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ESPID Reports and Reviews
Therapeutic Drug Monitoring for Anti-infective Agents in Pediatrics
The Way Forward
Nicole Ritz, MD, PhD,*†‡§ Julia Bielicki, MD,*†¶ Marc Pfister, MD,† and John van den Anker, MD, PhD†║
OPTIMAL ANTI-INFECTIVE DRUG
DOSES FOR CHILDREN
Anti-infective agents are among the most
commonly prescribed drugs in children. What is
considered the optimal dose of an anti-infective
agent is determined by how the child handles the
drug and the resulting drug concentration in the
body (pharmacokinetics, PK) as well as by the
effect of the drug on the target pathogen (pharmacodynamics, PD). Among pediatric patients,
considerable PK differences exist, including agerelated variation in drug absorption, distribution,
protein binding, metabolism and elimination. For
many anti-infective agents, there is therefore no
direct evidence for pediatric dosing recommendations and, as a consequence, adult-based dose
recommendations are modified based on body
weight or surface area. This may be an oversimplified approach, as it fails to account for many
key maturational and developmental changes
that influence drug concentrations and ultimately
efficacy of treatment (Fig. 1). In addition, there
are a number of specific patient groups, including individuals with cystic fibrosis, critical illness, obesity and immunocompromise, as well
as preterm and term neonates for whom PK and
PD properties are even more complex.
OPTIMAL ANTI-INFECTIVE DRUG
DOSE TO KILL THE PATHOGEN
For many infections, an accurate dosing
might not always be critical, either because of a
From the *Infectious Diseases Unit, †Paediatric Pharmacology Department, University of Basel Children’s
Hospital Basel, Basel, Switzerland; ‡Department of
Paediatrics, The University of Melbourne, Parkville,
Australia; §Infectious Diseases Unit, Royal Children’s
Hospital Melbourne, Parkville, Australia; ¶Paediatric
Infectious Diseases Research Group, Infection and
Immunity, St George’s University of London, United
Kingdom; and ║Division of Clinical Pharmacology,
Children’s National Health System, Washington, DC.
The authors have no funding or conflicts of interest
to disclose.
Address for correspondence: Nicole Ritz, MD, PhD,
Infectious Diseases and Paediatric Pharmacology,
University Children’s Hospital Basel, Spitalstrasse
33, CH-4031 Basel, Switzerland. E-mail: nicole.
[email protected]
Copyright © 2016 Wolters Kluwer Health, Inc. All
rights reserved.
ISSN: 0891-3668/16/3505-0570
DOI: 10.1097/INF.0000000000001091
broad therapeutic range of the chosen drug and
the resulting minimal risk of toxicity or because
the pathogen is highly sensitive to low drug concentrations. The latter relates to anti-infective
PD, which describes the relationship of the dose
observed in the body and the ability to kill and/
or inhibit the growth of the pathogen. To define
this relationship, the minimal inhibitory concentration (MIC) of a particular pathogen is the
key factor which is used to define PK/PD targets for anti-infective agents. Traditionally, the
majority of anti-infective agents can be classified into 2 broad groups depending on their PK/
PD properties: time-dependent anti-infective
agents [efficacy dependent on the time or the
area under the curve (AUC) during which the
drug concentration is above MIC; T>MIC; and
AUC/MIC] or concentration-dependent antiinfective agents (efficacy dependent on the ratio
of peak concentration over MIC; Cmax/MIC).
WHAT IS THERAPEUTIC DRUG
MONITORING?
Decisions on optimal drugs used to treat
infections are based on many assumptions,
including that a given dose will lead to a certain drug concentration in the body (PK) and
that this drug concentration will be sufficient
to kill and/or inhibit growth of the pathogen
(PD). However, in certain clinical situations
such assumptions are inaccurate, and it has
been shown that outcome improves when drug
concentrations are measured (as opposed to be
assumed) as part of therapeutic drug monitoring (TDM). TDM is defined as measuring
drug concentrations in serum or plasma with
subsequent dose adjustment for the individual
patient. TDM can be used to both minimize
toxicity and maximize efficacy. Today, routine
measurement of drug concentrations for a number of anti-infective agents is available; these
include aminoglycosides, antiretroviral drugs,
antimycobacterial drugs, triazoles and vancomycin. The challenge of TDM is the accurate
interpretation of the measured concentrations,
for which a multidisciplinary team is required
including specialists in pharmacology, microbiology and pediatric infectious diseases. Decisions on dosing recommendations are based
on a careful evaluation of a number or criteria
including: dose and interval of administration,
time since initiation of treatment, exact time of
drug administration, total duration of infusion
for intravenous drugs, exact time of TDM blood
specimen taken, age, weight or body surface
area, renal and hepatic function, expected or
confirmed pathogen, resistance profile of the
pathogen, including MIC, underlying diseases
and concomitant medication and nutrition.
