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Therapeutic drug monitoring (TDM) of plasma samples is used in many circumstances to adjust pharmaceutics to desired concentrations. It is predominantly employed for drugs with a narrow therapeutic window (to avoid both underdosing and toxic levels) and/or where large inter- and intra-individual variations of concentrations are expected (e.g., antiepileptic drugs, anticoagulants, and immune modulators).
Antimicrobials: life-saving drugs with a difficult pharmacology
The effects of antimicrobials against pathogens are dependent on either peak concentrations or time above the minimal inhibitory concentration (MIC) or a combination of both, at the site of infection. Antimicrobial concentrations are influenced by drug distribution and elimination, which vary extensively in critically ill patients [1]. Therefore, treatment with “standard doses” of antimicrobials will be unpredictable [2]. Even though this knowledge is gaining momentum throughout the critical care community [3] the implementation of TDM has been slow [4].
TDM: why do we need it?
TDM of antimicrobials has the potential to detect and improve this variability [1]. While TDM was traditionally used to avoid specific toxicities of antimicrobials (e.g., glycopeptides or aminoglycosides), its focus has shifted towards improving therapeutic efficiency. β-Lactams are at the center of this development, but TDM of fluoroquinolones has recently gained more attention [4]. Apart from variations in target, the concept of TDM is applicable to most antimicrobials. The approach of controlling concentrations of antimicrobial drugs over time (pharmacokinetics, PK) to optimize their biological actions (pharmacodynamics, PD) is called “PK/PD-optimized dosing”. Several studies demonstrated the potential of TDM to improve the probability of target attainment (PTA) of antimicrobials in intensive care unit (ICU) patients. The use of TDM for PK/PD optimization has increased [5, 6], although technical demands (assay availability) and associated costs are still an obstacle. Beyond these barriers, other uncertainties need to be recognized.
Areas of uncertainty
What concentrations should be targeted and where?
There is significant heterogeneity in TDM studies regarding the definition of target concentrations, and the PTA of empirical dosing is dependent on if “high” or “low” targets are defined [7]. As an example, while there is consensus that concentrations for ß-lactams should be above the MIC of pathogens for the better part of a dosing interval, it is debated whether target concentrations of up to 4–6 × MIC add further benefit [1, 8]. As individual MICs are often not available, the use of empiric MICs for the respective antimicrobial, usually at the higher end of “sensitive”, is common. While the use of high MICs in combination with high target attainment aims at avoiding underdosing, the necessity of such high targets is questionable as it also increases the risk of attaining potentially toxic levels. It is unclear whether targets should be adjusted according to local resistance epidemiology and if TDM is particularly valuable in settings with high rates of resistance [9]. It must also be recognized that antimicrobial concentrations are usually measured in plasma samples, that not necessarily reflect concentrations at the site of infection and will thus act as a surrogate marker.
How do we adjust dosing when concentrations are out of range?
A recent study showed that the implementation of TDM in the ICU requires a dedicated effort and benefits from expert pharmacological advice. This might be an important component of antimicrobial stewardship programs in the ICU [10]. Unfortunately, there are no clear definitions of how doses should be adjusted in complex ICU patients. Many TDM studies assume a linear relationship [11], but situations in ICU patients are often dynamic. The two most important determinants of drug concentrations in critically ill patients, volume of distribution and clearance, may vary substantially, especially in patients with sepsis and septic shock. This is further complicated by extracorporeal organ support [12]. Various types of dosing calculation software are available, incorporating different pharmacokinetic models. Future models will likely be further enhanced with artificial intelligence. In such models, results from TDM are used to refine the modelling and enable ICU physicians to better individualize antimicrobial dosing [12].
Is steady state a prerequisite for TDM to offer meaningful information?
An often overlooked issue with TDM is the first 1–2 days of therapy. Most TDM protocols recommend sampling at steady-state level which is anticipated after 4 doses or at 24–48 h after initiation of therapy [13]. Even though this is meaningful for the correction of steady-state levels, it imposes a risk of not achieving antibiotic target concentrations during the “golden” first 24–48 h of therapy [14]. A loading dose or an extra dose within the first dosing interval is often recommended to more rapidly achieve target and steady-state levels. However, this is still empirical dosing and a protocol for earlier TDM, also in this early phase, could probably increase target attainment, but this will need further exploration Fig. 1.
What outcomes make sense when studying TDM in critically ill patients?
We do not know whether higher PTA of antimicrobials is beneficial to patients, and thus, the evidence in favor of TDM is still lacking. Recent trials did not show significant effects of TDM on mortality [4, 11]. However, a meta-analysis revealed positive effects of TDM on clinical and microbiological cure and treatment response [15]. Does this imply that we should not use TDM and halt its ongoing implementation? In an era of evidence-based medicine, this question can be answered with both yes and no. Since the evidence for benefit on patient-centered outcomes is still scarce, it could be argued that we should not introduce methods that are laborious and costly. On the other hand, current data suggest that TDM helps improve PTA by avoiding over- and underdosing. By gathering further data, different target achievements can be analyzed retrospectively and further enhance our knowledge. Also, besides patient outcomes, microbiological outcomes are important when discussing antimicrobial treatment. Although clinical data are lacking for this subject, adequate target attainment might reduce the emergence of resistant bacteria. Thus, there are also ecological benefits that need to be considered when analyzing the pro/con of TDM.
