Clin Pharmacokinet (2014) 53:581–610
DOI 10.1007/s40262-014-0147-0
REVIEW ARTICLE
Pharmacokinetics and Pharmacodynamics of Antibacterials,
Antifungals, and Antivirals Used Most Frequently in Neonates
and Infants
Jessica K. Roberts • Chris Stockmann • Jonathan E. Constance
Justin Stiers • Michael G. Spigarelli • Robert M. Ward •
Catherine M. T. Sherwin
Published online: 29 May 2014
Ó Springer International Publishing Switzerland 2014
Abstract Antimicrobials and antivirals are widely used
in young infants and neonates. These patients have his-
torically been largely excluded from clinical trials and, as a
consequence, the pharmacokinetics and pharmacodynam-
ics of commonly used antibacterials, antifungals, and an-
tivirals are incompletely understood in this population.
This review summarizes the current literature specific to
neonates and infants regarding pharmacokinetic parameters
and changes in neonatal development that affect antimi-
crobial and antiviral pharmacodynamics. Specific drug
classes addressed include aminoglycosides, aminopenicil-
lins, cephalosporins, glycopeptides, azole antifungals,
echinocandins, polyenes, and guanosine analogs. Within
each drug class, the pharmacodynamics, pharmacokinetics,
and clinical implications and future directions for proto-
typical agents are discussed. b-Lactam antibacterial
J. K. Roberts  C. Stockmann  J. E. Constance 
M. G. Spigarelli  R. M. Ward  C. M. T. Sherwin (&)
Division of Clinical Pharmacology, Department of Pediatrics,
University of Utah School of Medicine, University of Utah
Health Sciences Center, 295 Chipeta Way, Salt Lake City,
UT 84108, USA
e-mail: catherine.sherwin@hsc.utah.edu
C. Stockmann
Division of Infectious Diseases, Department of Pediatrics,
University of Utah School of Medicine, Salt Lake City,
UT, USA
C. Stockmann  M. G. Spigarelli
Department of Pharmacology/Toxicology, University of Utah
College of Pharmacy, Salt Lake City, UT, USA
J. Stiers  R. M. Ward
Division of Neonatology, Department of Pediatrics, University
of Utah School of Medicine, Salt Lake City, UT, USA
•
activity is maximized when the plasma concentration
exceeds the minimum inhibitory concentration for a pro-
longed period, suggesting that more frequent dosing may
optimize b-lactam therapy. Aminoglycosides are typically
administered at longer intervals with larger doses in order
to maximize exposure (i.e., area under the plasma con-
centration–time curve) with gestational age and weight
strongly influencing the pharmacokinetic profile. None-
theless, safety concerns necessitate therapeutic drug mon-
itoring across the entire neonatal and young infant
spectrum. Vancomycin, representing the glycopeptide class
of antibacterials, has a long history of clinical utility, yet
there is still uncertainty about the optimal pharmacody-
namic index in neonates and young infants. The high
degree of pharmacokinetic variability in this population
makes therapeutic drug monitoring essential to ensure
adequate therapeutic exposure. Among neonates treated
with the triazole agent fluconazole, it has been speculated
that loading doses may improve pharmacodynamic target
attainment rates. The use of voriconazole necessitates
therapeutic drug monitoring and dose adjustments for
patients with hepatic dysfunction. Neonates treated with
lipid-based formulations of the polyene amphotericin B
may be at an increased risk of death, such that alternative
antifungal agents should be considered for neonates with
invasive fungal infections. Alternative antifungal agents
such as micafungin and caspofungin also exhibit unique
pharmacokinetic considerations in this population. Neo-
nates rapidly eliminate micafungin and require nearly three
times the normal adult dose to achieve comparable levels
of systemic exposure. Conversely, peak caspofungin con-
centrations have been reported to be similar among neo-
nates and adults. However, both of these drugs feature
favorable safety profiles. Recent studies with acyclovir
have suggested that current dosing regimens may not result
582
in therapeutic central nervous system concentrations and
more frequent dosing may be required for neonates at later
postmenstrual ages. Though ganciclovir and valganciclovir
demonstrate excellent activity against cytomegalovirus,
they are associated with significant neutropenia. In sum-
mary, many pharmacokinetic and pharmacodynamic stud-
ies have been conducted in this vulnerable population;
however, there are also substantial gaps in our knowledge
that require further investigation. These studies will be
invaluable in determining optimal neonatal dosing regi-
mens that have the potential to improve clinical outcomes
and decrease adverse effects associated with antimicrobial
and antiviral treatments.
Key Points
Though many antibacterials have been around for
decades, variable pharmacokinetics of many drug
classes requires therapeutic drug monitoring in
neonates and infants.
Antifungal drugs display a safer toxicity profile in
neonates and infants than in older children and
adults.
Minimal studies have been published with neonatal
and infant antiviral drug use and more work needs to
be completed to correctly treat this population.
1 Introduction
Pharmacokinetic and pharmacodynamic data for the neo-
nate and infant populations are increasing, but remain
minimal for specific drugs and specific populations of
patients. Historically, neonates and infants have been
excluded from clinical trials for a variety of reasons,
including their small blood volume, lack of validated
endpoints, and ethical concerns related to frequent blood
draws [1]. Some of these limitations have been overcome
with the recent use of scavenged blood samples and dry
blood spot analysis. More recently, federal regulations
have promoted the study of drugs in newborns, which is
often required to account for developmental and matura-
tional processes that occur throughout the first year of life
[2, 3]. This review attempts to incorporate the pharmaco-
kinetic and pharmacodynamic data available in the litera-
ture on the treatment of neonates and infants 1 year of age
and younger, using the following representative antibac-
terial, antifungal, and antiviral classes: aminoglycosides,
aminopenicillins, glycopeptides, cephalosporins, azole
J. K. Roberts et al.
antifungals, echinocandins, polyenes, and guanosine ana-
logs. A prototypic drug or drugs were chosen for each drug
class and is discussed in detail. As a consequence of leg-
islative advancements, a large body of evidence is avail-
able for newer drugs, which are frequently investigated in
neonatal clinical trials and featured prominently in this
review. In addition, a larger emphasis was placed on the
known pharmacokinetics of each drug class. A literature
search was conducted using PubMed where the anti-in-
fectives specifically addressed in this review in conjunction
with key words, such as ‘neonate’, ‘infant’, ‘pharmacody-
namics’, and ‘pharmacokinetics’, were used to identify
relevant literature. Additional references were identified
from the reference lists of published articles. Pharmaco-
kinetics studies that did not stratify their analyses to enable
our evaluation of patients less than 1 year of age were not
included in this review.
2 Antibacterials
Neonatal sepsis has declined over the last 75 years, but still
remains the leading cause of mortality in neonates in
developed countries [4, 5]. Sepsis can be defined as early
onset (\7 days after birth confirmed by blood culture),
usually acquired from the mother, or late onset ([7 days
after birth confirmed by blood culture) acquired nosoco-
mially [4]. The overall incidence of early-onset sepsis, as
reported by the National Institute of Child Health and
Human Development Neonatal Research Network, is esti-
mated to be 0.98/1,000 births, although late-onset sepsis
occurs most commonly in pre-term very low weight infants
and is inversely related to gestational age (GA) [6]. Ami-
noglycosides, aminopenicillins, glycopeptides, and cepha-
losporins are commonly used to treat sepsis in neonates and
infants (pharmacodynamics in Table 1; pharmacokinetics
in Table 2).
2.1 Aminoglycosides: Gentamicin
2.1.1 Pharmacodynamics
Gentamicin is primarily used for the treatment of Gram-
negative sepsis [7]. Its mechanism of action is to bind
irreversibly to the 30S subunit of bacterial ribosomes,
which inhibits protein synthesis, and results in cell death
[8]. Resistance is largely due to transfer of plasmids and
the expression of aminoglycoside-modifying enzymes [9].
Gentamicin resistance occurs in a wide range of microbes
including Escherichia coli, Klebsiella, Pseudomonas,
Staphylococcus aureus, coagulase-negative staphylococci,
and Enterobacter [10–16]. Gentamicin penetrates several
tissues of the newborn, with the kidney and lung having the
Antimicrobial/Antiviral PK–PD in Neonates and Infants 583

Table 1 Antibacterial pharmacodynamics

Class Drug Mechanism of action Resistant microbes Tissue Adverse events References
penetration

Aminoglycosides Gentamicin Bind irreversibly to Escherichia coli, Kidney and Nephrotoxicity and [7–19, 206]
30S subunit of Klebsiella, lung [ heart otoxicity
bacterial ribosomes, Pseudomonas, and
disrupting protein Staphylococcus muscle [ brain
synthesis aureus, coagulase-
negative
staphylococci,
Enterobacter
Aminopenicillins Ampicillin Irreversibly inhibits Enterobacter cloacae, Penetrates most Erythematous rashes, [109, 138,
transpeptidase, an Enterococcus faecium tissues; poor vomiting, diarrhea, 207, 208]
essential enzyme for CSF hepatic impairment
bacterial cell wall penetration with chronic use,
fission hypersensitivity
reaction, seizures,
pseudomembranous
enterocolitis,
impaired platelet
function
Glycopeptides Vancomycin Inhibition of cell wall Vancomycin-resistant Penetrates most Nephrotoxicity, Red [209–211]
biosynthesis by Enterococcus (VRE) tissues; CSF man’s syndrome,
blocking spp., vancomycin- penetration is ototoxicity,
incorporation of N- intermediate increased by neutropenia
acetylmuramic acid Staphylococcus inflammation
and N- aureus (VISA), of the
acetylglucosamine vancomycin-resistant meninges
peptide subunits S. aureus (VRSA)
Cephalosporins Cefotaxime Inhibits penicillin- Enterobacter spp., Brain Hypersensitivity and [180–188,
binding proteins Ib Serratia spp., and gastrointestinal 212]
and III, inhibiting Citrobacter freundii
bacterial wall
synthesis
CSF cerebrospinal fluid

highest concentrations, followed by the heart and muscle,
with very low levels in the brain [17]. Nephrotoxicity,
though not as common in the neonate, has been correlated
with high trough levels above 2 lg/mL, and ototoxicity has
been associated with peak serum concentrations[12 lg/mL
[18, 19]. The pharmacodynamic parameter that has been
most strongly associated with bactericidal activity is the
area under the plasma concentration–time curve (AUC),
which is maximized by the use of larger doses, which are
administered infrequently [20].
2.1.2 Pharmacokinetics
In 1972, the US FDA approved a pediatric formulation of
gentamicin [21]. McCracken and Jones [22] evaluated
gentamicin use in 42 neonates, where dosage, weight, GA,
and postnatal age (PNA) were taken into consideration as
factors affecting pharmacokinetic parameters. At a dose of
1.5 mg/kg every 8–12 h, researchers reported a higher
maximum (peak) concentration (Cmax) in full-term infants
(2.72 lg/mL) than pre-term infants (\35 weeks; 2.60 lg/mL),
which is consistent with the larger extracellular fluid
compartment and volume of distribution (Vd) reported
among pre-term infants. However, beyond the first week of
life, pre-term infants had a higher Cmax (4.74 lg/mL) than
full-term infants (3.00 lg/mL). Among full-term infants,
higher birthweights associated with a decreased Vd were
correlated with higher serum gentamicin levels during the
first 2 h after administration. In babies under 1 week of
age, the elimination half-life (t‘) for gentamicin was also
affected by the baby’s weight: t‘ = 11.5 h for infants
under 1,500 g, 8 h for infants 1,500–1,999 g, and 4.25–5 h
for infants over 2,000 g. When patients were stratified by
PNA, pre-term infants less than one week of age had a t‘
of 6.25 h, where all other infants ([1 week, \1 month)
ranged from 3.25 to 4.5 h, possibly due to more mature
kidney function in the older infants. In three infants treated
for meningitis, cerebral spinal fluid (CSF)/serum ratios
ranged from 10 to 120 %, with higher ratios correlating
with higher cell counts and protein in the CSF. A follow-up
study evaluated the role of intramuscular (IM) dosing,
serum creatinine, and weight on urinary clearance in 32
 584

