Therapeutic drug monitoring (TDM) in real-time: a need for the present future

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 constantly showed that appropriate antimicrobials treatment is associated 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 pharmacology, ‘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 causing 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 consider 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 antimicrobial’s propensity to either remain in the plasma or redistribute to other tissue compartments. By measuring antibiotic plasma concentrations, physicians can adjust antimicrobial dosing in individual patients through the application of therapeutic 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 exposure necessary for maximizing the killing or inhibition of bacterial growth, determined by the minimum inhibitory concentration (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 infections 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 antimicrobials 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 therapeutic 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 however 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 concentration for immediate dose adjustment to prevent adverse events while also ensuring treatment efficacy. Additionally, optimal dosage of antimicrobials allows efficient use of costly antimicrobials and may reduce the development of antimicrobial resistance 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 measurement in body fluids or tissues have been done. Experimentally, some methods assess antimicrobial tissue distribution, such as microdialysis, a minimally-invasive sampling technique that is used for continuous pharmacokinetics measurement and drug metabolism of free, unbound analyte concentrations [15]. Microdialysis hasn’t ‘jumped’ into the clinical practice due to the difficulties in value interpretation, technical challenges to correct the dialysate solution flow, and the need for continuous calibration of the microdialysis system for in vivo studies.

The patient’s blood compartment could be accessed via existing ports such as catheters, in which different technologies can be inserted (Figure 1). The selective detection of small molecules is today possible by exploiting the use of spectroscopy. Additionally, these devices should be prepared for being connected to patient monitoring systems and storage in the patient’s electronic health record (EHR) allowing data collection, processing, and immediate, automated analysis by a dedicated software solution. Table 1 displays the challenges for continuous monitoring and the potential solutions.

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

Table 1. Challenges and potential solutions for continuous PK/PD monitoring of drugs in clinical settings.

Challenges for ICU continuous monitoring	Future solutions
Continuous access to the blood compartment	Develop capabilities for reagent- and label-free sensors of body fluids, transcutaneously, or in a minimally invasive way
Safe continuous sensing of blood	Spectroscopy solutions using of light sources without unacceptable phototoxic effects.
Specific and selective detection of antimicrobial presents at low concentration in whole blood	Combined the ultra-sensitive photodetector with advanced machine learning algorithms robust to within- and between-patient variability
Real-time information provided to the medical team	Antimicrobial concentration (low-volume electrochemical sensors) available in real-time on a patient monitor with possibility to set alarms and integrated to EHR

In summary, to fill the gap between the need to ensure that the right dose is continuously within the targeted therapeutic window to cure the infection and the lack of availability of simple tools to bring antimicrobial TDM at the patient’ side, recent advances in label- and reagent-free technic would offer unprecedented opportunities for real-time TDM. Such continuous measurements enable new advanced diagnostics to identify the development of complications. Real-time monitoring allows the detection of early concentration deviation; hence assume we could improve up to 50% MIC target compliance and increase the clinical cure rate.

Declaration of interest

I Martin-Loeches discloses advisory board membership and lectures for Spiden, Pfizer, MSD and Menarini. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.