Typically, drugs and diseases most suitable for
TDM are those where a correlation between
drug concentration and efficacy (PK/PD target) and/or toxicity is established. In addition, a
number of drugs have unpredictable concentrations as a result of human genetic variation in
drug metabolism making TDM essential.
EXAMPLES OF CURRENT USE OF
TDM FOR ANTI-INFECTIVES
Aminoglycosides
TDM of aminoglycosides has become
standard clinical practice in pediatrics, and traditionally, the prevention of toxicity has been
the main reason for use of TDM in this drug
class. Many studies evaluating toxicity of aminoglycoside trough concentrations in adults
and children, comparing multiple daily doses
with extended-interval (eg, once daily) doses,
have shown that the latter results in lower
trough concentrations with reduced nephrotoxicity in adults.1 However, this has not been consistently observed in the pediatric population,
possibly because children generally exhibit
lower aminoglycoside-associated nephrotoxicity. The mechanisms underlying ototoxicity are
still controversial. It has been suggested that
ototoxicity is mainly related to the cumulative
dose of aminoglycosides over time.2 In addition, it is also related to a genetic predisposition resulting from mutations in mitochondrial
DNA, and that in individuals affected a single
dose can cause ototoxicity.3 Several mutations
in mitochondrial DNA are linked to increased
susceptibility to aminoglycoside-associated
ototoxicity, and the prevalence of the most
common mutations is estimated to be around
1–2%.3 These findings challenge the view of
routinely monitoring aminoglycoside trough
concentrations in pediatrics, and selectivetargeted TDM has been advocated in children
who have prolonged treatment or are exposed
to concomitant nephrotoxic drugs.
The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approved
independently by the Editorial Board of ESPID.
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The Pediatric Infectious Disease Journal • Volume 35, Number 5, May 2016
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The Pediatric Infectious Disease Journal • Volume 35, Number 5, May 2016
Therapeutic Drug Monitoring
FIGURE 1. Factors influencing efficacy of anti-infective treatment.
TDM of aminoglycosides to optimize
effect, including Cmax measurements, is less
commonly performed. Cmax is usually determined 30–60 minutes after the end of intravenous administration, and a second concentration is ideally measured before the lower limit
of detection is reached. These measurements
should be obtained after steady state has been
reached, which is commonly considered to be
the case after approximately 5 half-lives of the
drug have elapsed (see also below). Barriers to
the implementation of TDM for efficacy optimization in aminoglycosides are the need for
multiple blood samples as well as the lack of
information on the optimal Cmax/MIC ratio. In
adults, maximal efficacy seems to be achieved
when Cmax/MIC ratio is 8–10 or AUC/MIC is
75–260.4 In children, however, only indirect
evidence is available from a meta-analysis suggesting that once daily dosing, associated with
higher Cmax tends to have a better efficacy and
improved microbiological eradication rates
when compared with multiple daily dosing.5
Vancomycin
Vancomycin is another example of a
drug for which monitoring of serum concentrations is recommended by product labels as
well as national and institutional guidelines.
However, the implementation of these recommendations in pediatrics is challenging.
A study in the US showed implementation of
vancomycin TDM to be variable, with only
81% of children on vancomycin for more
than 3 days having at least 1 serum concentration measured.6 As for aminoglycosides,
specific PK/PD targets for vancomycin TDM
in pediatrics are missing. In adults, AUC24/
MIC > 400 has been suggested as the best
predictor for treatment outcome of invasive
methicillin-resistant Staphylococcus aureus
infections. However, calculation of the AUC
is not feasible in a routine clinical setting as
this requires concentration measurements on
multiple samples and the use of prediction
equations. Therefore, in 2011, the Infectious
Diseases Society of America suggested the
use of trough concentrations of 15–20 mg/L
as a surrogate for AUC24/MIC > 400,
explicitly stating that this recommendation
“requires additional study” in children.7
Indeed, several studies comparing predicted
or measured AUC24 with trough concentrations in children found a poor correlation
and/or that lower trough concentrations corresponded with a AUC24/MIC > 400 in children (reviewed by Neely et al8). In addition,
studies investigating efficacy of vancomycin
AUC24/MIC > 400 in children with different
types of infections as well as other pathogens for which vancomycin is used are lacking, as the number of patients with positive
cultures included in the currently available
studies are limited. This results in the problematic situation in which dose adjustments
based on trough concentrations alone may be
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inaccurate, but evidence to change this practice is currently lacking.