Table 2 Antibacterial pharmacokinetics

Class Drug Recommended dosing Therapeutic range Metabolism Clearance References

Aminoglycosides Gentamicin PNA B14 days, 5 mg/kg/q48 h IV Peak 5–10 lg/mL NA Kidney, [7–19, 206]
\1 kg unchanged
PNA B7 days, 5 mg/kg/q48 h IV
1–2 kg
PNA 15–28 days, 4–5 mg/kg/q24–48 h IV
\1 kg
PNA 8–28 days, 4–5 mg/kg/q24–48 h IV Trough Below 2 lg/mL
C1–2 kg
PNA B7 days, 4 mg/kg/q24 h IV
[2 kg
PNA 8–28 days, 4 mg/kg/q12–24 h IV
[2 kg
Aminopenicillins Ampicillin PNA B7 days, 50 mg/kg q12 h IV, IM NA Hepatic (10 %) Kidney [109, 138,
\2 kg (25–40 %) 207, 208]
PNA B7 days, 50 mg/kg q8 h IV, IM
C2 kg
PNA [7 days, 50 mg/kg q8 h IV, IM
\2 kg
PNA [7 days, 50 mg/kg q6 h IV, IM
C2 kg
Glycopeptides Vancomycin PMA B29 weeks, 10–15 mg/kg q18 h, IV Peak 30–40 mg/L NA Kidney, [209–211]
PNA 0–14 days infusion 1 h (PNA [14, unchanged
q12 h)
PMA 30–36 weeks, 10–15 mg/kg q12 h, IV
PNA 0–14 days infusion 1 h (PNA [14, q8 h)
PMA 37–44 weeks, 10–15 mg/kg q12 h, IV Trough 5–15 mg/mL, 15–20 mg/mL
PNA 0–7 days infusion 1 h (PNA [7, q8 h) for invasive infection
PMA C45 weeks 10–15 mg/kg q6 h, IV infusion
1h
Cephalosporins Cefotaxime Neonates \1 week 50 mg/kg q12 h IV NA Liver— Kidney [180–188,
Neonates [1 week 50 mg/kg q8 h IV desacetylcefotaxime 212]
(active metabolite)
Older infants 50 mg/kg q 6h IV
IM intramuscular, IV intravenous, NA not available, PMA postmenstrual age, PNA postnatal age, qx h every x hours
J. K. Roberts et al.
Antimicrobial/Antiviral PK–PD in Neonates and Infants
neonates [23]. In this study, excretion of gentamicin was
directly correlated with PNA and creatinine clearance
(increased PNA correlated with increased clearance).
Gentamicin is primarily eliminated via the kidneys and its
clearance is closely correlated with creatinine clearance; as
such, with increases in creatinine clearance, the t‘
decreases [24]. Subsequent studies evaluating different
dosing regimens and very low birthweight (VLBW) infants
(\1,500 g) support these pharmacokinetic findings [25–
45]. Other groups found a greater correlation between
postconceptional age and t‘ or clearance [19, 46, 47]. One
study suggested sex played a role on clearance, with girls
having a faster clearance than boys [48]. A study by Szefler
et al. [49] suggested that a longer dosing interval of 18 h be
used in pre-term infants\35 weeks. To further simplify the
dosing interval, Hindmarsh et al. [50] suggested a higher
dose every 24 h. Longer dosing intervals have subse-
quently been supported by other studies, in which dosing
intervals ranged from 24 to 36 h [44, 51–78], though safety
of once daily dosing in extremely low birthweight (ELBW)
infants is not well-established.
The route of administration alters the pharmacokinetics
of gentamicin in ways that are clinically important. Paisley
et al. [79] compared IM with intravenous (IV) adminis-
tration in 18 infants. Cmax concentrations for IM and IV
were similar, but both the magnitude and the timing of
Cmax varied much more widely after IM administration.
This difference has also been shown by others [80]. This
could be attributed to the pharmacodynamic observation
that sick infants usually have decreased blood flow to their
extremities, which decreases the absorption of drug after
IM injection. Half-lives were similar for IM and IV, with
mean concentrations equal to 4 h. Additionally, this study
identified PNA as a significant pharmacokinetic variable,
as the t‘ decreased significantly after 7 days of life.
Overall, the authors found no difference in the pharmaco-
kinetics of IM and IV gentamicin. The authors recom-
mended a dose of 2.5 mg/kg given every 8 h, though they
acknowledged the wide range of variability in their study
population, which supported therapeutic monitoring to
guide clinical dosing. McCracken et al. [81] came to the
same conclusion in their study. Gentamicin exhibits con-
centration-dependent killing, emphasizing the importance
of Cmax values. To achieve therapeutic Cmax earlier, Wat-
terberg et al. [82] evaluated the use of a 4 mg/kg loading
dose. Ninety-two percent of the patients who received the
loading dose achieved gentamicin serum concentrations in
the therapeutic window after the first dose, compared with
only 45 % of patients who were given the usual dose of
2.5 mg/kg. There was no effect upon steady-state phar-
macokinetics. The authors suggested a loading dose of
4 mg/kg in all neonates receiving gentamicin therapy,
which was later supported by additional studies [83–86].
585
Giacoia and Schentag [87] evaluated multiple daily dosing
versus continuous infusion and found that infants who
received gentamicin via continuous infusion had a larger
Vd, a larger AUC, a longer terminal t‘, and slower clear-
ance. Additionally, creatinine clearance was significantly
lower in infants who received continuously infused gen-
tamicin. The authors concluded that infants receiving
gentamicin via continuous infusion were at higher risk for
nephrotoxicity. Subsequently, Sherwin et al. [88] deter-
mined that ELBW (\1,000 g) neonates have prolonged IV
gentamicin delivery due to slow IV flow rates and small
administered volumes, which result in only 60 % of the
drug delivered in 60 min. The authors suggested that bolus
doses be given to this population to ensure the total dose is
delivered.
Gentamicin renal toxicity had been well-documented in
adults, which prompted Haughey et al. [89] to evaluate this
further in pre-term infants. The researchers determined that
clearance in neonates was threefold higher than adults
when adjusted for body surface area, which has been
supported by other aminoglycoside work [90]. Utilizing a
two-compartment model to fit the data, neonates had a
twofold higher mean Vd. Aminoglycosides are reabsorbed
by the proximal tubule. However, pre-term infants have
immature renal proximal tubules and the authors hypoth-
esized that this protects neonates from renal toxicity. These
findings were supported by Landers et al. [91] who iden-
tified a low incidence of nephrotoxicity in VLBW infants.
Many neonatal patients receiving gentamicin therapy
have additional co-morbidities affecting gentamicin phar-
macokinetics and renal function. Friedman et al. [92]
evaluated gentamicin pharmacokinetics in asphyxiated
newborns with impaired renal function and found that the
t‘ and clearance were prolonged in asphyxiated infants,
with clearance and urine output also correlating to mean
arterial pressure. Part of this finding could be attributed to
hypothermia used to treat asphyxiated newborns to prevent
further neurological injury, which also decreases glomer-
ular filtration rate. This finding suggests that lower doses or
longer dosing intervals may be needed in asphyxiated
infants. Bravo et al. [93] studied malnourished infants and
reported that the Vd was 18.3 % higher in the malnourished
population, resulting in a higher time to Cmax (tmax).
Watterberg et al. [94] determined that patients with patent
ductus arteriosus (PDA) had a significantly increased Vd
and serum t‘. However, the Vd decreased after ductal
closure. While the effect of PDA on gentamicin pharma-
cokinetics has been demonstrated in multiple studies, it has
not been shown to have clinical relevance and dosing
adjustments based on the presence of a PDA are not nec-
essary [95, 96]. The effect of extracorporeal membrane
oxygenation (ECMO) on gentamicin pharmacokinetics has
been variable. Southgate et al. [97] found ECMO treatment
586
did not significantly affect Vd in infants, but increased the
elimination t‘ by more than 3 h. As a result, the authors
suggest starting at the usual 2.5 mg/kg, but using an
extended dosing interval of at least 18 h. Another study
evaluating 18 infants compared individual patient phar-
macokinetic parameters before and after ECMO [98]. As
expected, this group found that patients had a higher Vd.
However, a lower clearance and a prolonged t‘ while
undergoing ECMO necessitated a decrease in the dose by
25 % in addition to lengthening the dosing interval despite
the increased Vd. This finding was also supported by Dodge
et al. [99] using a population pharmacokinetic approach.
Other groups, however, found no significant impact of
ECMO on gentamicin pharmacokinetics [100, 101]. A
study by Lingvall et al. [102] examined Vd differences
between babies that were septic and those that were not.
Septic babies had a 14 % increase in their Vd. Sherwin
et al. [103] evaluated whether this increase was due to IV
volume expanders, but determined the Vd was not affected
by cumulative volume expanders. Neither UV light therapy
associated with jaundice [104] nor being large for GA
[105] had a significant effect on the pharmacokinetic
properties of gentamicin.
2.1.3 Clinical Implications and Future Research
Gentamicin is one of the most commonly prescribed anti-
bacterials in the neonatal intensive care unit [106]. His-
torically, pharmacodynamic studies have demonstrated that
peak antibacterial activity occurs when the maximum
blood concentration exceeds 5 lg/mL [107]. Additionally,
the risk of nephrotoxicity is minimized by targeting trough
concentrations \2 lg/mL to prevent the accumulation of
gentamicin in the proximal renal tubule [108]. For most
populations, trough monitoring for safety should be ade-
quate. However, for some special populations (e.g., renally
impaired or cystic fibrosis) two post-distributive samples
should be taken and the AUC should be used for adjusting
the dose. For neonates with varying degrees of renal
maturity, optimal IV gentamicin dosing regimens incor-
porate the age and weight of the newborn, such that for
newborns \1 kg the recommended dosing regimen is
5 mg/kg every 48 h for neonates B14 days of age, and
4–5 mg/kg every 24–48 h for neonates 15–28 days of age
[109]. Similarly, recommended gentamicin doses for
infants 1–2 kg are 5 mg/kg every 48 h for neonates
B7 days of age and 4–5 mg/kg every 24–48 h for neonates
8–28 days of age [109]. Finally, for infants [2 kg, the
recommended dosing is 4 mg/kg every 24 h for neonates
B7 days of age and 4 mg/kg every 12–24 h for neonates
8–28 days of age [109]. These extended interval and once-
daily dosing regimens have been evaluated in a large sys-
tematic meta-analysis and were found to be associated with
J. K. Roberts et al.
fewer failures to attain therapeutic peak and trough con-
centrations than multiple daily dosing (relative risk: 0.22;
95 % CI 0.11–0.47) [110]. Recently, in vitro time-kill
experiments and semi-mechanistic pharmacokinetic and
pharmacodynamic modeling studies have suggested that
due to gentamicin’s extended t‘ in neonates, extended
interval dosing is not likely to promote the emergence of
adaptive resistance to gentamicin [111].
The pharmacokinetics and pharmacodynamics of gen-
tamicin have been rigorously studied in pre-term and term
neonates over the last 50 years. Appropriately, many of
these studies have focused on identifying patient charac-
teristics that influence the likelihood of achieving a good
clinical outcome. However, additional studies are needed
in unique neonatal subpopulations, including those with
intra-uterine growth restriction and perinatal asphyxia, for
which data are scarce. Conditions such as these have been
reported to alter gentamicin pharmacokinetics and there-
fore further study is needed to determine if alternative
dosing regimens are required to optimize the achievement
of target peak and trough concentrations that are associated
with therapeutic success.
2.2 Aminopenicillins: Ampicillin
2.2.1 Pharmacodynamics
Ampicillin features activity against many of the most
common etiological agents of early-onset neonatal sepsis,
including group B streptococci [112]. Ampicillin is dis-
tinguished from penicillin G by the presence of an amino
group, which aids in its penetration of Gram-negative cell
membranes [113]. The bactericidal activity of ampicillin
stems from its irreversible inhibition of transpeptidase,
which is an essential component required for bacterial cell
wall synthesis and binary fission [114]. Ampicillin displays
time-dependent bactericidal activity, which means that the
pharmacodynamic parameter that has been most strongly
correlated with maximal bacterial killing is the time above
the minimum inhibitory concentration (MIC) [T [ MIC] of
the infecting organism [115, 116]. To achieve optimal
bactericidal activity and to minimize the emergence of
microbial resistance, it is not necessary for ampicillin
concentrations to exceed the MIC for the entire dosing
interval [117, 118]. In adults, a T [ MIC of 30–40 % of the
dosing interval has been strongly correlated with good
clinical outcomes, although studies have suggested that
40–50 % T [ MIC is required for neonates [115]. Ampi-
cillin concentrations that are much higher than the MIC do
not greatly enhance bactericidal activity [119].
Although rare, several hypersensitivity reactions can
occur in ampicillin-treated infants younger than 6 months
of age [120]. Patients with a history of b-lactam
Antimicrobial/Antiviral PK–PD in Neonates and Infants
hypersensitivity or previous IgE-mediated reactions should
not receive ampicillin due to the potential for severe, life-
threatening hypersensitivity reactions. Ampicillin admin-
istration to neonates and infants with confirmed penicillin
allergy should be avoided. Among other infants less than
6 months of age, ampicillin-associated drug rashes are rare,
but do occur and include: erythema multiforme, exfoliative
dermatitis, and urticaria [120]. Approximately 5–10 % of
patients treated with ampicillin experience an exanthema-
