J Infect Chemother 21 (2015) 9e329

31

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Journal of Infection and Chemotherapy

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Review article

Applications of the pharmacokinetic/pharmacodynamic (PK/PD)

analysis of antimicrobial agents

Eduardo Asín-Prieto a, b, Alicia Rodríguez-Gascon a, b, Arantxazu Isla a, b, *

a
Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-
Gasteiz, Spain b Centro de Investigacion Lascaray ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain

articleinfo The alarming increase of resistance against multiple currently available antibiotics is leading to a rapid
lose of treatment options against infectious diseases. Since the antibiotic resistance is partially due to a
misuse or abuse of the antibiotics, this situation can be reverted when improving their use. One strategy
Article history:
is the optimization of the antimicrobial dosing regimens. In fact, inappropriate drug choice and
Received 14 November 2014
suboptimal dosing are two major factors that should be considered because they lead to the emergence
Received in revised form
of drug resistance and consequently, poorer clinical outcomes. Pharmacokinetic/pharmacodynamic
20 January 2015
(PK/PD) analysis in combination with Monte Carlo simulation allows to optimize dosing regimens of
Accepted 2 February 2015
Available online 12 February the antibiotic agents in order to conserve their therapeutic value. Therefore, the aim of this review is to
2015 explain the basis of the PK/PD analysis and associated techniques, and provide a brief revision of the
applications of PK/PD analysis from a therapeutic point-of-view. The establishment and reevaluation of
clinical breakpoints is the sticking point in antibiotic therapy as the clinical use of the antibiotics
Keywords: depends on them. Two methodologies are described to establish the PK/PD breakpoints, which are a big
Pharmacokinetics part of the clinical breakpoint setting machine. Furthermore, the main subpopulations of patients with
Pharmacodynamics
altered characteristics that can condition the PK/PD behavior (such as critically ill, elderly, pediatric or
PK/PD analysis
obese patients) and therefore, the outcome of the antibiotic therapy, are reviewed. Finally, some
Monte Carlo simulation
recommendations are provided from a PK/PD point of view to enhance the ef ficacy of prophylaxis
Breakpoints
protocols used in surgery.
abstract
© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.
Published by Elsevier Ltd. All rights reserved.
1. Introduction and governments. At present, there is an intense activity against
antimicrobial resistance involving the World Health
Since the development of the first antibiotic, the utility of Organization (WHO) and health departments of national
the antimicrobial agents has been widely demonstrated and governments. The WHO's Assistant Director-General for Health
thus, the relevance of the antibiotic therapy in medicine is Security Dr. Keiji Fukuda highlighted the utility of the
indubitable. However, the alarming increase of resistance antibiotics as one of the pillars of modern medicine and pointed
against multiple currently available antibiotics is leading to a out that efforts must be made on prevention of infections and
rapid lose of treatment options against infectious diseases. also on the way of producing, prescribing and using antibiotics
High proportions of antibiotic resistance (ABR) are present in as the implications of the ABR problem could be devastating [2].
common infectious bacteria. In fact, a high percentage of Considering the current situation, different types of actions are
hospital-acquired infections are caused by necessary to address antimicrobial resistance: development of
new antimicrobial agents (included resistance mechanism
inhibitors or blockers), prevention of the infection in the first-
place,
* Corresponding author. Laboratory of Pharmacy and Pharmaceutical Technology, useofof advanced therapies and optimization of pre-existing
Faculty
Pharmacy, University of the Basque Country UPV/EHU, Paseo de la Universidad dosing regimens of currently available antibiotics.
7, 01006
Vitoria-Gasteiz, Spain. Tel.: þ34 945 01 34 69; fax: þ34 945 01 30 40.
E-mail address: arantxa.isla@ehu.es (A. Isla). 1.1. Development of new antimicrobial agents

http://dx.doi.org/10.1016/j.jiac.2015.02.001 The development of new classes of antimicrobials falls upon

highly resistant bacteria such as methicillin-resistant
Staphylococcus aureus or multidrug-resistant Gram-negative
bacteria. In Europe, it is estimated that 25,000 deaths per year
are due to ABR [1]. In the United States, more than 23,000
deaths per year are due to ABR, 10,000 of them by multidrug
resistant S. aureus (MRSA) infections [1]. Economically, the
ABR problem also implies huge amounts of money on direct
and indirect costs to the patients, public and private institutions
the pharmaceutical industry. However, the industry has lost
interest in developing new antibiotics because of their expected
limited return on the investment [3]. There are relatively few
new antimicrobial agents in the pharmaceutical pipeline [4].
Most of them are antiviral and antifungal agents in development,
and the majority of antibiotics developed in the last decade come
from re-engineered existing antibiotics with underlying
resistance mechanisms already present [5]. As a consequence,