In conclusion, TDM will likely increase target attainment of antimicrobials in critically ill patients, reducing extremes of both low and high values with a possible positive effect on patient and microbiologic outcomes. There are still areas of uncertainty that will need to be further addressed in future studies.
References
Rawson TM, Wilson RC, O’Hare D, Herrero P, Kambugu A, Lamorde M, Ellington M, Georgiou P, Cass A, Hope WW, Holmes AH (2021) Optimizing antimicrobial use: challenges, advances and opportunities. Nat Rev Microbiol 19:747–758
Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Kaukonen KM, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Lipman J, Study D (2014) DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 58:1072–1083
Silva CM, Baptista JP, Santos I, Martins P (2022) Recommended antibiotic dosage regimens in critically Ill patients with augmented renal clearance: a systematic review. Int J Antimicrob Agents 59:106569
Ewoldt TMJ, Abdulla A, Rietdijk WJR, Muller AE, de Winter BCM, Hunfeld NGM, Purmer IM, van Vliet P, Wils EJ, Haringman J, Draisma A, Rijpstra TA, Karakus A, Gommers D, Endeman H, Koch BCP (2022) Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial. Intensive Care Med 48:1760–1771
Lanckohr C, Boeing C, De Waele JJ, de Lange DW, Schouten J, Prins M, Nijsten M, Povoa P, Morris AC, Bracht H (2021) Antimicrobial stewardship, therapeutic drug monitoring and infection management in the ICU: results from the international A- TEAMICU survey. Ann Intensive Care 11:131
Tritscher P, Delannoy M, Agrinier N, Charmillon A, Degand N, Dellamonica J, Roger C, Leone M, Scala-Bertola J, Novy E (2022) Assessment of current practice for beta-lactam therapeutic drug monitoring in French ICUs in 2021: a nationwide cross-sectional survey. J Antimicrob Chemother 77:2650–2657
Luxton T, King N, Walti C, Jeuken L, Sandoe J (2022) A systematic review of the effect of therapeutic drug monitoring on patient health outcomes during treatment with penicillins. J Antimicrob Chemother 77:1532–1541
Sumi CD, Heffernan AJ, Lipman J, Roberts JA, Sime FB (2019) What antibiotic exposures are required to suppress the emergence of resistance for gram-negative bacteria? A systematic review. Clin Pharmacokinet 58:1407–1443
Liebchen U, Weinelt F, Scharf C, Schroeder I, Paal M, Zoller M, Kloft C, Jung J, Michelet R (2022) Combination of pharmacokinetic and pathogen susceptibility information to optimize meropenem treatment of gram-negative infections in critically Ill patients. Antimicrob Agents Chemother 66:e0183121
Gatti M, Cojutti PG, Bartoletti M, Tonetti T, Bianchini A, Ramirez S, Pizzilli G, Ambretti S, Giannella M, Mancini R, Siniscalchi A, Viale P, Pea F (2022) Expert clinical pharmacological advice may make an antimicrobial TDM program for emerging candidates more clinically useful in tailoring therapy of critically ill patients. Crit Care 26:178
Hagel S, Bach F, Brenner T, Bracht H, Brinkmann A, Annecke T, Hohn A, Weigand M, Michels G, Kluge S, Nierhaus A, Jarczak D, Konig C, Weismann D, Frey O, Witzke D, Muller C, Bauer M, Kiehntopf M, Neugebauer S, Lehmann T, Roberts JA, Pletz MW, Investigators TT (2022) Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial. Intensive Care Med 48:311–321
Roberts JA, Bellomo R, Cotta MO, Koch BCP, Lyster H, Ostermann M, Roger C, Shekar K, Watt K, Abdul-Aziz MH (2022) Machines that help machines to help patients: optimising antimicrobial dosing in patients receiving extracorporeal membrane oxygenation and renal replacement therapy using dosing software. Intensive Care Med 48:1338–1351
Wong G, Brinkman A, Benefield RJ, Carlier M, De Waele JJ, El Helali N, Frey O, Harbarth S, Huttner A, McWhinney B, Misset B, Pea F, Preisenberger J, Roberts MS, Robertson TA, Roehr A, Sime FB, Taccone FS, Ungerer JP, Lipman J, Roberts JA (2014) An international, multicentre survey of beta-lactam antibiotic therapeutic drug monitoring practice in intensive care units. J Antimicrob Chemother 69:1416–1423
Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, McIntyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Moller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M (2021) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med 47:1181–1247
Pai Mangalore R, Ashok A, Lee SJ, Romero L, Peel TN, Udy AA, Peleg AY (2022) Beta-lactam antibiotic therapeutic drug monitoring in critically Ill patients: a systematic review and meta-analysis. Clin Infect Dis 75:1848–1860
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Sjövall, F., Lanckohr, C. & Bracht, H. What’s new in therapeutic drug monitoring of antimicrobials?. Intensive Care Med 49, 857–859 (2023). https://doi.org/10.1007/s00134-023-07060-5
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DOI: https://doi.org/10.1007/s00134-023-07060-5