tous cutaneous eruption, although this figure rises to nearly
100 % among patients with viral infections (e.g., Epstein–
Barr virus) [121]. Management of an exanthematous
cutaneous reaction includes cessation of ampicillin therapy,
switching to an alternative antimicrobial agent, and the
addition of antihistamines or corticosteroids [122].
2.2.2 Pharmacokinetics
The American Academy of Pediatrics (AAP) recommends
that the optimal treatment of early-onset neonatal sepsis
include therapy with broad-spectrum antimicrobial agents,
including ampicillin and an aminoglycoside [123]. The
pharmacokinetic properties of ampicillin have been
extensively studied in pre-term and term-neonates, infants,
children, and adults [124–134]. An early study by Boe et al.
[124] examined serum concentrations of ampicillin fol-
lowing IM administration and reported markedly higher
concentrations and a longer t‘ in pre-term neonates than in
adults exposed to comparable doses. These findings are
supported by a larger study by Axline et al. [125], who
found that the serum t‘ of ampicillin decreases with
increasing PNA. A nearly identical rate of change was
observed at all PNA, despite differences in weight [125].
Cmax and tmax were not different among pre-term neonates
when compared with older children and adults following
IM administration of ampicillin [125, 135]. However, the
bioavailability of orally administered ampicillin is
increased in neonates and infants due to their high gastric
pH, which enhances the bioavailability of acid labile drugs
[126, 136]. By 3 years of age gastric acid production
reaches adult levels; however, until this time, neonates and
infants achieve higher serum concentrations of orally
administered ampicillin than older children and adults
[126, 135, 136]. Additionally, neonatal gastric emptying is
prolonged, which results in increased absorption of acid
labile drugs such as ampicillin [131, 135]. In infants 2
months of age and older, concomitant milk ingestion has
not been shown to alter ampicillin pharmacokinetics [131,
132]. In contrast, Ehrnebo et al. [137] demonstrated that
ampicillin displays age-dependent ampicillin protein
binding activity, with decreased protein binding observed
among neonates. This results in a larger fraction of
unbound ampicillin in the circulation and increases the Vd
587
relative to older children and adults. Competition for pro-
tein binding sites can further increase the fraction of
unbound drug, as occurs in neonatal hyperbilirubinemia
where endogenous bilirubin reduces ampicillin protein
binding [137].
2.2.3 Clinical Implications and Future Research
In the 1970s, Kaplan et al. [127] derived neonatal ampi-
cillin dosing recommendations on the basis of in vitro
experiments demonstrating ampicillin’s activity against
Gram-positive pathogens and E. coli as well as pharma-
cokinetic data obtained after administering doses of 50, 75,
and 100 mg/kg/dose to pre-term and full-term neonates.
Ampicillin dosing recommendations from the AAP and the
British National Formulary Committee [109, 138] are
similar to those reported by Kaplan et al. [127] and suggest
the use of 50 mg/kg every 12 h administered via IV push
for neonates B7 days PNA who weigh\2 kg. For neonates
B7 days PNA who weigh [2 kg or for those who
are [7 days PNA and weigh \2 kg the recommended dose
is 50 mg/kg every 8 h. For neonates [7 days PNA who
weigh C2 kg the recommended dose is 50 mg/kg every
6 h.
Ampicillin CSF concentrations range from 6 to 15 % of
serum concentrations [127]. Therefore, when ampicillin is
used in combination with an aminoglycoside for the
treatment of meningitis it is recommended that the dose be
doubled from 50 to 100 mg/kg/dose [109, 127, 138, 139].
Since the development of ampicillin more than half a
century ago, much has been learned about its optimal use in
the clinical setting. Current neonatal dosing recommenda-
tions are predicated upon carefully conducted pharmaco-
kinetic and pharmacodynamic studies and have been
associated with good clinical outcomes in multiple retro-
spective analyses. Conversely, relatively little is known
about how genetic variations may affect the response to
ampicillin therapy. Further investigation is warranted to
identify patient characteristics, including genetic profiles,
which may be used to predict the risk of developing an
ampicillin-associated hypersensitivity reaction. Addition-
ally, further research is needed to define the appropriate
antihistamine dose needed to effectively and safely treat
hypersensitivity reactions in neonates and infants.
2.3 Glycopeptides: Vancomycin
2.3.1 Pharmacodynamics
It is well-understood that vancomycin dosing regimens
need to be designed to clear the infection rapidly without
causing toxicity or promoting resistance [140, 141].
However, multiple studies of vancomycin use in pediatric
588
patients have found that previously recommended dosing
regimens often do not achieve designated therapeutic ran-
ges [142, 143]. This is especially concerning with reports
of decreased susceptibility of methicillin-resistant S. aur-
eus (MRSA) to vancomycin [140]. Although very limited,
there have been cases of MRSA treatment failure in chil-
dren with subtherapeutic vancomycin concentrations
(\5 mg/L) and in vulnerable patients, such as pre-term
neonates and immunocompromised children [144, 145].
Yet, reports of clinical failure of vancomycin in the pedi-
atric population have been rare [146]. In addition to the risk
of inefficacy, subtherapeutic vancomycin concentrations
select for resistant strains, including the vancomycin
intermediate S. aureus (VISA) [10].
The adverse drug reactions associated with vancomycin
in adults seem to be diminished in both severity and fre-
quency among neonates and infants [143, 146]. This phe-
nomenon is reflected in current therapeutic drug
monitoring (TDM) practices, where concerns over toxicity
have given way to ensuring vancomycin concentrations
meet therapeutic targets [147]. In light of studies con-
firming therapeutic targets are not consistently being met,
consensus statements recommending higher target con-
centrations, and a lack of evidence for severe vancomycin-
associated toxicity, there has been a trend toward the sue of
higher doses of vancomycin across pediatric age groups,
including neonates and young infants [148–150]. Conse-
quently, these factors and the collective experience of
infrequent treatment failure may be contributing to the
wide variation found among institutions in TDM and
vancomycin use practices in pediatric patients [151, 152].
The pharmacodynamic target best related to clinical
outcome is not known for neonates and young infants
[142]. Currently, therapeutic targets for MRSA infections
are derived from adult, animal, and in vitro studies, in
addition to therapeutic failures in newborns and infants. In
adults, the best outcomes are associated with an AUC/
MIC [400, which correlates with serum trough concen-
trations of [10 mg/L on a 12 h dosing schedule for an
isolate with a MIC \1 mg/L [153]. Recent studies, one of
which included children as young as 3 months, have
determined that a significant portion of children (from 75
to [90 %) with serum vancomycin trough concentrations
of approximately 7 to 10 mg/L will achieve an AUC/MIC
of [400, as long as the MIC is B1 mg/L [153, 154].
However, this finding has yet to be confirmed in neonates.
At present, the drive to increase vancomycin exposure in
pediatric patients through higher trough targets (i.e.,
increased from a historical [5–10 mg/L at steady state
to [10 mg/L, and to 15–20 mg/L for invasive infections
[155]) based on extrapolation from adult data has raised
concerns [147]. The most appropriate pharmacodynamic
target remains a matter of debate [156]. Central to this
J. K. Roberts et al.
debate is recognizing that the context for the use of van-
comycin often differs significantly for neonates versus an
adult population. For instance, in neonates, vancomycin is
frequently used empirically for suspected sepsis and for the
treatment of infections caused by coagulase-negative S.
aureus. Therefore, therapeutic targets based on treating
MRSA infection in adults may not be ideal for a neonate
[157].
2.3.2 Pharmacokinetics
The pharmacokinetic heterogeneity of vancomycin among
neonates and young infants poses a significant challenge
for dose optimization [140] and prevents the use of simple
standard dosing regimens without TDM [146, 158]. For
example, neonates have a higher percentage of bodyweight
as water and undergo rapid postnatal renal maturation
causing changes to elimination and clearance, particularly
within the first week of life. Integral to bacterial response is
the concentration of free vancomycin. In adults, protein-
bound vancomycin ranges from 24 to 64 % with a mean of
41.5 % [159]. In addition to the variability found in the
proportion of bound versus free vancomycin, neonates also
have decreased protein–drug binding due to lower albumin
concentrations comprised, in part, of fetal albumin, which
has a lower binding affinity for drugs [135]. Furthermore,
patients admitted to intensive care for complex disease
states such as renal failure, cardiovascular complications,
or severe lung disease represent pharmacokinetically dis-
tinct subsets of infants who may require different dosing
regimens [160, 161]. Attempts to understand and adapt
vancomycin use to the pharmacokinetic variability in
neonates and young infants are usually based on methods
seeking to quantify the most relevant covariates contrib-
uting to vancomycin clearance [162]. Since vancomycin is
eliminated unchanged almost exclusively by the kidneys,
covariates associated with the maturational changes in
renal function and development are central to all vanco-
mycin dosing strategies in neonates and young infants
[143, 163].
Vancomycin is distinctive among anti-infectives due to
the intensity with which it has been the focus of pharma-
cokinetic modeling and simulation efforts to refine its use.
While there has been much progress, an optimal dosing
regimen has yet to be defined [140]. The inter-individual
variability in vancomycin disposition in neonates and
young infants can, in part, be explained by covariates such
as postmenstrual age (PMA), PNA, weight, serum creati-
nine, and the concomitant use of certain drugs [164, 165].
However, even when the most significant covariates (i.e.,
age, bodyweight, and creatinine clearance) are accounted
for in neonates, the unexplained inter-individual variability
for clearance and Vd is still high [166]. Among pre-term
Antimicrobial/Antiviral PK–PD in Neonates and Infants
and term neonates (27–47 weeks PMA) the variability,
after accounting for serum creatinine and bodyweight, was
23 % for clearance and 47 % for the Vd as reported by
Oudin et al. [167]. Likewise, in neonates (\29 days of
age), de Hoog et al. [168] found that clearance had an
associated 31 % variability (0.057 ± 0.0018 L/h/kg) and
the Vd had 25 % (0.43 ± 0.013 L/kg) variability. A sub-
sequent study of pre-term neonates (\35 weeks’ PMA and
PNA \29 days) determined that the majority of the vari-
ability in vancomycin clearance was explained by the
child’s weight (49.8 %), PMA (18.2 %), and renal function
(14.1 %) [162]. It is important to recall that the newborn’s
serum creatinine does not reflect endogenous renal function
until maternal creatinine received across the placenta is
cleared, which takes several days after birth. In addition to
the covariates that relate to maturational changes, it is also
important to consider the influence of the assay method-
ology (i.e., serum creatinine and vancomycin quantification
analysis) on individual and population estimates [169].
Overall, population pharmacokinetic models still con-
tain sufficient levels of unexplained variability to warrant
continued TDM for post hoc dose adjustment to achieve a
given pharmacodynamic target concentration [140, 166].
Nonetheless, a recent external validation analysis across
multiple population pharmacokinetic models found that
most models led to ‘acceptable’ vancomycin concentra-
tions in neonates [166]. Although vancomycin pharmaco-
kinetics are best described as multi-compartmental with a
long distribution phase, one-compartment models perform
well in estimating pharmacokinetic parameters for the
purpose of individualizing dosage regimens [143, 158].
One-compartment models have the advantage of requiring
fewer serum samples than more complex models to esti-
mate pharmacokinetic parameters, which is particularly
relevant for neonates and infants [158].
2.3.3 Clinical Implications and Future Research
The glycopeptide antibacterial vancomycin has been
available to treat serious infections for more than half a
century, including in newborns and infants [170]. With the
relatively recent emergence of MRSA, the use of vanco-
mycin has increased significantly as it is the recommended
first-line antibacterial for the prophylaxis and treatment of
resistant Gram-positive infections [158, 171]. However,
coagulase-negative S. aureus remains the predominant
infectious organism for which vancomycin is used in
neonates and young infants [143, 172]. Within this youn-
gest patient population the t‘ of vancomycin can range
from 2 to 12 h, with highly variable rates of clearance and
Vd [140, 160, 173]. The physiologic and developmental
characteristics inherent in neonates and young infants make
vancomycin a challenging drug to use from a
589
pharmacokinetic perspective, and the situation is further
complicated by the lack of evidence of the best pharma-
codynamic measure for pediatric clinical outcomes.