1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
320 E. Asín-Prieto et al. / J Infect Chemother 21 (2015) 319e329
there have been no new classes of antibiotics since the late
1980s, [6] what has been characterized as the result of a
“Discovery Void” [7]. In this regard, in order to stop this
situation and encourage the industry to do research on new
antimicrobials, different programs are setting up, such as the
GAIN (Generating Antibiotic Incentives Now) program by the
Food and Drug Administration (FDA, of the United States) or
the IMI program (Innovative Medicines Initiative) which
launches different projects within the ND4BB (New Drugs for
Bad Bugs) series in Europe.
1.2. Prevention of the infection in the first-place
Prevention and control measures to avoid infection in the
firstline include strengthening hygiene, improving sanitation and
access to potable water, prophylactic and mechanical measures
in surgery and vaccination. Vaccines have been developed for
many different infectious diseases. A decrease on the resistance
emergence of some bacteria has been shown since the start of the
vaccination (Streptococcus pneumoniae and Haemophilus
influenzae), although there is no commercialized vaccine aiming
the multidrug resistant bacteria at the moment [8].
1.3. Use of advanced therapies
Advanced therapies include new medical products based on
genes (gene therapy), cells (cell therapy) and tissues (tissue
engineering). Considering antimicrobial therapy, gene therapy
can be used to transfect host cells in order to produce specific
proteins (such as antibodies) against the pathogen or use silent
nucleotide chains (such as siRNA or shRNA) to block the
transcription of necessary proteins for the replication of the
microorganism. Many studies are focus on gene therapy aimed
to viral diseases in order to avoid replication of virus inside the
human cells [9]. The antibiotic therapy has each place among
these therapies where phages have been proposed as vehicles for
DNA or RNA material to prevent or treat infections [10].
Recently, toxin-captor liposomes have been developed against
Gram-positive pathogens that secrete cytotoxic pore-forming
toxins for use alone or in combination with antibiotic therapy
[11].
1.4. Optimization of pre-existing dosing regimens of currently
available antibiotics
Since a big part of the ABR is due to a misuse or abuse of the
antibiotics, it seems possible to partially revert this situation if
their use is improved. In this regard, one strategy is the
optimization of the antibiotic dosing regimens. In fact,
inappropriate drug choice and suboptimal dosing of antibiotics
(due to low doses or short durations of treatment) are two major
factors affecting, and followed by, the emergence of drug
resistance and consequently, poorer clinical outcomes [12]. On
the other hand, high exposures are related to higher incidence of
side effects, treatment drop out and therefore, clinical failure and
high rate of resistance emergence (Fig. 1). Furthermore, the
success of the therapy is also conditioned by the inoculum size
and the time to treatment (which are highly correlated), and thus,
the treatment should be initiated as early as possible [13].
An ideal optimization requires a good knowledge of the
mechanisms involved on the effect of the antibiotics
(pharmacodynamics, PD) and the evolution of the antibiotic
concentration in the body of the patients (pharmacokinetics,
PK). Pharmacokinetic/ Pharmacodynamic (PK/PD) analysis
integrates them and studies the dosing required to enhance the
possibility of success of the antibiotic therapy, as well as
minimize the side effects and the emergence of resistances.
Provided that: 1) new antimicrobial agents development
and advanced therapies can result in extremely cost and long
procedures, and 2) no-drug-based-prevention measures are
useful only when there is no evidence or suspicion of
infection and/or the patient is not under high risk of infection
(accidents, wounds or surgical procedures); PK/PD analysis is
outlined as a needed strategy to wisely optimize dosing
regimens of the antibiotic agents in order to conserve their
therapeutic value. Therefore, the aim of this review is to
explain the basis of the PK/PD analysis and associated
techniques, and provide a brief revision of the applications of
PK/PD analysis from a therapeutic point-of-view.
2. Pharmacokinetic and pharmacodynamic principles
Since the moment an antibiotic drug is administered to a
patient, it undergoes some processes that condition its plasma
and tissue concentrations and therefore, the clinical outcome.
The evolution of the concentration of the drug in the different
fluids of the patient over time is studied by the
pharmacokinetics (colloquially known as 'what the body does
to the drug'). After the administration of a drug, it undergoes
ADME (absorption, distribution, metabolism and excretion)
processes that condition the kinetics of the drug and the
concentration-time profile, which may be characterized by the
PK parameters, such as total body clearance, volume of
distribution, protein binding or bioavailability.
Once the drug reaches the site of action at the required
concentration, it produces the desirable effect by its
mechanism of action, what is studied by the
pharmacodynamics (known as 'what the drug does to the
body'). In antimicrobial therapy, the effect is produced on the
bacterial pathogen responsible for the infection. The major
indicator of the effect of the antibiotics is the MIC or
minimum inhibitory concentration. It provides information on
the
Fig. 1. Probability of clinical success (solid line) and resistance emergence
rate (dotted line) over the drug exposure. Shaded area represents the optimal
dosage (OD) frame where the probability is minimum for emergence of
resistance and maximum for clinical success.
susceptibility of the pathogen against the antibiotic. It is
defined as the minimum concentration of the antibiotic drug
able to inhibit the bacterial growth. Its estimation is easy and
simple to perform by different methodologies (disk diffusion,
E-test, microdilution and macrodilution) in the laboratory.
However, the use of MIC values as the only marker of the
efficacy of an antibiotic agent can be misleading, as the
clinical outcome is conditioned by complex interactions
between the three elements of the antibiotic therapy: the host,
the microorganism, and the drug (Fig. 2). PK/PD analysis
integrates all this information allowing the researcher or
clinician to select the optimal antibiotic and dosing regimen
for each infectious process and patient in order to enhance the