Triazoles
One example of a drug class with
unpredictable concentrations is the class
of triazole antifungal agents. Itraconazole,
posaconazole and voriconazole have variable
metabolism as a result of polymorphisms
in the specific enzymes of the cytochrome
P450 system and also variable oral absorption caused by nutrition.9 This results in considerable interindividual variability in the
measured drug concentrations, and therefore,
TDM is commonly offered for this class of
drugs. Evidence is accumulating on both
concentration–efficacy and concentration–
toxicity relationships. For example, a voriconazole trough concentration <1 mg/L has
been shown to be associated with increased
mortality in children,10 whereas concentrations above 5.5 mg/L were associated with
increased phototoxicity and neurotoxicity.
Recent guidelines therefore suggest routine
triazole TDM in the majority of patients with
published target concentrations.11
Antiretroviral Agents
Several antiretroviral agents (ARVs)
have considerable interindividual variability
in drug concentration but only some ARVs
have known drug concentrations associated with improved virologic response and/
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Ritz et al
The Pediatric Infectious Disease Journal • Volume 35, Number 5, May 2016
or reduced toxicity. TDM is generally not
indicated for nucleotide reverse transcriptase
inhibitors as the serum or plasma concentrations do not reflect intracellular concentrations of the drugs adequately. For non-nucleoside reverse-transcriptase inhibitors and
protease inhibitors, several centers provide
drug concentration measurements. However,
routine TDM of ARVs is not recommended
for adults or children, and selective TDM for
special situations, including suspected drug
interactions and toxicity or adherence, is
instead advised.12
to influence both outcome and development
of resistance.14 Earlier, nonsteady state measurement of drug concentrations has therefore
been suggested.15 This could be achieved
with 1 or more measurements of drug concentrations together with software to model
individual PK from available concentrations.
In addition, decision support tools are currently being developed (www.ezechiel.ch or
www.doseme.com.au), which may assist clinicians in the future to optimize and personalize dosing.16
FUTURE APPLICATIONS AND
IMPROVEMENT OF TDM IN
PAEDIATRIC INFECTIOUS
DISEASES
Drug concentrations are measured
using serum or plasma and generally require
a volume of 1–2 mL. To minimize the volume of blood required, for example, in the
neonatal intensive care setting, and reduce
preanalytic sample handling errors, the use
of dried blood spots is being explored. Dried
blood spots–based levels can be determined
for many anti-infective agents, but the current lack of validation compared with serum
or plasma concentration precludes introduction into routine clinical practice. Moreover
less-invasive patient samples are being investigated for TDM use. For example, a recent
study showed a good correlation of fluconazole concentrations in saliva and serum.17
β-Lactam Antibiotics in Critically Ill
Patients
β-Lactam antibiotics are the most
commonly used group of anti-infective
agents in critically ill pediatric patients. Classically, β-lactam TDM is not offered because
of the generally wide therapeutic window
and relatively predictable drug concentrations. However, in an intensive care setting,
considerable PK changes occur resulting in
highly variable drug concentrations not only
between patients but also within the same
patient. Most clinicians are concerned about
increased drug concentrations and potential toxicity of anti-infective agents in critically ill patients as a result of renal impairment. Subtherapeutic drug concentrations
may equally be a challenge in these patients
resulting from extravascular volume expansion and glomerular hyperfiltration. In pediatrics, data on TDM of β-lactam antibiotics
in critically ill patients are lacking and data
on adults from a recent survey in 9 intensive
care units showed significant variations in
TDM practice.13 The antibiotics most commonly included for TDM were piperacillin,
meropenem, ceftazidime and ceftriaxone.
However, significant variation was observed
in the PK/PD targets applied and dose adjustment strategies used. Although studies in
adults have shown improved clinical outcome
associated with achieving defined PK/PD targets, definitions of optimal PK/PD targets
and optimal resulting modification strategies
need to be further explored.13
Earlier, Nonsteady State TDM
Currently, TDM is usually applied
when drug concentrations have reached a
steady state. Depending on the patient–drug
combination, this might take several days,
which is a considerable weakness, as rapid
achievement of best PK/PD targets is believed
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Optimization of Blood Sampling
CONCLUSION
TDM in pediatric infectious diseases is currently used in selected patient
groups and for certain anti-infective agents
only. Better understanding of PK for many
anti-infective agents in children has led to
improved dosing recommendations. Integration of pathogen data, including MIC, is of
critical importance to further improve TDM
practice. This also requires target PK/PD
ratios to be specifically assessed for pediatric
infections. In the future, applications, including software-based early TDM, may be possible and be particularly useful for critically
ill children.
ACKNOWLEDGMENTS
The authors would like to thank Frederique Rodieux and Aline Fuchs for helpful
discussions.
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Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.