Moreover, the last decade has seen an evolution in the
therapeutic target recommendations for adults, followed
by revisions to pediatric targets for vancomycin
concentrations.
Vancomycin dose optimization requires an understand-
ing of the pharmacokinetic profile of the patient and the
pharmacodynamic target best associated with microbio-
logical efficacy for that patient’s infection. At present,
there is a necessary complexity to vancomycin use in very
young patients, which has been associated with errors in
use [167]. Therefore, the successful implementation of
individualized regimens will also need to address pre-
scription difficulties to maximize the benefit to patients
[167, 174]. Attempts to simplify dosing regimens by
employing a single parameter, such as weight, may result
in 50–60 % of patients exposed to sub- or supra-therapeutic
concentrations [175]. Furthermore, static formulas and
nomograms are often regarded as overly simplistic for the
pharmacokinetic variability of neonates and young infants
[176].
Arguments have been made about simplifying the
manner of administration to reduce confusion and possibly
improve the safety of vancomycin dosing protocols. Van-
comycin has poor oral absorption, requiring IV adminis-
tration for systemic infections [151, 172]. The use of
continuous infusion has been proposed to offer advantages
of practicality and safety surrounding the implementation
of complex individualized dosing regimens [167]. Addi-
tionally, bactericidal activity may be improved with con-
tinuous infusion due to the ability to achieve a more
consistent AUC than intermittent dosing [141]. Unfortu-
nately, rapid infusions of vancomycin that might occur
when a catheter is flushed exposes the patient to risk of the
rapid release of histamine causing what has been called the
‘‘red man syndrome’’ [177]. Currently, both intermittent
and continuous infusions are used in neonates, with similar
clinical efficacy between the two methods, but safety and
pharmacokinetic data are much more limited with respect
to continuous infusion [168, 178].
The high degree of pharmacokinetic variability in neo-
nates and young infants make dose individualization of
vancomycin a challenge and a priority for optimizing
therapy [158]. Among the myriad physiologic, demo-
graphic, and clinical factors that influence vancomycin
pharmacokinetics in neonates and young infants, the most
important are weight, age, and renal function. While dosing
regimens incorporating these covariates have demonstrated
improved rates of attainment for currently recommended
therapeutic targets [168], more studies are required to
determine the pharmacodynamic target that best correlates
590
with clinical outcomes. Finally, a key component to
improving vancomycin therapy in infants will be imple-
menting dosing regimens and TDM protocols that are less
complicated for clinicians while adapting to the diverse
pharmacokinetics of this patient population [179].
2.4 Cephalosporins: Cefotaxime
2.4.1 Pharmacodynamics
Cefotaxime and its active metabolite desacetylcefotaxime
both display antimicrobial activity and are widely used in
the treatment of neonates and young infants [180, 181].
Cefotaxime inhibits bacterial wall synthesis by inhibiting
penicillin-binding proteins Ib and III [182–184]. Cefotax-
ime has activity against most Gram-negative bacteria and
some Gram-positive bacteria, with some resistance noted in
Enterobacter spp., Serratia spp., and Citrobacter freundii
[185]. Cefotaxime penetrates well into the central nervous
system (CNS) and is moderately bound by serum proteins
[186, 187]. Cefotaxime has a relatively large therapeutic
window with a general lack of serious adverse effects
associated with treatment in neonates and infants [188].
However, a retrospective study completed by Clark et al.
[189] compared cefotaxime combined with ampicillin to
gentamicin combined with ampicillin and found that cef-
otaxime combined with ampicillin for the empiric treat-
ment of neonates has an unexplained increase in mortality
(1.5 odds ratio), which was not related to renal failure or
meningitis.
2.4.2 Pharmacokinetics
A study completed by Kafetzis et al. [190] compared the
pharmacokinetics of neonates born pre-term and full-term at
the ages of \1 and 1–4 weeks. Pre-term neonates \1 week
had a significantly longer t‘ (5.7 h) than infants and adults
(1 h). All term neonates and pre-term neonates[1 week old
averaged a t‘ around 2–4 h. In addition, Vd was significantly
higher than in adults, but clearance was significantly
decreased in all neonates. Differences between neonates and
adults can be attributed to decreased glomerular filtration
rates. These results are in agreement with other studies
independent of GA, with McCracken et al. [191] suggesting
that all infants \1 week receive 50 mg/kg every 12 h and
infants [1 week receive 50 mg/kg every 8 h, which has
subsequently been supported by others [192–197]. However,
a study evaluating VLBW neonates (\1,500 g) found an
even longer t‘ with accumulation of the active metabolite in
the serum and suggested increasing the dosing interval to
24 h [198]. Studies among infants \1 year of age reported
similar Vd, clearances, and t‘ values to older children and
adults [186, 199, 200]. A recent study evaluated infants on
J. K. Roberts et al.
ECMO and found that their Vd was higher, but their clearance
and t‘ were similar to non-ECMO infants [201]. The authors
also reported that only one patient had serum concentrations
below the MIC for more than half of the dosing interval,
suggesting that no change in dosing is required for infants on
ECMO.
2.4.3 Clinical Implications and Future Directions
The third-generation cephalosporin cefotaxime possesses
several features that make it an attractive antibacterial
agent for the treatment of neonatal sepsis. Principally,
cefotaxime displays potent activity against group B strep-
tococcus, as well as E. coli, and other Gram-negative
enteric bacilli [202]. However, cefotaxime monotherapy is
not recommended owing to the fact that large microbio-
logical surveillance studies have demonstrated that only
79 % of the bacterial organisms identified from neonates
with late-onset sepsis were susceptible to cefotaxime alone
[203]. In contrast, 95 % of the isolated organisms were
susceptible to combination therapies with amoxicillin and
cefotaxime or gentamicin and amoxicillin [203]. Never-
theless, the empiric use of cefotaxime has been reported to
increase the risk of developing invasive candidiasis in pre-
term neonates and was associated with an increased risk of
death in both pre-term and term neonates when compared
with gentamicin [189, 204]. For these reasons, the empiric
use of cefotaxime is discouraged [205]. However, in cases
of suspected or proven Gram-negative bacillary meningitis,
the use of cefotaxime is encouraged due to its superior CSF
penetration, which has been reported to result in CSF
concentrations ranging from 0 to 20 % of serum concen-
trations, with improved blood–brain barrier penetration
when the meninges are inflamed [186, 202]. For neo-
nates \2 kg with suspected neurologic involvement, the
recommended dosing schedule is 75 mg/kg every 12, 8,
and 6 h for neonates B7, 8–28, and [28 days of age,
respectively [109]. Similarly, among neonates C2 kg, the
recommended dosing schedule is 50 mg/kg every 6 h for
neonates B7 days of age and 75 mg/kg every 6 h for all
neonates and infants [7 days old [109].
3 Antifungals
The incidence of invasive fungal infections is increasing in
the neonatal population [213]. Invasive candidiasis is a sig-
nificant problem in the neonatal ICU with mortality rates as
high as 25 % for sepsis and up to 36 % for meningitis [213].
Advances in medical technology, such as parenteral lines,
enteral feeding tubes, central vascular catheters, broad-
spectrum antibacterials, and lower GA newborns have
increased the susceptibility of pre-term neonates to invasive
Antimicrobial/Antiviral PK–PD in Neonates and Infants
fungal infections [214]. Incubators also add challenges with
skin care management and incubator humidity. In addition,
pre-term infants’ immunodeficiency, immature skin, and
increased permeability of cutaneous barriers increase their
risk for fungal infections [215, 216]. The most common
invasive fungal infection that affects neonates and infants is
candidiasis [217]. Invasive candidiasis can lead to death,
neurodevelopmental impairment, lung disease, advanced
retinopathy of prematurity, and periventricular leukomalacia
[218–221]. As such, any patient less than 3 months of age
should be considered to be at risk for invasive Candida
infections and should be monitored closely for signs and
symptoms of infection. Polyenes, azoles, and echinocandins
are the most common drug classes used in neonates and
infants to treat disseminated candidiasis (pharmacodynam-
ics in Table 3; pharmacokinetics in Table 4).
3.1 Polyenes: Amphotericin B Deoxycholate and Lipid
Formulations
3.1.1 Pharmacodynamics
One of the first and most common drugs used to treat
invasive fungal infections in neonates is amphotericin B
deoxycholate [222], which binds to ergosterol in fungal cell
membranes, resulting in cell death [223]. Resistance to
amphotericin B is rare, though there are reports of Candida
glabrata, C. krusei, C. lusitaniae, and C. parapsilosis
resistance [224, 225]. Mechanisms of resistance usually
stem from a decrease in the ergosterol content in the cell
membrane, leading to a decrease in amphotericin B binding
affinity [226]. Amphotericin B deoxycholate is poorly
absorbed orally, is highly protein bound, and widely dis-
tributed in the liver, spleen, and kidneys [227]. Ampho-
tericin B deoxycholate has been associated with high
toxicity due to binding to the cholesterol elements of
mammalian cells [228]. Some studies evaluating ampho-
tericin B deoxycholate in neonates reported hypokalemia
[229–231]. Although nephrotoxicity is common in adults, it
is not as apparent in neonates [232]. However, a study
completed by Turcu et al. [233] found that infants with
high sodium intake displayed a lower level of nephrotox-
icity, confirming a previous study [234], and suggesting
that sodium loading may prevent or decrease nephrotoxi-
city in neonates. In addition, some neonates do experience
infusion-related immediate hypersensitivity reactions
resulting in fevers and chills at a similar rate to adults.
Toxicity is rarely reported with lipid formulations [231].
3.1.2 Pharmacokinetics
The first pharmacokinetic studies evaluating neonates were
published in the late 1980s. Starke et al. [235] evaluated
591
seven infants and their data fit a one-compartment model.
Serum concentrations in infants were lower than reports of
adults and children. Infants also cleared the drug more
rapidly, possibly protecting this population from the
nephrotoxicity seen in adults, but also suggesting infants
may need a higher dose. Weight was a significant covariate
on Vd and clearance. The youngest pre-term neonate
demonstrated an extended t‘ of 693 h, suggesting that pre-
term neonates may need dosing intervals of [24 h. A
similar study evaluated five pre-term neonates and the
authors concluded that a lower dose of 0.5 mg/kg/day was
sufficient to achieve a Cmax of 0.99 ± 0.48 lg/mL [236]. A
study completed by Baley et al. [237] followed up on their
previous work, which reported renal failure in VLBW
infants when treated with amphotericin B and 5-fluorocy-
tosine [230]. They sought to determine if lower combined
doses would decrease renal toxicity in infants. The study
showed that with combined therapy of amphotericin B and
5-fluorocytosine, a lower dose could be used to prevent
renal toxicity. Five infants had CSF fluid obtained and CSF
amphotericin B concentrations were 40–90 % of serum
concentrations, demonstrating good penetration into the
CSF. Unfortunately, 5-fluorocytosine is not available in a
parenteral dosage form and must be given enterally.
Higuchi et al. [238] evaluated continuous infusion of
amphotericin B deoxycholate among ELBW neonates with
and without renal failure. Serum concentrations of
amphotericin B ranged from 0.31 to 0.78 lg/mL with daily
doses ranging from 0.2 to 0.55 mg/kg/day. Linear regres-
sion using the daily dose and serum creatinine reliably
predicted serum concentrations.
Lipid formulations of amphotericin B were developed to
decrease the toxicity of amphotericin B deoxycholate, though
neonates appear to be less susceptible to amphotericin B-
induced nephrotoxicity than older children and adults. Early
studies showed that lipid formulations were safer at higher
doses [239]. There are three lipid formulations on the market:
liposomal amphotericin B, amphotericin B lipid complex,
and amphotericin B colloidal dispersion. Liposomal
amphotericin B incorporates amphotericin B into unilamellar
liposomes with a diameter \100 nm. Amphotericin B lipid
complex incorporates a 1:1 ratio of dimiristoyl phosphati-
dylcholin/dimiristoyl phosphatidylglycerol, with a size
ranging from 500 to 5,000 nm. The last formulation com-
plexes amphotericin B with cholesteryl sulfate with a
diameter of 100 nm [223]. Complexing amphotericin B with
lipids results in a longer t‘ and decreased clearance when
compared with amphotericin B deoxycholate. In addition, the
large size of the complexes prevents glomerular filtration and
renal elimination, protecting the kidneys but also preventing
effective treatment of fungal balls in the bladder [231].
One of the first pharmacokinetic papers published with
neonatal data compared concentrations of liposomal
 592