effect of the antibiotic, minimizing the side effect incidence
and the emergence of resistance.
The quantitative relationship between a pharmacokinetic
parameter and a microbiological parameter is known as a
PK/PD index. The three main PK/PD indices associated with
the effect of the antibiotics and used for PK/PD analysis to
predict the antimicrobial efficacy are the time during which
the concentration of the drug was over the MIC (T >MIC), the
peak concentration and MIC ratio (Cmax/ MIC), and the ratio
of the 24-h area under the concentration-time curve divided
by the MIC (AUC/MIC), (Fig. 3) [14].
These PK/PD indices are the best descriptors of antibiotic
efficacy depending on the activity pattern of each antibiotic.
Three major patterns of antimicrobial activity have been
described. The first pattern of antimicrobial activity exhibits
concentrationdependent killing along with prolonged
persistent effects. The second applies to antimicrobials with
time-dependent killing and no or very short persistent effects.
The third shows concentrationindependent killing and
prolonged persistent effects.
1. Antimicrobials with concentration-dependent killing
along with prolonged persistent effects. The PK/PD
indexes for these drugs are C max/MIC or the AUC/MIC
ratios, because the prolonged persistent effects protect
against regrowth when active drug concentration falls
below the MIC. This pattern is observed with a large
number of antimicrobials including aminoglycosides,
fluoroquinolones, polymyxins, daptomycin
metronidazole.
2. Antimicrobials with time-dependent killing and no or
very short persistent effects. The best PK/PD index
correlated with efficacy in this case is the duration of time
that active antibiotic concentrations exceeded the MIC. It
is usually expressed as the percentage of the dosing
interval and only the fraction of drug not bound to
proteins is considered. This pattern has been described for
all of the b-lactam antibiotics, such as penicillins,
cephalosporins, carbapenems, and monobactams.
3. Antimicrobials with concentration-independent killing
and prolonged persistent effects. Like in the first case, due
to the
E. Asín-Prieto et al. / J Infect Chemother 21 (2015) 319e329 321
When applying PK/PD analysis one must select not only an
adequate PK/PD index as surrogate marker of efficacy, but also
the magnitude of the index that is required for antimicrobial
efficacy. Table 1 shows the magnitude or value of the PK/PD
indices associated with the success of therapy for different
antimicrobials. In order to establish which PK/PD index and the
pharmacodynamic target (PDT) both in vitro and in vivo studies
are used [15].
In this sense, in vitro time-kill kinetic studies allow to
emulate the PK of the antibiotic and study the PD against the
pathogen. It should be highlighted that the main limitation of the
MIC is that it is estimated as a value after incubation of the
bacteria in presence of a static concentration of antibiotic [16].
Thus, no information about the evolution of the bacterial growth
in the presence of changing antibiotic concentrations is provided.
As said before, the concentrations of the antibiotic are never
static but changing in the human body fluids. Hence, in vitro
time-kill kinetic studies provide a closer approach to what
happen in the patients [16]. It is possible to study the effect of
different dosing regimens, altered clearance, infection site,
protein binding, starting inoculum size and some others.
Different designs have been developed [17]. Later, PD modeling
can be applied to estimate different parameters which
characterize the pharmacodynamics of the antibiotics [18]. Due
to the complexity of this time-kill in vitro studies, they are
mainly applied in drug development [19].
or

Fig. 3. PK/PD indices associated with the efficacy of the antibiotics.

prolonged persistent effects that protect against regrowth

when active drug concentration falls below the MIC, the best
PK/PD indexes for these drugs are C max/MIC or the
AUC/MIC. This pattern is characteristic of tetracyclines,
tigecycline, macrolides, azithromycin, clindamycin, linezolid
and other oxazolidinones, chloramphenicol, trimethoprim,
sulfonamides or vancomycin.
322
On the other hand, in vivo studies are also very useful in the
evaluation of the antimicrobial therapy. Andes and Craig [15]
highlighted the contribution of animal models for determining
Table 1
PK/PD index and target magnitude for each antimicrobial agent.
E. Asín-Prieto et al. / J Infect Chemother 21 (2015) 319e329
target is similar among different infection sites, various
pathogens and some antibiotics of the same class.
2.1. Monte Carlo simulation for antimicrobial agents

Once specific PK/PD indices have been identified as major

determinants of efficacy and of avoiding the emergence of
resistance, the clinician should consider the PK behavior of a
drug in the patient. However, therapeutic drug monitoring of
many antimicrobials is not routine in clinical setting; therefore,
we must select the antimicrobial and determine the optimal dose
regimen to maximize the probability to reach the targeted
exposure, considering the pharmacokinetics of the drug in a
population that is as similar to the individual as possible. Apart
from the altered pharmacokinetic parameters, larger variability
on them is often observed in patients than in healthy volunteers.
When considering situations where uncertainty is present,
such as dosing to a patient without previous knowledge about the

