to be assigned accord-
ing to postmenstrual and postnatal age, whereas minimum
240 A. KONTOU ET AL.
dosing interval is 24 h [13]. Yet, according to the multicenter
European point prevalence study of neonatal Exposure to
Excipients, a multiple daily dosing regimen of aminoglycosides
was only used in 14% of cases [10].
Due to lack of evidence-based data in neonates, many
antimicrobial drugs are given with doses derived from adults
or older children. This is suboptimal as neonates have func-
tional and anatomical differences compared to older patients,
and consequently distinct PK and toxicity associated with the
antimicrobial agents. Infants are not just small children or
even more small adults. Term and especially preterm neonates
are a unique population; one could say that a neonate is a
rapidly evolving biological system [14,15]. Growth, maturation,
and specific pathophysiological characteristics (e.g. body com-
position, protein binding capacity, renal function and struc-
ture) influence PK behavior of antibiotics (absorption,
distribution, metabolism, elimination) and result in significant
interindividual variability in drug exposure. Moreover, disease
characteristics (sepsis, hemodynamic changes, renal impair-
ment, perinatal asphyxia, intrauterine growth restriction),
comedications, other treatment modalities like extracorporeal
membrane oxygenation, therapeutic hypothermia, and other
covariates including pharmacogenetics have a great impact on
PK and pharmacodynamic (PD) behaviors of many drugs in
neonates, further aggravating the variability within the specific
population [14,15]. Such scientific concerns along with regu-
latory and ethical issues make clinical trials in neonates diffi-
cult to perform and study design challenging.
During recent years, quantitative PK approaches for the
optimization of drug dosing regimens in neonates have been
developed and gained wide acceptance. PK modeling using
compartmental analysis can predict drug concentration at any
time, offers a more flexible timetable for PK samples collection,
allows less blood sampling while quantifies the effect of several
factors (covariates) on PK parameters explaining intra- and
intersubject PK variability [16]. Pharmacometric modeling and
simulation, tailored to term/preterm neonates, are valuable
tools for understanding PK behavior of antibiotics, providing
the basis for dose optimization and treatment individualization
in this vulnerable population [16]. Population PK-PD modeling
and simulation using nonlinear mixed effect modeling is a well-
established approach of great value and similar studies encour-
aged by regulatory agencies are constantly increasing [17].
Studies using newer methodologies adapted to the specific
demands of neonatal population, such as ultra-low-volume
drug concentration assays, opportunistic protocols, dried matrix
spot samples, physiologically based PK modeling, microdosing
are emerging with promising results, although some of these
approaches/techniques need further validation [18].
The US federal legislation and the European pediatric reg-
ulation significantly contributed to the increase of pediatric
studies resulting in a rise in drug-labeling changes. However,
few of these refer to neonates, which remain one of the last
therapeutic orphans [19]. Design and reporting of RCTs in
neonates seem to be of poor quality without any substantial
improvement during the past years, as identified by Kaguelidou
et al. in a systematic review of RCTs of antibiotics for neonatal
infections [20]. A survey in the US FDA databases identified that
among the 43 drugs studied in neonates between 1998 and
2014, only 20 were approved and just 2 of them were antibio-
tics (meropenem and linezolid) resulting in labeling with dose
recommendations for preterm neonates [21].
As optimal dosing in neonates, infants, and children is a
matter of public health and a prerequisite for high-quality
care, there is a growing body of studies on pharmacometric
modeling and simulation trying to evaluate and optimize
dosing strategies of antibiotics prescribed in term/preterm
neonates. A sixfold increase in the number of neonatal drug
trials, registered in the clinicaltrials.gov database was noted
from 1999 to 2012, whereas systemic anti-infectives were
among the 3 most commonly studied drug groups [22]. An
excellent systematic review by Wilbaux et al. on population PK
approaches for the antibiotics primarily eliminated through
kidneys in neonates identified 69 models for 13 antibiotics
with vancomycin and gentamicin being the most studied,
although there is no consensus on the optimal dosing for
preterm or term neonates [23]. Unwillingness on behalf of
the pharmaceutical industry to conduct clinical trials in neo-
nates [22] has shifted this responsibility to the academic
society and publicly funded bodies such as the European
Commission, the UK National Institute for Health Research
and the US National Institute of Child Health and Human
Development to sponsor pediatric and neonatal clinical trials.