Table 3 Antifungal pharmacodynamics

Class Drug Mechanism of action Mechanism of Resistant microbes Tissue Adverse events References
resistance penetration

Polyenes Amphotericin B Binds to ergosterol Decrease in Candida glabrata, Liver, spleen, Nephrotoxicity [222–227, 229–234, 239,
deoxycholate fungal cell ergosterol C. krusei, C. lusitaniae, kidneys 240, 273, 306–309]
membranes, content in cell C. parapsilosis,
Liposomal resulting in cell membrane C. guilliermondii Lungs, liver,
amphotericin B death spleen
Amphotericin B
lipid complex
Amphotericin B
colloidal
dispersion
Azoles Fluconazole Inhibits ergosterol Alteration in C. glabrata, C. krusei Kidney, CSF, Gastrointestinal, elevation [243–252, 254–257, 265–
biosynthesis, ergosterol liver, joint of liver enzymes 267, 273, 310, 311]
inhibiting cell synthesis spaces, saliva,
membrane repair vitreous humor
Voriconazole Uncharacterized C. glabrata Kidney, CSF, Elevated hepatic
liver transaminases, abnormal
vision, skin reactions due
to photosensitization
Echinocandins Caspofungin Inhibits (1,2)-b-D- Mutations to C. parapsilosis, Lung, liver, None in neonates [279–297, 312–315]
Micafungin glucan synthase FKS1 gene C. albicans, C. glabrata, spleen, kidney Elevated alanine/aspartate
enzyme, disturbing C. krusei, C. tropicalis aminotransferases,
cell wall synthesis temperature elevation,
hypokalemia,
hyperbilirubinemia
CSF cerebrospinal fluid
J. K. Roberts et al.
Table 4 Antifungal pharmacokinetics
Class Drug Recommended dosing Therapeutic range Metabolism Clearance References

Polyenes Amphotericin B deoxycholate All infants 1 mg/kg/day IV NA NA Liver, [222–227, 229–

unchanged 234, 239,
Liposomal amphotericin B All infants 5 mg/kg/day IV Uncharacterized 240, 273, 306–309]
Amphotericin B lipid complex All infants 5 mg/kg/day IV
Amphotericin B colloidal All Infants 5 mg/kg/day IV
Antimicrobial/Antiviral PK–PD in Neonates and Infants