Fig. 2. Triangle of the interactions among host, pathogen and antibiotic used to treat the infectious diseases.
Antibiotic PK/PD index Magnitude Ref individual
PK parameter values for the antibiotic drug, or setting
b-lactams
dosing recommendations applicable to a future patient, the data
Penicillins f % T>MIC 50e60 must come from population studies. In these studies, the PK
[101]
Cephalosporins f % T>MIC 60e70 parameters are not a single value, but a typical value for the
[101]
Carbapenems f % T>MIC 40e50 population
[101] (qCL) plus the associated inter-individual variability
Amynoglicosides Cmax/MIC 10 (hi).
[102]
Quinolones AUC/MIC 125 [103,104]
Tetracyclines
Tetracycline AUC/MIC 25 CLi ¼qCL þhi
[105]
Glucopeptides
Vancomycin AUC/MIC 400 When the variability between patients is considered in
[106]
Teicoplanin Cmin/MIC 10 for serious Gram-positive [107,108]
PK/PD analysis, a simple approach based on a single value
infections
(mean) of the PK parameters seems a poor predictor and a
20 for deep-seated infections
simulation based approach including this variability is needed.
Macrolides
In this regard, Monte Carlo simulation is an advanced
Clarithromycin f AUC/MIC 25 [105]
Azithromycin f AUC/MIC 25
statistical modeling tool that allows to expand the sample size
[105]
Daptomycin AUC/MIC 666 considering the variability of the PK and PD parameters on the
[109]
Tigecycline AUC/MIC 17.9 estimation of the PK/PD indices in order to provide predictions
[110]
Linezolid AUC/MIC 100 of the likely result of different therapeutic approaches, or the
[111]
Colistin f AUC/MIC 27.6e45.9 achievement of therapeutic targets [20,21].
[112]
f % T>MIC: percentage of time that the antimicrobial free serum concentration Roberts et al. [20]. described that the principal
remained above the MIC. Cmax/MIC: Maximum concentration divided by the requirements to perform Monte Carlo simulation are: 1) a
MIC. Cmin/MIC: Minimum concentration divided by the MIC. AUC/MIC: The validated population PK model including the structural model
area under the concentration-time curve over 24 h in steady-state divided by the
(providing population PK parameters), a variability model
MIC. f AUC/ MIC: The area under the free concentration-time curve over 24 h in
steady-state divided by the MIC. (providing inter-individual variability) and a covariate model
(studying the influence of patient characteristics on the PK
parameters) and 2) a PD model where the interrelationship of
the 1) relationship between plasma and tissue concentrations, 2) the PK and PD parameters has been studied. In this sense, the
time-course of antimicrobial activity in vivo, 3) PK/PD index nonlinear mixed effect modeling allows to study population
that correlates with the activity of the antibiotic and 4) PD target data, determining simultaneously the population typical value
associated to the efficacy. They also pointed out that although the and the individual value of the parameters to characterize any
PK/PD index varies depending on the class of antibiotics, the PD
 E. Asín-Prieto et al. / J Infect Chemother 21 (2015) 319e329
kind of kinetic or dynamic system. Fig. 4 depicts the scheme
of the antibiotic therapy modeling and simulation.
Regarding the PK/PD analysis and Monte Carlo
simulation for antibiotics, two different estimations of the
clinical outcome can be done. On the one hand, the
probability of target attainment (PTA) is defined as the
probability that a specific value of the PK/PD index
associated with the efficacy of the antibiotic is achieved at a
certain MIC [14]. In other words, it corresponds to the
percentage of simulated patients with an estimated PK/PD
index equal to or higher than the value related to the efficacy
of the antibiotic against a pathogen with a certain MIC. This
cut-off value is known as the pharmacodynamic target (PDT).
As an example, the PK/PD index and PDT associated with the
efficacy of linezolid is the AUC/MIC >100. Canut et al. [22]
simulated linezolid PK profiles given 600 mg every 12 h
intravenously obtaining PTAs higher than 90% against a
pathogen presenting an MIC of 2 mg/L, around 40% for 4
mg/L and almost 0% for an MIC of 8 mg/L or higher.
On the other hand, the cumulative fraction of response
(CFR) is defined as the expected population PTA given a
population of microorganisms for a specific dosing regimen
[14]. In other words, it must be understood as the expected
probability of success of a dosing regimen against bacteria in
the absence of the specific value of MIC, and thus, the
population distribution of MICs is used. It is calculated as
n
CFRð%Þ ¼ XPTAi Fi
i¼1
where the CFR(%) results from the total sum of the products of
the PTA at a certain MIC times the frequency (F) of isolates of
Fig. 4. Modified triangle of the antibiotic therapy that includes the modeling
tools to describe the interactions between the three elements of the therapy.
Monte Carlo simulation is performed with the information provided by
modeling to adjust the dosing regimens of the antimicrobials. PK modeling:
pharmacokinetic modeling; PD modeling: pharmacodynamic modeling; DP
modeling: disease progression modeling.
microorganism exhibiting that MIC over the range of
susceptibility of the pathogen.
This approach is especially useful in community medicine
and in critical situations where suspicion or a partial diagnose
has been made but the pathogen susceptibility has not been
determined at the moment. In this regard, a key point is the
selection of the adequate population distribution of MICs as
the susceptibility may vary along time and among countries,
areas or health centers. In the study by Canut et al. [22],
taking into account the population distribution of methicillin-
323
resistant S. aureus for linezolid in Belgium, United
Kingdom/Ireland and Spain, the estimated CFR was 98%,
98% and 91%, respectively. These results have sense as the
majority of the isolates presented an MIC lower than or equal
to 2 mg/L (PTA >90%) in Belgium (100% of isolates), United
Kingdom/Ireland (100% of isolates) and Spain (90% of
isolates).
The estimation of CFR may also be useful to determine
which antimicrobial and dose regimen would have the best
likelihood of success to treat bacterial isolates from a
particular hospital. In a recent study [23] different dosing
regimens for cefepime and carbapenems were compared to
determine the best dosing strategy for achieving optimal
pharmacodynamic exposures in critically ill patients against
an institution-specific population of Pseudomonas aeruginosa
isolates. Monte Carlo simulation allowed to determine that
none of the evaluated imipenem regimens achieved a CFR
90%, whereas 1e2 g q8h meropenem or 0.5, 1, or 2 g q8h
doripenem, or 2 g q8h cefepime administered as prolonged
infusions were needed to achieve CFR values 90%.
All these examples demonstrate the potential of
pharmacodynamic modeling to select optimal dosing
regimens to guide antimicrobial therapy. Fig. 5 summarizes
the steps needed to apply PK/ PD analysis and Monte Carlo
simulation in clinical setting.
The use of bacteria susceptibility data alone, without a
more global overview considering PK/PD approach, can be
misleading and could lead to higher risk of treatment failure
and resistance development, which would be related also with
increased cost associated to the management of infectious
diseases.
3. Applications of the PK/PD analysis
The PK/PD analysis can be applied in drug development
to scale from animal studies, establish the optimal dosing
regimens in clinical trials or describe the kinetic and dynamic
relation for new drugs, as regulatory agencies have started to
require. Furthermore, PK/PD analysis applications also
include the setting of susceptibility breakpoints by national
and international microbiology committees, and optimization
of pre-existing dosing regimens with direct application on
clinical situations.
3.1. Application to setting and reevaluating antibacterial
susceptibility breakpoints
A clinical or susceptibility breakpoint is an interpretative
criteria based on the likelihood of a favorable response of the
antibiotic therapy against a microorganism. Bacterial strains are
categorized in three groups based on the clinical or susceptibility
breakpoints: clinically susceptible, clinically intermediate and
clinically resistant. The establishment of the susceptibility
breakpoints is critical as they are used by clinical laboratories to
guide clinicians on the prescription of the antibiotics in the
clinical practice (to select or discard antibiotic agents).
Consequently, a wrong establishment of the breakpoints can lead
to clinical failure. PK/PD principles must be taken into
consideration when setting and revising antimicrobial
breakpoints. Actually, wild-type MIC distribution, PK/PD data
(PK/PD breakpoint) and clinical data have been pointed out as
information necessary to establish appropriate antibacterial
breakpoints [24].
324 E. Asín-Prieto et al. / J Infect Chemother 21 (2015) 319e329
PK/PD breakpoints are regimen-dependent (species-
independent) and therefore, different PK/PD breakpoints can be
obtained for the same drug. Two different methodologies have
been used to estimate PK/PD breakpoints. Firstly, the PK/PD
breakpoint can be estimated as the highest MIC value at which a
high probability of target attainment is obtained (PTA 90%, Fig.
6A). This approach was used by some authors in the comparison
of PK/PD breakpoints with the ones published by the
committees against both Gramnegative and Gram-positive
bacteria [21,25]. The second methodology to estimate the
PK/PD breakpoints is by graphical representation of the PK/PD
index as a function of the MIC (Fig. 6B). Then, the MICs that
are supposedly covered by the dosing regimen can be read
directly from the graph at the intersection of the PDT and the
lower confidence interval. The highest MIC value covered by the
dosing regimen is the PK/PD breakpoint. It is reported that the
PK/ PD breakpoint obtained when using a confidence interval of
80% corresponds to the one obtained by using the method of
PTA 90%. However, the European Committee on Antimicrobial
Susceptibility Testing (EUCAST) uses confidence intervals of
95% or even 99%, providing more conservative PK/PD
breakpoints (no discrepancy,

