Expert Review of Anti-infective Therapy

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Therapeutic drug monitoring (TDM) in real-time: a

need for the present future

Ignacio Martin-Loeches

To cite this article: Ignacio Martin-Loeches (2022) Therapeutic drug monitoring (TDM) in real-time:
a need for the present future, Expert Review of Anti-infective Therapy, 20:10, 1245-1247, DOI:
10.1080/14787210.2022.2110070

To link to this article: https://doi.org/10.1080/14787210.2022.2110070

Published online: 10 Aug 2022.

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EXPERT REVIEW OF ANTI-INFECTIVE THERAPY
2022, VOL. 20, NO. 10, 1245–1247
https://doi.org/10.1080/14787210.2022.2110070
EDITORIAL
Therapeutic drug monitoring (TDM) in real-time: a need for the present future
a,b,c,d
Ignacio Martin-Loeches
a
Department of Intensive Care Medicine, St. James’s Hospital, Multidisciplinary Intensive Care Research Organisation (MICRO), Dublin, Ireland;
b
Trinity College Dublin, Dublin, Ireland; cCIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; dPulmonary
Department, Hospital Clinic, Universitat de Barcelona, IDIBAPS, ICREA, Barcelona, Spain
ARTICLE HISTORY Received 2 June 2022; Accepted 2 August 2022
KEYWORDS Sepsis; TDM; shock; pneumonia; ICU
Patients with severe infections are exposed to very high mortality
[1]. Early suspicion and recognition of organ failure along with
effective and fast source control is the primary way to optimize
their outcome [2]. Antimicrobial treatment is a cornerstone in
managing patients with a severe infection. Several prospective
and retrospective studies gathering thousands of patients con­
stantly showed that appropriate antimicrobials treatment is asso­
ciated with favorable outcomes [3]. The main problem in clinical
practice is when the term ‘appropriate’ is discussed without
much understanding. Coming back to the basics of pharmacol­
ogy, ‘appropriateness’ is related to the ‘five rights’ of medication
use: the right patient, drug, time, dose, and route [4].
In the critical care setting, two items are easy to define:
patient and route, as the patient is severely ill, and the route is
always intravenous. The majority of the studies on infections
have looked at the drug’s sensitivity matching with the caus­
ing pathogen, obviously in a timely fashion [5]. Indeed, the
surviving sepsis campaign has recently implemented and
recommended a 1-hour bundle in patients with the most
severe spectrum of infections: septic shock.
A common unresolved problem that arises in the treatment
of severe infections is to determine the right dose [6]. First and
foremost, recommendations are mainly based on nonspecific
populations and mainly healthy volunteers in very controlled
clinical conditions. Interestingly, patient’s doses should con­
sider clinical disease patterns, varying levels of antimicrobial
resistance or drug availability. We have learnt over the years
that patients with sepsis and septic shock are often at risk of
underdosing due to an increased volume of distribution (Vd),
which is probably one of the most unknown pharmacokinetic
(PK) parameters that we consider when treating a critical care
patient. More specifically, Vd represents the individual antimi­
crobial’s propensity to either remain in the plasma or redis­
tribute to other tissue compartments. By measuring antibiotic
plasma concentrations, physicians can adjust antimicrobial
dosing in individual patients through the application of ther­
apeutic drug monitoring (TDM) [7]. This approach has two
potential benefits: to improve clinical outcome from infections
and to reduce the development of antimicrobial resistance.
The benefit of TDM focuses on two specific parameters: PK
and pharmacodynamics (PD) to define the antimicrobial
CONTACT Ignacio Martin-Loeches imartinl@tcd.ie Department of Intensive Care Medicine, St. James’s Hospital, Multidisciplinary Intensive Care Research
Organisation (MICRO), St James’s Street, Dublin, Ireland
© 2022 Informa UK Limited, trading as Taylor & Francis Group
exposure necessary for maximizing the killing or inhibition of
bacterial growth, determined by the minimum inhibitory con­
centration (MIC). As plasma concentrations are paramount to
eradicating the cause of the infection by sterilizing the
affected tissue, the concentration of antimicrobials should be
adequately measured and controlled during treatment [8,9].
A frequent discussion in the ICU is whether the antimicrobials
concentration is enough for both the patient and the medical
condition. Only a few drugs can be measured in central clinical
laboratories as part of routine care [10]. This is mainly for drugs
that need to minimize toxicity when administered to treat infec­
tions and maximize their effectiveness. An example of these
drugs are certain aminoglycosides (e.g. gentamicin, tobramycin
and amikacin), glycopeptides (vancomycin and less frequently
teicoplanin) and some antifungals (voriconazole). Interestingly,
these drugs are those that do not represent the major source of
antimicrobial administration: β -lactams [11]. This class of anti­
microbials is the best example of concentration–effect relations
for antimicrobials. Additionally, β-Lactam are often the most
prescribed drugs in ICU [12]. β-Lactam TDM has a wide thera­
peutic window and a large PK variability depending on the type
of patients such as those with obesity, critically ill, burns, acute
kidney injury (AKI). Implementing TDM would help safety how­
ever not always feasible in many institutions due to the cost and
a lack of suitable infrastructure. Furthermore, TDM necessitating
central laboratory analyses cannot provide real-time concentra­
tion for immediate dose adjustment to prevent adverse events
while also ensuring treatment efficacy. Additionally, optimal
dosage of antimicrobials allows efficient use of costly antimicro­
bials and may reduce the development of antimicrobial resis­
tance by avoiding the exposure of bacteria to sub-inhibitory
concentrations driving a pressure to acquire resistance.
Targeting drugs and being in between sub-therapeutic and
supra-therapeutic resulting in growth and selection of resistance
species, respectively [13,14].
Over the past two decades, several attempts for drug mea­
surement in body fluids or tissues have been done.
Experimentally, some methods assess antimicrobial tissue dis­
tribution, such as microdialysis, a minimally-invasive sampling
technique that is used for continuous pharmacokinetics mea­
surement and drug metabolism of free, unbound analyte
1246 EDITORIAL