dispersion
Azoles Fluconazole Loading 25 mg/kg IV AUC [400 mgh/L NA Kidney, [243–252, 254–257,
dose unchanged 265–267, 273, 310,
Maintenance 12 mg/kg/day 311]
IV
Voriconazole Loading 7 mg/kg q12 h Plasma 1–5 lg/L Liver—CYP2C19 Liver
dose IV concentrations
Therapeutic monitoring for
maintenance
Echinocandins Caspofungin Loading 70 mg/m2 IV NA Liver—hydrolysis and N- Liver [279–297, 312–315]
dose acetylation
Maintenance 50 mg/m2/day
IV
Micafungin Neonates 10 mg/kg/day
IV
Infants 1–4 mg/kg/day
IV
AUC area under the plasma concentration–time curve, CYP cytochrome P450, IV intravenous, NA not available, q12 h every 12 hours
593
594
amphotericin B in adults, children, and neonates [240].
Neonatal serum concentrations were reported to be sig-
nificantly lower than in adults, which the authors attributed
to a higher Vd.
The first population pharmacokinetic study of ampho-
tericin B lipid complex in neonates enrolled 28 neonates.
Blood serum data were fitted with a one-compartment
model with additive error. Clearance and Vd were scaled
allometrically. Mean serum blood concentrations did not
significantly differ from values reported in the adult liter-
ature and a non-compartmental analysis determined a mean
t‘ of 395 h. High concentrations of drug were reported in
the urine, but very low concentrations in the CSF, demon-
strating that the lipid formulation did not penetrate the CSF.
A retrospective data analysis of infants compared
amphotericin B deoxycholate and amphotericin B lipid
products, along with fluconazole, an azole antifungal drug
[241]. Infants who were treated with amphotericin B lipid
products had a higher mortality than those treated with
amphotericin B deoxycholate or fluconazole, which the
authors attributed to several factors, including inadequate
penetration of products in the kidneys or inappropriate
dosing in pre-term infants. This finding may suggest that
alternative antifungal classes with improved safety profiles
should be considered for neonates with invasive fungal
infections. However, such a study suffers from many
challenges that are common to pediatric data: retrospective
design, no control of severity of illness, and potential for
non-random selection of treatment.
3.1.3 Clinical Implications and Future Directions
Historically, given the decreased cost, similar efficacy,
safety, and tolerance compared with liposomal formula-
tions, amphotericin B deoxycholate is recommended as the
drug of choice for invasive candidal infections in neonates,
dosing at 1 mg/kg/day IV [241]. However, those infants
with existing renal disease or life-threatening infections
warranting increased doses may benefit from liposomal
formulations [242], which are recommended to be dosed at
5 mg/kg/day IV. Unfortunately, limited data exist on the
pharmacokinetics and pharmacodynamics of lipid-based
formulations of amphotericin B in neonates, complicating
dosing recommendations. Further studies are needed to
improve our knowledge of their adverse effect profiles as
the cost of these agents continues to decrease.
3.2 Azoles: Fluconazole and Voriconazole
3.2.1 Pharmacodynamics
The mechanism of action for triazoles is to inhibit fun-
gal cytochrome P450 (CYP)-mediated lanosterol 14
J. K. Roberts et al.
a-demethylation, inhibiting ergosterol biosynthesis and cell
membrane repair [243]. Prophylactic use of fluconazole has
contributed to increased resistance of C. glabrata and C.
krusei [244–247], and has decreased its use as a primary
antifungal agent. Conversely, voriconazole has activity
against a broad spectrum of fungi, including C. glabrata and
C. krusei [248–250]. Resistance to triazoles is usually
caused by an alteration in ergosterol synthesis, most com-
monly seen with changes to delta desaturase [251]. High
concentrations of triazoles have been found in the kidney
and liver [252], with close to 80 % of plasma concentrations
in the CSF and vitreal humor [253]. The most common
adverse effects of fluconazole are gastrointestinal irritation
and an elevation of liver enzymes [254]. Voriconazole
studies have also documented abnormal vision in addition
to elevated hepatic transaminases [255–257].
3.2.2 Pharmacokinetics
Fluconazole is a first-generation triazole. The first study to
evaluate fluconazole pharmacokinetics in infants was
published by Saxen et al. [258]. Twelve pre-term neonates
were enrolled. During the first two weeks of life their Vd
increased from 1.18 to 2.25 L/kg, their clearance increased
from 0.011 to 0.031 L/kg/h, and their t‘ decreased from
88.6 to 55.2 h. These parameters are consistent with
physiological changes that occur in the early postnatal
period. The authors suggested that at 6 mg/kg, patients
should be dosed at least every other day and possibly every
third day.
Nahata et al. [259] compared enteral to IV dosing of
fluconazole in pre-term neonates. The pharmacokinetic
parameters were similar between the two dosing methods,
suggesting that enteral and IV dosing were comparable. A
smaller study of three neonates completed by Wenzl et al.
[260] came to the same conclusion.
A population pharmacokinetic study by Wade et al.
[261] evaluated fluconazole pharmacokinetics in 55
infants. A one-compartment model best fit the data, with
significant covariates of weight, GA at birth, PNA, and
serum creatinine on clearance and weight on Vd. Clearance
doubled during the first month of life. This model sug-
gested that dosing of fluconazole will change based on GA
at birth and PNA due to the role kidney maturity plays in
clearance. This same study population was then used to
determine the optimal dosing regimen for neonates [262].
The authors concluded that a dose of 12 mg/kg/day should
achieve an AUC [400 mgh/L. However, it was noted that
it took 5 days for plasma concentrations to reach the
desired AUC [261–263].
A follow-up study of eight infants evaluated a loading
dose of 25 mg/kg followed by a maintenance dose of
12 mg/kg/day [264]. A median AUC of 479 mgh/L was
Antimicrobial/Antiviral PK–PD in Neonates and Infants
achieved after the first 24 h. Five of the eight infants
achieved an AUC [400 mgh/L after the first 24 h, which
suggests a loading dose achieves the therapeutic target
more rapidly than a maintenance dose of 12 mg/kg/day.
Voriconazole is a second-generation triazole that
exhibits high pharmacokinetic variability in pediatric
patients and is frequently reserved for treatment of severe
fungal infections, such as aspergillosis [265]. It can be
administered orally with high bioavailability, although IV
administration is preferred in neonates. Voriconazole is
extensively metabolized by CYP2C19 and requires dose
adjustments in patients with hepatic failure or with genetic
polymorphisms [266, 267]. Neonatal pharmacokinetic data
are scarce, potentially owing to reports of visual distur-
bances in older children and adults, which may adversely
affect retinal development [255]. In addition, the require-
ment to study voriconazole in patients \24 months has
been waived by the FDA [268]. However, studies and case
reports have demonstrated that younger children require
higher oral doses due to increased hepatic clearance by
CYP2C19 than adults, with children B3 years of age
demonstrating variable pharmacokinetics, further support-
ing the importance of voriconazole TDM [269–272].
A case report evaluating a single pre-term infant given
9 mg/kg every 12 h reported a Vd of 1.045 L/h/kg, clear-
ance of 0.240 L/h/kg, and a t‘ of 3.0 h [271]. The authors
found that an increase in dose was required to achieve
trough concentrations [1 lg/mL due to weight-based
dosing not accurately predicting serum concentrations. In
addition, the only clinical study published to date that
solely evaluated neonatal patients was a retrospective study
of 17 patients [257]. Patients were first administered
amphotericin B, but due to lack of response in treatment,
the infants were switched to voriconazole. The study used a
loading dose of 4–6 mg/kg twice daily, followed by a
maintenance dose of 2–3 mg/kg twice daily for at least
21 days. Of those treated, 11 patients were cured. Because
of the retrospective data, additional endpoints (Vd, clear-
ance, AUC, etc.) were not evaluated in this study.
3.2.3 Clinical Implications and Future Directions
Recommendations by the Infectious Diseases Society of
America (IDSA) for fluconazole suggest a loading dose of
25 mg/kg IV, followed by 12 mg/kg/day in neonates [273].
Fluconazole shows similar efficacy to amphotericin B for
the treatment of invasive Candida infections and has also
been shown to significantly reduce length of therapy in pre-
term infants [274, 275]. However, its decreased activity
against C. krusei and C. glabrata has limited its usefulness
as a primary antifungal agent.
Fluconazole has been studied extensively as a prophy-
lactic antifungal agent. The ease of administration and
595
tolerability of fluconazole, as well as the long t‘ and
increased concentration in skin, mucosal, urine, and CSF,
makes fluconazole a strong candidate for a prophylactic
antifungal [253]. Given high rates of invasive fungal
infections, as well as the high mortality associated with late
treatment, antifungal prophylaxis may be useful in extre-
mely premature newborns [276]. Several randomized
controlled trials have evaluated the utility and safety of
fluconazole prophylaxis. A recent Cochrane review showed
prophylactic antifungal therapy reduces the incidence of
invasive fungal infections in VLBW infants [277]. How-
ever, the results must be interpreted cautiously as the
incidence of invasive fungal infection was much higher in
the control groups than large cohort studies have shown (16
vs. \5 %). Also, meta-analysis of these studies did not
show any significant effect on mortality [278]. Further
study is required to evaluate the effect of antifungal pro-
phylaxis on long-term outcomes, including neurodevelop-
mental outcomes and patterns of resistance.
Data are sparse regarding voriconazole use in the neo-
natal and infant populations and are primarily limited to
anecdotal case reports [271]. However, several case reports
have emphasized the need to perform TDM for vorico-
nazole, owing to its marked variability and the need to
maintain effective concentrations. Additional studies are
needed in neonates and infants to identify dosing algo-
rithms that may allow voriconazole to be used more safely
and effectively.
3.3 Echinocandins: Caspofungin and Micafungin
3.3.1 Pharmacodynamics
The mechanism of action for echinocandins is to inhibit the
(1,3)-b-D-glucan synthase enzyme, more specifically the
FKS1 gene product, Fsk1p, which disturbs cell wall syn-
thesis [279–281]. This class of drugs has broad-spectrum
activity against Candida and Aspergillus species [282,
283]. Clinical resistance is rare for echinocandins, though it
has been shown that mutations in the FKS1 gene confer
resistance [284–287]. Echinocandins are highly permeable
to all tissues, including the lung, liver, and spleen [288].
Rare adverse effects of micafungin include elevated ala-
nine/aspartate aminotransferases, temperature elevation,
hypokalemia, and hyperbilirubinemia [289–292]. No
adverse effects due to caspofungin exposure have been
reported in neonates [293–296].
3.3.2 Pharmacokinetics
Caspofungin was approved by the FDA in 2001 for use in
adults, and in 2008 in children 3 months of age and older.
Early studies by Merck and Co. Inc. noted a decrease in
596
trough concentrations when caspofungin was administered
concomitantly with dexamethasone [297]. The only study
to evaluate caspofungin pharmacokinetics in only neonates
and infants \3 months was published in 2009 [293]. This
study enrolled 18 infants and Cmax values were similar to
those in adults. It was suggested that pre-term neonates and
infants may be dosed at 25 mg/m2, which is lower than the
currently recommended dosing regimen (Table 4); how-
ever, there were not enough infants enrolled to issue
definitive dosing recommendations. All other caspofungin
pharmacokinetic studies in infant populations have also
included older pediatric patients. It is worth mentioning
that studies including patients 3–24 months [298] or
3 months to 17 years [299] have achieved pharmacokinetic
results that were similar to those reported by Saez-Llorens
et al. [293].
Micafungin, a more recently developed echinocandin,
was approved for adult use by the FDA in 2005 and has
received approval for pediatric patients C4 months of age
in 2013. In addition, marketing authorization was obtained
in Europe in 2008.
A study completed in 2006 by Heresi et al. [291] initially
enrolled 18 pre-term neonates and found that ELBW neo-
nates had a nearly twofold greater clearance than their lar-
ger counterparts. However, adding seven more infants to the
low birthweight group decreased the large discrepancy in
clearance between the two groups. Comparing the clearance
data from the pre-term neonates with older children and
adults showed a decrease in clearance of micafungin as the
patient population increased in age [300, 301]. This
decrease in clearance due to age has been hypothesized to
be attributed to changes in protein binding or body com-
position [291, 302]. The authors predicted that a 5–7 mg/kg
dose in infants [1,000 g would be sufficient, though the
approved dosing is now 2 mg/kg in infants [4 months.
A pharmacokinetic study completed by Smith et al.
[289] evaluated high-dose micafungin among 12 pre-term
neonates. This study did not find any differences between
ELBW patients and those above 1,000 g, as suggested by
Heresi et al. [291]. As compared with adults, ELBW
infants required three times the dose to achieve the same
systemic exposure (15 mg/kg/dose compared with 5 mg/
kg/dose) [289], demonstrating that clearance for micafun-
gin is higher in pre-term neonates than in adults.
The most recent study evaluating neonates included 13
infants and aimed to determine what doses were appro-
priate to achieve serum concentrations that would provide
CNS protection [290]. The authors concluded that low
birthweight neonates (\1,000 g) dosed at 7 mg/kg/day and
higher birthweight neonates ([1,000 g) dosed at 10 mg/kg/
day provided serum concentrations that are predicted to
yield therapeutic CNS concentrations. This was supported
by a study by Hope et al. [303].
J. K. Roberts et al.
3.3.3 Clinical Implications and Future Directions
Since the first prospective trials of echinocandins in the
early 2000s, their use has continued to increase. This is
likely related to their comparable efficacy and improved
safety profile as compared with other classes of systemic
antifungals [304]. However, the majority of these studies
have been performed in older children and adults. Data
regarding the efficacy and pharmacokinetic parameters of
these newer treatments in neonates are limited and almost
exclusively represented by micafungin, which may be
attributed to its high spectrum of activity [305]. However,
the appropriate dose of micafungin for neonates and infants
is still under debate and current clinical trials are trying to
address this issue. Despite these limitations, echinocandins
appear to have a favorable safety profile in neonates and
young infants. The echinocandins also may have utility in
treating the youngest patients with resistant fungal organ-
isms or biofilms that resist penetration by other antifungals.
Importantly, drug–drug interactions, the appropriate phar-
macodynamic exposure–response relationships, and opti-
mal dosing of the echinocandins remain to be elucidated in
the neonatal and young infant populations. The higher
dosing required for neonates, as compared with adults and
older children, focuses attention on the uniqueness of this
population and the need for further study to fully establish
clinical utility without compromising safety. Nonetheless,
based on the limited safety and efficacy data to date and
ongoing studies, echinocandins are on a trajectory to
become key agents in the antifungal arsenal for treating
invasive fungal infections in neonates and young infants.
4 Antivirals
Neonatal herpes simplex virus (HSV) infections occur in 1
of 3,200 deliveries in the USA [316], of which two-thirds
develop some form of CNS disease [317]. Eighty-five per-
cent of cases occur as a consequence of peripartum trans-
mission, whereas 10 % are postnatally acquired, and 5 %
are acquired in utero [318]. The risk of neonates contracting
HSV is decreased through cesarean delivery, prior to
maternal infection with antibody production, and with
maternal antiviral treatment in the third trimester [317].
HSV can be divided into three clinical representations: skin,
eye, and/or mouth disease (SEM); CNS disease; or dis-
seminated, systematic disease [317]. A guanosine analog
that is commonly used to treat HSV is acyclovir (pharma-
codynamics in Table 5; pharmacokinetics in Table 6).
Cytomegalovirus (CMV) infection is the most common
congenital infection in the developed world, affecting about
0.6 % of births in the USA [319]. Of these infants, 7–10 %
will have clinically evident symptoms at birth with the
Antimicrobial/Antiviral PK–PD in Neonates and Infants 597