Fig. 6. Representations of the two estimation methods commonly used for

setting PK/ PD breakpoints in the case of a carbapenem (target: f % T >MIC 40).
Panel (a) corresponds to the first method. The PTA (%) is represented over a
range of doubling MIC. In the example, the PK/PD breakpoint is 2 mg/L, as it
is the highest MIC obtaining a PTA >90%. Panel (b) corresponds to the second
method. The magnitude of the PK/PD index for the mean, 95th percentile and
99th percentile of the simulations is represented over a range of doubling MIC.
In the example, the PK/PD breakpoint is 1 mg/L as it is the MIC read when
matching the selected PD target (f % T>MIC 40) with the 95th percentile.

one-fold or two-fold MIC discrepancies can be observed with

respect to the previous method depending on the variability
included in the simulation and the kinetics of the drug) [26].
Some studies were performed to estimate the PK/PD

Fig. 5. Scheme of the steps needed to apply PK/PD analysis and Monte Carlo simulation in clinical setting.
breakpoints and evaluate the susceptibility breakpoints published
by committees. In these studies, they estimated the PK/PD
breakpoints using the first method and obtaining the PK data
from the literature (for critically ill patients and healthy
volunteers). DeRyke et al. [27] studied the PK/PD breakpoints of
15 dosing regimens (8 different drugs) using PK information of
 E. Asín-Prieto et al. / J Infect Chemother 21 (2015) 319e329 325
critically ill patients. Discrepancies between the PK/PD 3.2.1. PK/PD analysis in critically ill patients
breakpoints and the clinical and laboratory standards institute The particular pathophysiological situation of critically ill
(CLSI) published breakpoints against Gramnegative rods were patients makes it difficult to handle infectious diseases using
detected and the difference between the PTA and the percentage standard antibiotic protocols. Differences in the clinical
of susceptibility at the CLSI breakpoint was studied using the outcome are most often when analyzing critically ill, due to
Meropenem Yearly Susceptibility Test Information Collection the altered PK and PD. Figure 7 shows an overview of the
(MYSTIC) database. These discrepancies between the PK/PD PK/PD analysis in ICU patients. Actually, diminished
breakpoints and the susceptibility breakpoints defined by susceptibility microorganisms are commonly found in the
committees were also detected by other authors. Frei et al. [25] hospital environment among critically ill patients [31]. The
evaluated 21 dosing regimens (13 different drugs) against wide use of antibiotics in hospital environment provokes
Gramnegative aerobic bacteria. The PK data were obtained from selective pressure of resistant strains.
studies with healthy volunteers. CLSI and EUCAST breakpoints On the other hand, in the critically ill patients the PK of
were compared to the PK/PD breakpoints, and the percentage of antibiotics are altered due to their clinical situation and the
bacterial isolates affected by these discrepancies based on the intensive care procedures they undergo. Five main issues can
MYSTIC database was estimated. Breakpoint agreement was be detected in critically ill patients regarding altered PK:
detected for imipenem, meropenem, and aminoglycosides. increased volume of distribution (Vd), altered protein
However, discrepancies were found for piperacillin/tazobactam, binding, augmented renal clearance, impaired renal clearance
cephalosporins, ertapenem, aztreonam and fluoroquinolones. and hepatic dysfunction [32]. Polytraumatism, severe
Differences up to four-fold MIC were detected. In the case of P. infection (such as sepsis, bacteriemia, pneumonia) and severe
aeruginosa, more than 30% of isolates were affected by the burn are some of the illnesses commonly present in the ICU
discrepancies between breakpoints for cefepime, aztreonam and and associated to the systemic inflammatory response
levofloxacin. Regarding Gram-positive bacteria, Asin et al. [21] syndrome. Impairments affecting cardiovascular system
studied 47 dosing regimens (13 antibiotics) using PK data from might condition the blood flow to tissues and excretion
studies with healthy volunteers. Discrepancies between PK/PD organs. Critically ill patients usually present expanded Vd due
and published breakpoints were also detected. For some to inflammatory response and capillary leak. Bleeding and
antibiotics, differences up to eight-fold MIC were detected. As in drains produce higher rate of elimination of the drug. As a
the previous study, the impact of these discrepancies on the consequence, the
percentage of isolates based on the British Society for
Antimicrobial Chemotherapy (BSAC) database was estimated.
For b-lactams, the percentage affected was relatively low
(<15%), but higher differences were detected for low doses of
vancomycin, daptomycin and linezolid (up to 100%).
Additionally, susceptibility breakpoints based on PK/PD data
may be different depending on the infection site as shown by
some authors [28,29].
The consequences of these discrepancies on the
breakpoints have a direct effect on clinic. On the one hand,
PK/PD breakpoints higher than published clinical breakpoints
could lead to deny effective dosing regimens and antibiotics
and to the prescription of higher doses that could result toxic.
On the other hand, when PK/PD breakpoints are lower, an
isolate may be considered susceptible when failure is
predicted by PK/PD analysis. This situation can explain
clinical failures, what reinforced the necessity of considering
PK/PD data when setting and reevaluating susceptibility
breakpoints for new and old antimicrobials [21].
Currently, EUCAST and CLSI are promoting the use of
PK/PD data as one of the gears in the susceptibility
breakpoint setting machine [30]. Actually, EUCAST
highlights the PK/PD data as the basis for setting clinical
breakpoints for new and old antimicrobials and rationale
documents (available at: http://www.eucast.org/
documents/rd/) are provided where PK/PD analysis and
Monte Carlo simulation have been performed to review
breakpoints for all commonly used agents.