Figure 1. Graphic representation of the future in drug in vivo monitoring.

concentrations [15]. Microdialysis hasn’t ‘jumped’ into the clin­ window to cure the infection and the lack of availability of
ical practice due to the difficulties in value interpretation, simple tools to bring antimicrobial TDM at the patient’ side,
technical challenges to correct the dialysate solution flow, recent advances in label- and reagent-free technic would offer
and the need for continuous calibration of the microdialysis unprecedented opportunities for real-time TDM. Such contin­
system for in vivo studies. uous measurements enable new advanced diagnostics to
The patient’s blood compartment could be accessed via identify the development of complications. Real-time monitor­
existing ports such as catheters, in which different technolo­ ing allows the detection of early concentration deviation;
gies can be inserted (Figure 1). The selective detection of small hence assume we could improve up to 50% MIC target com­
molecules is today possible by exploiting the use of spectro­ pliance and increase the clinical cure rate.
scopy. Additionally, these devices should be prepared for
being connected to patient monitoring systems and storage
Funding
in the patient’s electronic health record (EHR) allowing data
collection, processing, and immediate, automated analysis by This paper was not funded.
a dedicated software solution. Table 1 displays the challenges
for continuous monitoring and the potential solutions.
In summary, to fill the gap between the need to ensure that Declaration of interest
the right dose is continuously within the targeted therapeutic I Martin-Loeches discloses advisory board membership and lectures for
Spiden, Pfizer, MSD and Menarini. The author has no relevant affiliations or
Table 1. Challenges and potential solutions for continuous PK/PD monitoring of financial involvement with any organization or entity with a financial
drugs in clinical settings. interest in or financial conflict with the subject matter or materials dis­
Challenges for ICU continuous cussed in the manuscript apart from those disclosed.
monitoring Future solutions
Continuous access to the blood Develop capabilities for reagent- and
compartment label-free sensors of body fluids,
transcutaneously, or in a minimally
Reviewer disclosures
invasive way Peer reviewers on this manuscript have no relevant financial or other
Safe continuous sensing of blood Spectroscopy solutions using of light relationships to disclose.
sources without unacceptable
phototoxic effects.
Specific and selective detection of Combined the ultra-sensitive
antimicrobial presents at low photodetector with advanced ORCID
concentration in whole blood machine learning algorithms
Ignacio Martin-Loeches http://orcid.org/0000-0002-5834-4063
robust to within- and between-
patient variability
Real-time information provided to the Antimicrobial concentration (low-
medical team volume electrochemical sensors)
available in real-time on a patient
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