Table 5 Antiviral pharmacodynamics

Class Drug Viral activity Mechanism of Mechanism of Tissue Adverse events References
action resistance penetration

Guanosine Acyclovir Herpes simplex, Inhibits viral Mutations in viral Kidney, Neutropenia, renal [317, 322–
analogs varicella zoster DNA thymidine lung, liver, dysfunction 327]
polymerase kinase or viral heart, skin
activity, chain DNA vesicles,
terminator polymerase CSF
Ganciclovir Cytomegalovirus Inhibits viral Mutations in Aqueous Neutropenia, [317, 342–
[ herpes simplex DNA phosphatase or humor, thrombocytopenia, 356,
polymerase viral DNA subretinal anemia 372]
activity, slows polymerase fluid, CSF,
elongation brain
Valganciclovir Herpes simplex, Inhibits viral Mutations in Aqueous Neutropenia, [121, 317,
cytomegalovirus, DNA phosphatase or humor, anemia, increased 357–
varicella zoster, polymerase viral DNA subretinal ALT, 363]
Epstein–Barr activity, slows polymerase fluid, CSF, hyperbilirubinemia
elongation brain
ALT alanine aminotransferase, CSF cerebrospinal fluid

Table 6 Antiviral pharmacokinetics

Class Drug Recommended Metabolism Clearance Other References
dosing

Guanosine Acyclovir 20 mg/kg/q8 h IV NA Kidney Low oral bioavailability [317, 322–327]

Analogues Ganciclovir 6 mg/kg/q12 h IV NA Kidney Low oral bioavailability [317, 342–356, 372]
Valganciclovir 15 mg/kg/q12 h oral Serum and liver— Kidney Dosed based on age and [121, 317, 357–363]
de-esterification for renal function, pro-drug
activation to ganciclovir
IV intravenous, NA not available, qx h every x hours

