Personalized Antibiotic Therapy in Critically ill Patients: A Comprehensive Review of Pharmacokinetic/Pharmacodynamic Optimization in the Intensive Care Unit
DOI:
https://doi.org/10.55544/jrasb.5.2.18Keywords:
Personalized antibiotic therapy, ICU, pharmacokinetic, pharmacodynamic, Therapeutic drug monitoring, SepsisAbstract
Infection-related morbidity and mortality remain disproportionately high in the intensive care unit (ICU), a challenge exacerbated by the global surge in multidrug-resistant organisms (MDROs) and a stagnating antimicrobial pipeline. Traditional "one-size-fits-all" antibiotic dosing regimens, largely derived from healthy volunteer data, routinely fail in critically ill patients. Sepsis and septic shock induce profound pathophysiological shifts including capillary leakage, massive fluid resuscitation, augmented renal clearance, and acute organ dysfunction that alter the volume of distribution (Vd) and clearance (CL) of hydrophilic and lipophilic antimicrobials alike. Suboptimal drug exposure drives clinical failure and accelerates the selection of resistant strains, while excessive exposure induces severe organ toxicities.
This review explores the mechanism-based rationale for personalized antibiotic therapy in the ICU. We evaluate key pharmacokinetic and pharmacodynamic (PK/PD) indices required for treatment optimization (fT > MIC, AUC24/MIC, and Cmax/MIC), outline the clinical integration of therapeutic drug monitoring (TDM), and discuss the utility of model-informed precision dosing (MIPD) using Bayesian forecasting software. Finally, we synthesize findings from recent landmark trials and outline future paradigms incorporating machine learning, point-of-care biosensors, and patient genomics to deliver true precision antimicrobial stewardship at the bedside.
Downloads
References
Abdul-Aziz, M. H., Alffenaar, J. W. C., Bassetti, M., Bracht, H., Dimopoulos, G., Marriott, D., Neely, M. N., Paiva, J. A., Pea, F., Sjovall, F., Timsit, J. F., Udy, A. A., Wicha, S. G., Zeitlinger, M., De Waele, J. J., & Roberts, J. A. (2020). Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper. Intensive Care Medicine, 46(6), 1127–1153. https://doi.org/10.1007/s00134-020-06050-1
Abdulla, A., Ewoldt, T. M. J., Hunfeld, N. G. M., Muller, A. E., Rietdijk, W. J. R., Polinder, S., van Gelder, T., Endeman, H., & Koch, B. C. P. (2020). The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial. BMC Infectious Diseases, 20(1), 1–8. https://doi.org/10.1186/s12879-020-4781-x
Blondiaux, M., & De Waele, J. J. (2022). Optimizing antibiotic dosing in the intensive care unit: The role of continuous infusions. Journal of Critical Care, 67(2), 45–52.
Cotta, M. O., & Roberts, J. A. (2021). Precision antimicrobial dosing in the critically ill: Are we there yet? Current Opinion in Infectious Diseases, 34(6), 624–631.
De Waele, J. J., Carrette, S., Carlier, M., Stove, V., Boelens, J., Claeys, G., Hoste, E., & Depuydt, P. (2014). Therapeutic drug monitoring-guided dosing of beta-lactam antibiotics in critically ill patients: A selective approach. International Journal of Antimicrobial Agents, 43(4), 379–382.
Fratoni, A. J., Nicolau, D. P., & Kuti, J. L. (2021). A guide to therapeutic drug monitoring of β‐lactam antibiotics. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 41(2), 220–233. https://doi.org/10.1002/phar.2505
Gatti, M., & Pea, F. (2021). Antimicrobial therapeutic drug monitoring in the ICU: Tricks of the trade. Antibiotics, 10(9), 1085.
Guilhaumou, R., Benaboud, S., Bennis, Y., Dahyot-Fizelier, C., Dailly, E., Gandia, P., Goutelle, S., Lefeuvre, S., Mongardon, N., Notet, J., Paal, G., Robert, A., Roger, C., Ruiz, S., Takahashi, Y., & Boulamery, A. (2019). Optimization of the treatment with beta-lactam antibiotics in critically ill patients: Guidelines from the French Society of Pharmacology and Therapeutics and the French Society of Anaesthesia and Intensive Care Medicine. Critical Care, 23(1), 104.