Global Research in Pediatrics (GRiP), another initiative that
focuses on pediatric clinical pharmacology training, stimulates
and facilitates drug development and safe use of medicines in
children, as well [24].
In recent years, several studies on antimicrobial dosing in
preterm/term neonates have been or are conducted. As part
of the TINN (Treat Infection in NeoNates) project funded by
the European Commission, a prospective, open-label popula-
tion PK study of ciprofloxacin for neonates and infants
<3 months old was conducted. Doses of 7.5 mg/kg and
12.5 mg/kg given twice daily were suggested for neonates
with PMA <34 and ≥34-week gestation, respectively. As, how-
ever, external validation was not performed, this regimen
needs to be evaluated in clinical practice to confirm its bene-
fits [25]. Ampicillin, despite being one of the most commonly
used antibiotics in the NICU setting, lacks FDA labeling on
dosing for preterm/term neonates, and it has been evaluated
only recently by the Pediatric Trials Network (PTN) in the
Pharmacokinetics of Understudied Drugs Administered to
Children Per Standard of Care (POPS) trial. The latter aimed
to identify appropriate dosing of several understudied drugs
in children that are given as part of the standard medical care.
Investigators proposed ampicillin doses of 50–75 mg/kg every
8–12 h according to gestational and postnatal age, and were
able to achieve therapeutic targets (trough serum concentra-
tions ≥8 mg/L) in over 90% of the studied subjects [26].
Another study by PTN determined meropenem PK in pre-
term and term infants ≤90 days of age with suspected or
complicated intra-abdominal infections. In this investigation,
in which dosing strategy was modified according to gesta-
tional and postnatal age, meropenem was proved to be suffi-
cient for clinical and microbiological cure [27]. FDA recently
changed the label for meropenem to reflect these findings
(available at www.pediatrictrials.org). The results of a
European multicenter RCT (NEOMERO project) aiming to

Table 1. Algorithm for improving the current situation about dosing of anti-
biotics in the neonate.
● PK and toxicity studies of available antibiotics should be funded by interna-
tional or national public organizations to be performed in neonates
● PK and toxicity studies of new antibiotics should be funded by industry to be
performed in neonates
● Evidence-based guidelines are structured and disseminated in the neonatal
centers via scientific societies or regulatory initiatives
● Neonatal reference books used in everyday clinical practice should be revised
and updated according to the existing data
evaluate PK, safety, and efficacy of meropenem in neonatal
late-onset sepsis and meningitis in infants aged <3 months are
under publication [28].
The Antibiotic Safety in Infants With Complicated Intra-
Abdominal Infections (SCAMP) trial (clinicaltrials.gov:
NCT01994993) is an ongoing partially randomized, multicen-
ter, open-label safety study that aims to determine the safety
of clindamycin, ampicillin, metronidazole, and piperacillin-
tazobactam in infants with the above type of infections.
Secondary objectives of the study include efficacy, PK, identi-
fication of biomarkers related to disease severity and antibiotic
exposure, and diversity or shift of intestinal microbiota. An
antistaph-trio study (clinicaltrials.gov: NCT01728363) aims to
determine pharmacokinetics and safety of three antistaphylo-
coccal antibiotics (rifampin, clindamycin, and ticarcillin-clavu-
lanate) in term and premature infants. In order to better use
teicoplanin in preterm neonates, we conduct a study on its PK
involving neonates of different gestational and postnatal age.
In addition, NEOVANC RCT (clinicaltrials.gov: NCT02790996)
will compare two vancomycin-dosing regimens, a short one
with loading dose and a standard 10 day regimen in neonates
with sepsis due to coagulase-negative staphylococci. Among
Pediatric Investigation Plans submitted to European Medicines
Agency, only very few are on neonatal infections.
Neonatologists face the everyday problem of using many
off-label antimicrobial agents and receive a high volume of
information regarding newer data of PK and safety studies.
Moreover, pharmacologists or infectious diseases experts are
lacking from many NICUs. These make decision-making diffi-
cult. To overcome these issues, reference books used in every-
day clinical practice should be revised and updated according
to the existing data (Table 1). It is imperative that evidence-
based guidelines are structured and disseminated in the neo-
natal centers via scientific societies or regulatory initiatives, so
that to provide the optimal antimicrobial dosing and health
care to the sick infants.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 241
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
ORCID
Emmanuel Roilides http://orcid.org/0000-0002-0202-364X
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