majority of these infants having evidence of CNS involve-
ment [320]. Approximately half of the symptomatic CMV-
infected infants and nearly 14 % of asymptomatic infants
will go on to have permanent sequelae, including hearing
loss, mental retardation, learning difficulties, developmental
delays, chorioretinitis, and optic nerve atrophy [321]. Addi-
tionally, the mortality rate from congenital CMV infection is
5–10 %, usually related to non-CNS disease. Most neonatal
cases of CMV are contracted in utero, but transmission can
also occur during delivery or postnatally through breast milk
[317]. Two guanosine analogs commonly used to treat these
infections include ganciclovir and valganciclovir (pharma-
codynamics in Table 5; pharmacokinetics in Table 6).
4.1 Guanosine Analogs: Acyclovir
4.1.1 Pharmacodynamics
The most common antiviral used to treat HSV and varicella
zoster virus (VZV) infections in neonates and infants is
acyclovir (also known as aciclovir), which has been in
clinical use for over 30 years [317]. Originally introduced as
acycloguanosine, acyclovir is a deoxyguanosine analog,
which is phosphorylated by viral thymidine kinase, and
subsequently polyphosphorylated by host enzymes [322].
The activated form of acyclovir inhibits viral DNA poly-
merase activity and also acts as a chain terminator with 100
times more affinity for viral than cellular polymerases [322,
323]. The most common modes of resistance to acyclovir are
mutations in the viral thymidine kinase gene or mutations in
viral DNA polymerase [324]. A common adverse event seen
in acyclovir treatment is bone marrow suppression, specif-
ically neutropenia, which has been identified with an inci-
dence from 20–40 % of infants [325, 326]. In a recent
pharmacokinetic study, only one adverse event of elevated
serum creatinine was reported in a single infant and no
episodes of neutropenia were reported [327]. Adverse events
of bone marrow suppression and elevated serum creatinine
typically resolve upon discontinuation of acyclovir [317].
4.1.2 Pharmacokinetics
The first IV pharmacokinetic studies evaluating acyclovir
in infants were published in 1982 [328, 329]. These studies
evaluated mean Cmax and trough concentrations as well as
t‘ values for acyclovir in neonatal patients. At doses of 5,
598
10, and 10 mg/kg, the mean Cmax was 30.0, 61.2, and
86.1 lg/mL, respectively. The mean t‘ for all doses was
3.78 h, with an overall mean recovery of 65 % in the urine.
A study completed 10 years later by Englund et al. [330]
further defined the neonatal pharmacokinetics by including
pre-term infants and infants with kidney failure. The
authors reported a significant influence of serum creatinine
levels on clearance in their two-compartment model.
Infants with kidney failure had a t‘ three times longer than
those with normal renal function. Therefore, infants with
decreased kidney function require dosing adjustments to
avoid acyclovir accumulation.
The most recent IV acyclovir population pharmacoki-
netic study was in pre-term and term infants with normal
kidney function, published by Sampson et al. [331]. Their
final one-compartment model found that PMA and weight
were significantly correlated with increased clearance.
Kidney maturation plays a key role in acyclovir accumu-
lation in the neonatal population as demonstrated by a 4.5-
fold increase in clearance from 25 to 41 weeks. This study
also aimed to determine if the recommended 20 mg/kg/
dosage every 8 h was sufficient to achieve a CSF con-
centration of C1 mg/L, which is required to effectively
exceed the half-maximal inhibitory concentration (IC50)
[332]. To study this, two groups were used: one group of
patients was dosed following the recommended 20 mg/kg
every 8 h and another group was dosed according to their
GA and PMA. The results of the study showed that all
infants averaged around 2 mg/L in the CSF, suggesting
they were all above the desired IC50. In addition, they
proposed a new dosing regimen based on PMA: 20 mg/kg
every 12 h for infants \30 weeks, 20 mg/kg every 8 h in
infants 30 to\36 weeks, and 20 mg/kg every 6 h in infants
36–41 weeks.
4.1.3 Clinical Implications and Future Directions
Early recognition of HSV infection and prompt initiation of
acyclovir treatment improves mortality and long-term
sequelae [325, 333–335]. The standard dose of acyclovir
for confirmed HSV infection is 20 mg/kg/dose every 8 h
for at least 14 days [317, 336]. However, the recent study
by Sampson et al. [331] found that PMA could be used to
improve pharmacodynamic target achievement. The effect
of using a PMA-based dosing regimen on mortality and
long-term morbidities has not been established or validated
and future work is needed to confirm this suggested dosing
regimen.
It is also unknown whether long-term suppression with
acyclovir in HSV infected neonates prevents CNS recur-
rence. Studies have shown that using oral acyclovir at
300 mg/m2 per dose three times per day for 6 months
appears to improve neurodevelopmental outcomes [337].
J. K. Roberts et al.
However, more research needs to be completed to confirm
these findings.
The benefits, risks, and cost effectiveness of starting
acyclovir empirically in other situations is also not clear
[338–340]. Some experts feel that asymptomatic HSV-
exposed neonates only require routine prophylactic acy-
clovir if the maternal HSV infection is a primary infection
with active lesions at the time of delivery. Recurrent HSV
infection with active lesions at the time of delivery results
in a low rate of transmission and some infectious disease
experts consider prophylactic acyclovir to be unnecessary
unless additional risk factors for transmission exist (pro-
longed rupture of membranes, prematurity, scalp electrodes
or skin abrasions). Similarly, acyclovir is indicated for
VZV infection in neonates, although no clinical trials have
evaluated the risks, benefits, and cost of this treatment
[341].
4.2 Guanosine Analogs: Ganciclovir
and Valganciclovir
4.2.1 Pharmacodynamics
A homolog of acyclovir, ganciclovir is a nucleoside analog
of guanosine and was the first antiviral drug to be effective
against CMV [342, 343]. In addition, ganciclovir is also
effective against herpes viruses and Epstein–Barr virus
[344–347]. Similar to acyclovir, ganciclovir has to be
phosphorylated to ganciclovir triphosphate, which can
inhibit viral DNA polymerases [348]. The product of the
CMV UL97 gene, phosphotransferase, phosphorylates
ganciclovir for incorporation into DNA and consequently
slows its elongation, disrupting cellular function [343, 348–
351]. The primary mode of resistance to ganciclovir is a
mutation in the UL97 gene preventing phosphorylation of
ganciclovir [352]. These mutations account for 95 % of
ganciclovir-resistant viral strains [352]. The minority of
resistance to ganciclovir is caused by mutations in the viral
DNA polymerase, encoded by UL54, which prohibits the
binding of ganciclovir [352].
Neutropenia is the most common adverse event seen
with ganciclovir [353], with an incidence of 40 % in
patients [354] while one in seven patients require dosage
adjustments [355]. In a safety and tolerability study con-
ducted in neonates, dosing was decreased by 50 % if the
absolute neutrophil count fell below 500 cells/lL or
platelets below 50,000/lL [353]. In this study, 38 %
(n = 16) of patients presented with this adverse effect; of
those, 19 % (n = 3) had to discontinue treatment with the
drug because of persistent neutropenia. Neutropenia did not
seem to be dose dependent in neonates, although it does
seem to be dose dependent in adults [354]. Similarly, a
study published in 2003 [356] reported that 63 % (n = 19)
Antimicrobial/Antiviral PK–PD in Neonates and Infants
of infants who received ganciclovir had neutropenia; 14
required dose reductions and four discontinued treatment.
In each case, neutropenia was reversed upon discontinua-
tion of the drug. However, this can take a week or more,
increasing the risk for increased infection in these patients.
Additionally, thrombocytopenia (38 %) and anemia (2 %)
have been documented in infants while being treated with
ganciclovir [353].
To resolve the oral bioavailability issues common with
earlier-generation guanosine analogs, an L-valine ester pro-
drug of ganciclovir named valganciclovir was developed.
This moiety increased bioavailability to about 60 % [357].
Valganciclovir is transported in the intestine by a peptide
transporter, rapidly converted to ganciclovir in the liver
and intestines by esterase activity, and follows the same
mechanism of action as ganciclovir [121]. Valganciclovir
is used to treat CMV, VZV, Epstein–Barr virus, and HSV
[121]. Adverse events reported for infants administered
valganciclovir are inconsistent, with some reporting no
adverse events [358–360], and others neutropenia [361,
362], anemia, and, rarely, hyperbilirubinemia, increased
ALT, and thrombocytopenia [362, 363].
4.2.2 Pharmacokinetics
To date, there have been three pharmacokinetic studies
published on ganciclovir pharmacokinetics that have
focused on or enrolled infants and neonates [353, 364, 365].
The first study published by Trang et al. [364] studied the
pharmacokinetics of ganciclovir in neonates randomized to
two IV dosing groups: 4 or 6 mg/kg every 12 h for 6 weeks.
The data were fit to a single-compartment open model
assuming zero-order input and first-order elimination. There
was no significant difference between Vd, clearance, t‘, and
Cmax in each dosing group when normalized to bodyweight.
In addition, the values were similar to those reported in
adults [366]. Individual values of Vd and the Vd at steady
state (Vss) for each patient varied widely and increased with
increasing bodyweight. Ganciclovir was found to be pri-
marily excreted unchanged in the urine and clearance was
reported to increase with age. A similar study by Zhou et al.
[365] reanalyzed the same data using a population phar-
macokinetics approach and calculated similar results for Vd
and clearance, but also evaluated 13 covariates that could
have an impact on ganciclovir pharmacokinetics. The study
concluded that serum creatinine affected clearance and
bodyweight influenced Vd, supporting suggestions made by
Trang et al. [364]. A larger study published by Whitley et al.
[353] included data from Zhou et al. [365] and Trang et al.
[364] as well as additional neonates (totaling 42 patients)
receiving ganciclovir IV and reported results consistent
with earlier published reports, including the use of a one-
compartment model with zero-order input and first-order
599
elimination, the effect of renal function on clearance, and
the relationship between increased weight and Vd.
Most of the pharmacokinetic studies evaluating val-
ganciclovir have included IV dosing with ganciclovir either
before or after oral valganciclovir administration [362, 367,
368]. The first pharmacokinetic study conducted by Galli
et al. [367] evaluated eight infants. Patients were first
administered a week-long course of IV ganciclovir therapy
and were then transitioned to oral valganciclovir. The first
four infants enrolled received 15 mg/kg/day of valganciclo-
vir, but they failed to achieve adequate plasma concentra-
tions. Therefore, the next four infants received 15 mg/kg
twice a day. The infants who received twice-daily dosing had
Cmax comparable with IV doses of ganciclovir, demonstrat-
ing that oral twice-daily dosing of valganciclovir was as
effective as IV ganciclovir. These findings were later cor-
roborated by Lombardi et al. [363]. A larger study completed
by Acosta et al. [368] reported results of two trials that
employed different study designs. The first study had a rigid
study design that resulted in the consistent refusal of study
participation. As a result, only five patients were enrolled.
The second version of the study enrolled 19 infants that
began oral valganciclovir therapy for one dose, followed by
IV ganciclovir for 2 weeks. At completion of their 2-week
course of ganciclovir, patients began a 4-week course of oral
valganciclovir at home. Three dosing regimens were evalu-
ated in the second version of the study (14, 16, and 20 mg/
kg), all of which were well-described by a one-compartment
model, and found bodyweight to be the most important
covariate. The oral formulation of valganciclovir achieved
the same pharmacokinetic parameters as IV ganciclovir,
including approximately 54 % oral bioavailability. Kimber-
lin et al. [362] evaluated the same pharmacokinetic data from
these infants and found that bioavailability increased by
32 % for oral valganciclovir in the first version of the study,
resulting in an unchanged AUC from time zero to 12 h
(AUC12), as compared to IV ganciclovir, which demon-
strated a 41 % decrease in AUC12, corresponding to a 73 %
increase in clearance during the first 6 weeks of life. This
finding reveals that oral valganciclovir does not exhibit
pharmacokinetic properties similar to other antivirals and
suggests that valganciclovir should be considered for the
prolonged oral treatment of congenital CMV infection.
4.2.3 Clinical Implications and Future Directions
In randomized clinical trials, ganciclovir has not been
demonstrated to significantly reduce mortality in neonates
with symptomatic CMV disease [356]. However, clinical
trials in symptomatic CMV-positive neonates have dem-
onstrated benefit with ganciclovir in decreasing sensori-
neural hearing loss and lower rates of neurodevelopmental
delay [369, 370]. Ongoing clinical trials are currently
600
investigating whether long-term therapy with ganciclovir
and/or valganciclovir (6 months) is superior to 6 weeks of
ganciclovir and/or valganciclovir for neonates with symp-
tomatic CMV disease (NCT00466817). In addition, it is
currently unknown whether treatment of asymptomatic
neonates with CMV infection reduces their risk of devel-
oping long-term neurological and auditory sequelae [371].
Multicenter, longitudinal studies are needed to address this
pressing clinical question.
5 Conclusion
Historically, neonates and infants have not been included in
clinical trials. Continued research has shown that these
patients are not miniature adults, nor are they small children.
Their pharmacokinetic and pharmacodynamic parameters
differ from those of adults and even older pediatric popu-
lations. As a consequence of these findings, recent legisla-
tion including the Best Pharmaceuticals for Children Act,
passed as part of the FDA Safety and Innovation Act in 2012,
and the European directive 1901/2006 on medicinal pro-
ducts for pediatric use requires new drugs to be studied in
newborns, unless the studies are either deferred or waived.
The National Pediatric Research Network Act will encour-
age more research of pediatric populations in general.
Despite the improvements in pediatric drug research, the
study of drugs in neonates is sparse and what little data are
available often does not reflect clinical use [1]. As much of
the low-hanging fruit has already been harvested, to advance
the field in the twenty-first century multicenter collabora-
tions will be essential. To this end, central institutional
review boards (IRBs) and standing trial protocols may be
useful in further defining the pharmacokinetics and phar-
macodynamics of antibacterials, antifungals, and antivirals
that are used in neonatal medicine. Individual institutions
can also play an important role by leveraging their retro-
spective electronic medical record data to identify clinical
characteristics, patient co-morbidities, and adverse events
that impact the safety and effectiveness of many commonly
prescribed drugs. As many antimicrobials are no longer on-
patent, there is little financial incentive for drug makers to
sponsor new pediatric and neonatal clinical trials. Conse-
quently, the responsibility for improving use of these drugs
rests on the shoulders of clinicians and biomedical
researchers. To successfully meet this challenge, innovative
approaches may be needed, including analytical techniques
that make use of dried blood spots and/or scavenged blood
samples. An inherent challenge in conducting neonatal
pharmacokinetic studies is the limited volume of blood that
may be sampled to establish drug concentrations; however,
we are convinced that further research in this field can
J. K. Roberts et al.
substantially reduce this barrier to conducting clinically
important studies in this vulnerable population.
The data presented in this review demonstrate that
though a considerable amount of research has been con-
ducted, the pharmacokinetics and pharmacodynamics of
several antimicrobial agents are poorly characterized in
neonates and infants. Tragically, many of these agents are
commonly used in routine clinical practice. As such, fur-
ther research is needed to decrease the gap between our
understanding of adult, pediatric, infant, and neonate
pharmacokinetics to develop effective and safe dosing
regimens.
Acknowledgments None.
Funding JKR is supported by the Pharmacotherapy Subspecialty
Award from the Primary Children’s Medical Center Foundation.
RMW is supported by NIH Grants: 1 R01 HD070795-01A1 and 5
R01 HD060559-05.
Transparency declarations The University of Utah receives
reimbursement for the conduct of a clinical trial involving micafun-
gin. RMW receives no direct payment. All other authors declared no
conflicts of interest.
Contributors JKR, CS, JEC, JS, MGS, RMW, and CMTS wrote
the initial draft of the review. All authors also contributed to the
reviewing and finalization of the document.
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