3.2. Application to special situations

The estimation of the PK parameters, and therefore, the

establishment of the dosing regimens of new drugs is based
on clinical trials conducted with healthy volunteers.
Nevertheless, the host of an infection is never a healthy
subject but a patient presenting a special situation that may
vary the PK profile and the expected outcome of the therapy.
326
Fig. 7. Changes in the ICU patients that modify different PK and PD parameters and therefore, the outcome of the therapy. The pathophysiological situation as well as the intensive care procedures
might alter the pharmacokinetic parameters, and therefore, the antibiotic concentrations in the body. There is a balance between the bound (B) and unbound (UB) antibiotic concentrations ([AB]) in
the plasma fluid. Only the unbound drug is able to access to the tissue where a new balance is set between the bound and unbound drug tissue concentrations. Only the unbound antibiotic at the
infection site is responsible of the effect. On the other hand, a selective pressure affects the pathogens to decrease their susceptibility against the antibiotic (higher MICs are shown). SIRS: systemic
inflammatory response syndrome; Vd: volume of distribution; CL: total body clearance; PB: protein
binding.
concentrations of the antibiotic will be lower. On the contrary,
excretion organ impairment (kidney or liver) can provoke an
accumulation of the drugs in plasma and therefore, higher
concentrations. Nevertheless, the intensive care procedures are
also important factors affecting the PK profile of antibiotics.
ICU patients are loaded with large volumes of physiologic and
drug solutions expanding the plasma volume and/or they might
undergo continuous renal replacement therapies (CRRT) which
could lead to a decrease of the concentrations of the
antimicrobials. Anyway, only the unbound antibiotic is able to
penetrate to the infection site and produce the desirable effect.
Fluctuations on the plasma protein concentrations
(hypoalbuminaemia is commonly found in the critically ill)
might change the fraction unbound, which is mainly important
with antibiotics presenting a high extraction rate [33]. Then, the
unbound fraction of the drug must penetrate to the target tissue
which is conditioned by the local blood flow and edema
formation. Furthermore, the ICU patients present impaired the
natural mechanisms against infections, such as broken skin
barrier (wounds, catheter procedures) or inadequate immune
response (immunosuppressive diseases or treatments). PD target
is commonly established on in vivo studies with neutropenic
animal models. Even so, this situation must be taken into
account and higher PD targets are recommended.
As a result, in ICU patients either altered PK or PD, or
both, affect the PK/PD index magnitude, and in turn, the
probability to achieve the PD target [34]. Therefore,
antibiotic individualization is recommendable to assess the
antibiotic dosing and enhance the clinical outcome of the
antibiotic therapy by applying PK/PD analysis.
Among the possible ways to handle infections in the ICU
patients in order to enhance the clinical outcome of the
antibiotic therapy, it has been proposed to use combinations
E. Asín-Prieto et al. / J Infect Chemother 21 (2015) 319e329
of different antibiotics to avoid resistance mechanisms and/or
increasing antibiotic exposures [35].
PK modeling is especially valuable when considering the
small sample size and heterogeneity of the ICU patients, as the
interindividual variability can be explained by the
pathophysiologic characteristics influencing the PK profile of the
antibiotics. As mentioned above, population PK models can be
applied in PK/PD analysis to perform Monte Carlo simulation
allowing to individualize the antibiotic therapy and simulate
different scenarios to enhance the clinical outcome (such as
higher doses, extended or continuous infusion, altered PK
characteristics, or higher PD targets).
PK/PD analysis has been performed to evaluate different
antibiotics in this patient population: b-lactams [36e43], colistin
[44], arbekacin [45], vancomycin [46], daptomycin, linezolid,
tigecycline [22,42], and fluoroquinolones [47,48].
PK/PD principles have also been applied to evaluate the
implications of using extended and continuous infusion instead
of short infusion of antibiotics with time-dependent or
concentration-independent activity to reach the PD target,
[49e51] whereas, others evaluated concentrating once a day the
daily dose of antibiotics with concentration-dependent activity
instead of sparing it in lower doses more times a day [52e54]. As
example, the optimization of the use of b-lactams has aroused a
huge interest because it is the most commonly prescribed class
of antimicrobials, routinely recommended as first-line therapy in
many guidelines. In this regard, Monte Carlo simulation has
shown that for b-lactams, the probability of obtaining f T >MIC
targets can be improved in the critically ill by increasing the
dose, shortening the dosing interval or prolonging the infusion
time of the drug [55]. These results justify that for critically ill
patients with resistant pathogens, modifications of the dosing
strategy administering higher doses in combination with the
prolonged-infusion time has gained widespread popularity.
Current evidence from clinical studies suggests that prolonging
 E. Asín-Prieto et al. / J Infect Chemother 21 (2015) 319e329
the infusion duration can increase efficacy and may improve
patient outcomes.
Recently, a special interest is focused on CRRT, as significant
variability in antibiotic concentrations has been detected and
empirical dosing failed to achieve the target trough concentration
in patients undergoing these extracorporeal techniques [56].
Particularly, our research group has developed PK models for
meropenem and piperacillin-tazobactam in critically ill patients
undergoing CRRT and recommendations based on PK/PD
criteria have been suggested [57,58]. Some reviews have been
published collecting studies where b-lactam dosing regimens
were evaluated based on PK/PD principles for critically ill
patients undergoing CRRT [34,59].
Further PK/PD research is required to handle critically ill
patients in order to choose the right antibiotic administered at the
optimal dosing regimen in the first place, to study the utility of
combination therapy in the management of serious infections
[16] and to individualize the therapy based on prior knowledge,
pathogen susceptibility and therapeutic drug monitoring when
possible [60]. In this sense, dosing nomograms have been
created for some antibiotics to assist ICU clinicians [61e63].
3.2.2. PK/PD analysis depending on the infection site
Liu et al., [64] pointed out that only the free tissue
concentrations of antibiotics at the target site, which are
commonly lower than the total plasma concentrations, are
responsible for therapeutic effect. Several techniques have been
developed to study free tissue concentrations, but the most
important one is microdyalisis [65]. Briefly, it is based on the
diffusion of the drug between the interstitial fluid (IF) and the
dialysis solution which is perfused via a thin probe inserted in
the tissue. Nevertheless, this technique can be uncomfortable and
long for the patient and requires trained personnel to achieve the
target tissue and therefore, it is not commonly used in
prospective studies. Furthermore, human microdialysis studies
have shown that the unbound drug concentrations in IF of tissues
can be predicted on the basis of plasma concentration profiles
and plasma protein binding data [66]. However, this assumption
is not always justified, it depends on the antibiotic agent and the
target tissue [67]. The pathophysiological condition of the
patient is another factor modifying the relation between plasma
and tissue concentrations, such as septicemia, septic shock or
intensive care procedures. As a consequence, PK/PD analysis
can predict effective antibiotic concentrations in plasma,
whereas the tissue concentrations are not enough to overcome
the infection [31,66].
Some of the most challenging infections are located in tissues
with a limited access of drug such as cerebral, bone, ocular or
respiratory tract infections. As an example, patients with cystic
fibrosis often suffer from respiratory tract infections. This
disease is associated with higher volume of distribution and
clearance and limited penetration of the antibiotic into the site of
action (12% of the plasma drug was estimated to access the site
of action for aminoglycosides). Hence, local administration of
the antibiotic has been suggested obtaining higher concentrations
at the site of action and minimizing the side effects [68].
However, they are the less the cases where a local administration
of the antibiotic is possible. The feasibility of local
administration depends on the clinical situation of the patient,
the antibiotic characteristics and the type of infection. Some
studies have demonstrated differences on the limited cerebral
penetration of some antibiotics and the implications regarding
PK/PD analysis. The ratio of the area under the
concentrationetime curve in brain to that in plasma for the
327
different antibiotics ranged from 0.01 to 1, and thus the PK/PD
analysis based on plasma concentrations might overestimate the
antibacterial activity in the cerebral tissue [69,70].
Therefore, for PK/PD analysis our suggestion is to use
free tissue concentrations when possible (required when local
administration). In this sense, Ikawa et al. [71] evaluated
meropenem and biapenem dosing for the treatment of biliary
tract infections and detected differences in the PTA when
using bile concentrations or free plasma concentrations. If
free tissue concentrations are not available, free plasma
concentrations may be used but it is recommendable to
provide any marker, ratio or descriptor with information on
the magnitude of (free) plasma drug that access the interstitial
tissue (target tissue preferable) to support the simulations and
the applicability of the PK/PD based recommendations.
Gonçalves-Pereire and Povoa [72] reviewed the b-lactam
therapy in critically ill patients from a PK/PD point-of-view
providing the PD target and tissue penetration found in
several studies.
3.2.3. PK/PD analysis in obese patients
Obese patients is a subgroup of population continuously
increasing in developed countries. Because of their special
clinical situation, antibiotic pharmacokinetic parameters are
significantly influenced by physiologic changes in these
patients. In fact, obesity is not commonly a standalone disease
but linked to other pathologies (such as diabetes,
hypercholesterolemia, cardiac failure, renal and hepatic
impairment, and so on). Actually, obesity has been associated
to antibiotic treatment failure as a significant risk factor [73].
A relationship between obesity and higher Vd and CL for
several drugs have been detected [74], whereas the need of
changes on the standard dosing regimens is not clear.
Cheatham et al. [75] studied the meropenem
pharmacokinetics in morbidly obese critically ill patients
performing PK/PD simulations and concluded that standard
doses are sufficient to achieve the PD target in this
population. Chen et al. [76] compared the pharmacokinetics
of ertapenem in normal-weight, obese and extremely obese
patients. PK/ PD simulations revealed modest differences on
the PTA depending on the weight. On the contrary,
piperacillin and tazobactam CL and Vd were altered in obese
patients, and larger doses might be needed to achieve the
same PD exposures as in non-obese patients [77]. In another
study, it is considered that weight-adjusted dosing based on
actual body weight will yield adequate tissue levels for
ciprofloxacin [78]. Consequently, further research in this field
seems necessary to elucidate whether dosing adjustments are
needed. In this sense, population studies with patients with
different body weights are recommended to study the
influence of body weight on the PK parameters and simulate
different doses to achieve adequate antibiotic PD exposures.
3.2.4. PK/PD analysis and the effect of the patient age
Pharmacokinetic changes in the elderly patients include a
reduction in the renal and hepatic clearance and an increase in
the volume of distribution of lipid soluble drugs (hence
prolongation of elimination half-life) [79]. As a consequence,
higher mortality rate has been demonstrated in elderly septic
patients [80]. The need for additional adjustment seems
necessary as a simple approach based on just the renal
clearance was not sufficient, and the age should be considered
in the case of some fluoroquinolones [81]. In another study,
differences in PK parameters between elderly and younger
patients were detected, and the patient age was included in the
328 E. Asín-Prieto et al. / J Infect Chemother 21 (2015) 319e329
population PK model for linezolid, conditioning the PK/PD
analysis
[82].
On the other hand, pediatric dosing is a challenging issue
in current medicine. Pediatric patients cannot be considered
simply “small adults”, because important physiological and
biochemical differences among neonates, infants, children,
adolescents and adults lead to differences on drug absorption,
distribution, metabolism and elimination processes [83]. The
PK variability will be essentially conditioned by patient size,
maturation and organ function. In this sense, children (2
years) are similar to adults (ie., mature) and differ only in
size, while maturation is extremely important in infants (<2
years) and neonates and consecutively, this cohort can be
viewed as immature children [84]. Considering all of this,
dosages for neonates, infants, children and adolescents may
require adjustment as compared with adult doses.
Initially, the used method is to apply empirical scaling
from adult to pediatric using allometric size adjustments
based on body weight. Recently, a simple approach has been
developed to simulate age-matched weight and body mass
index, which can be applied to adjust dosing in children [85].
Later, PK profile must be characterized to better understand
and adjust the administration of antibiotics in pediatric. A
recent review points out that “knowledge of PK/PD principles
is crucial when prescribing antibiotics in children,
particularly when treating serious infections and in special
populations of children who have altered pharmacokinetics
[86]”. As an example, the body weight of the children
resulted to be a significant covariate on meropenem PK
parameters, and PK/PD simulation was applied to suggest
recommendations based on the body weight [87]. In other
study, researchers performed Monte Carlo simulations based
on previously published PK data for gentamicin, applied the
results in a prospective study in premature infants confirming
the utility of the PK/PD analysis in optimizing the antibiotic
therapy [88].
A frequent and challenging infectious disease in children
is the acute otitis media. Our group evaluated the treatment of
this infection by PK/PD analysis and suggested different
dosing regimens and antibiotics depending on the local
susceptibility data for the most common pathogens (S.
pneumoniae and H. influenzae)
[89,90].
In our opinion, PK/PD modeling can provide better
approaches when prescribing to elderly and pediatric patients.
It is especially in pediatric population where PK/PD analysis
results highly useful for optimizing drug dosing due to the
lack of scarce of studies in this patient population.
3.2.5. PK/PD analysis in prophylaxis
The administration of perioperative antibiotic prophylaxis
is aimed to prevent post-operative infections, mainly surgical
site infections (SSI). The choice of an antibiotic prophylactic
agent must be performed based on the susceptibility of the
most likely pathogens responsible for SSI, the kinetic profile
of the drug and its distribution to the interstitial tissue around
the surgical wound. In this regard, antibiotic prophylaxis
must cover aerobic and anaerobic bacteria commonly found
in that special situation, and taking into account the
susceptibility against antimicrobials. Moreover, the drugs
must be administered previously to the surgery in such a way
that therapeutic concentrations are maintained in both plasma
and interstitial tissue around the surgical wound until its
closing. As contamination can occur at any time during the
surgical procedure, free drug concentrations must be above
the highest possible MIC until the end of the surgery and
even longer [91]. When considering this premise, shorter
interdose intervals or extended infusions may be needed [92].
Some reviews of the perioperative prophylactic protocols
have been performed based on a PK/PD point-of-view in
different kinds of surgeries such as cardiothoracic surgery
[93], prostate biopsy [94], cesarean delivery [95], gastric
bypass [96], and so on.
However, the biggest challenge when considering
perioperative prophylaxis is upon colorectal surgery. In this
kind of surgery, the prophylactic protocol is crucial as the risk
of postoperative infection is extremely high compromising
even more the health and prognosis of the patient. Our
research group has evaluated the adequacy of two current
prophylactic protocols based on cefoxitin [97] and
cefuroxime-metronidazole [98] in colorectal surgery by
prospective studies performing population modeling and
PK/PD simulation. In both studies, the pharmacodynamic
target was to maintain free drug concentrations over the MIC
of the potential pathogens until the closing time of the
surgery. Recommendations were suggested in all cases
depending on the patient characteristics (such as creatinine
clearance or body weight) and the length of the surgery.
Furthermore, the PK/PD principles of the prophylaxis
protocols can also be studied focused on the pathogen. This is
the case of anthrax disease where some authors evaluated the
postexposure prophylaxis for Bacillus anthracis [99,100].
4. Conclusion
PK/PD analysis is postulated as the main tool to fight
resistance emergence by optimization of the dosing regimens of
new and old antibiotics. Its application leads to an enhancement
of the probabilities of success of the therapy, minimization of the
resistance emergence and reduction of the adverse effects. A
combination of the PK/PD analysis with population PK
modeling and Monte Carlo simulation support antibiotic
prescription, which is even more relevant in special
subpopulations of patients such as critically ill, elderly or
pediatric patients considering their particular pathophysiological
characteristics. Firstly, setting PK/PD breakpoints which provide
general guidance to face the infectious diseases considering the
susceptibility of the pathogen. And secondly, considering the
individual characteristics of the patient and adjusting the
antibiotic therapy to its clinical situation.
Conflict of interest
There is no conflict of interest to declare.
Acknowledgments
This work was supported by the Department of Education,
Universities and Research (IT341-10), Basque Government,
Spain. We would like to thank the Basque Government for
research grants awarded to Eduardo Asín-Prieto.
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