Heffernan, A. J., Sime, F. B., Lipman, J., & Roberts, J. A. (2022). Individualising antimicrobial dosing in the ICU: Can we do it better? Anaesthesia Critical Care & Pain Medicine, 41(3), 101061.
Imani, S., Buscher, H., Marriott, D., Gentili, S., & Sandaradura, I. (2017). Too much of a good thing: A retrospective study of beta-lactam antibiotic toxicity in the intensive care unit. Journal of Antimicrobial Chemotherapy, 72(10), 2891–2897.
Legg, A., Carmichael, S., Chai, M. G., Roberts, J. A., & Cotta, M. O. (2023). Beta-lactam dose optimisation in the intensive care unit: Targets, therapeutic drug monitoring and toxicity. Antibiotics, 12(5), 870. https://doi.org/10.3390/antibiotics12050870
Liebchen, U., Scharf, C., Zoeller, M., Weinelt, F., Kloft, C., & Michels-Zander, A. (2021). Variability of piperacillin exposure in critically ill patients and impact on target attainment. Intensive Care Medicine, 47(5), 621–623.
Lonsdale, D. O., & Lipman, J. (2021). Global personalization of antibiotic therapy in critically ill patients. Expert Review of Precision Medicine and Drug Development, 6(2), 87–93. https://doi.org/10.1080/23808993.2021.1874823
Luyt, C. E., Bréchot, N., Trouillet, J. L., & Chastre, J. (2014). Antibiotic stewardship in the intensive care unit. Critical Care, 18(5), 1–11. https://doi.org/10.1186/s13054-014-0480-6
Monogue, M. L. (2026). Antimicrobial pharmacokinetic and pharmacodynamic considerations in special populations: A call to action. Open Forum Infectious Diseases, 13(3), ofag093.
Muller, A. E., Huttner, B., & Harbarth, S. (2022). Personalized antibiotic stewardship: Merging PK/PD with diagnostic precision. The Lancet Infectious Diseases, 22(8), e215–e224.
Onita, T., Ishihara, N., & Yano, T. (2025). PK/PD-guided strategies for appropriate antibiotic use in the era of antimicrobial resistance. Antibiotics, 14(1), 92. https://doi.org/10.3390/antibiotics14010092
Pai Mangalore, R., Chai, M. G., Pope, J., Lee, S. J., Padiglione, A., Diehl, A., Roberts, L., Sim, K., Rawson-Harris, P., Wicha, S., Schneider, H. G., Peel, T. N., Jenney, A., Ayton, D., Peleg, A. Y., & Udy, A. A. (2024). Study protocol for ADAPT-TDM: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled trial using Therapeutic Drug Monitoring. BMJ Open, 14(6), e083635. https://doi.org/10.1136/bmjopen-2023-083635
Pea, F., Viale, P., Cojutti, P., & Furlanut, M. (2012). Therapeutic drug monitoring of beta-lactams in critically ill patients: Is it time to act? International Journal of Antimicrobial Agents, 40(4), 289–295.
Rhee, C., Kadri, S. S., & Klompas, M. (2023). Sepsis management and precision antimicrobial therapy in the ICU. JAMA Network Open, 6(4), e238910.
Roberts, J. A., De Waele, J. J., Dimopoulos, G., Koulenti, D., Martin, C., Montravers, P., Rello, J., Rhodes, A., Starr, T., Wallis, S. C., & Lipman, J. (2012). DALI: Defining Antibiotic Levels in Intensive care unit patients: a multi-centre point of prevalence study to determine whether contemporary antibiotic dosing for critically ill patients is therapeutic. BMC Infectious Diseases, 12(1), 1–9. https://doi.org/10.1186/1471-2334-12-152
Roberts, J. A., Paul, S. K., Akova, M., Bassetti, M., De Waele, J. J., Dimopoulos, G., Kaukonen, K. M., Koulenti, D., Martin, C., Montravers, P., Rello, J., Rhodes, A., Starr, T., Wallis, S. C., & Lipman, J. (2014). DALI: Defining Antibiotic Levels in Intensive care unit patients: Are critically ill patients receiving appropriate antibiotic dosing? Clinical Infectious Diseases, 58(8), 1072–1083.
Roger, C., Nucci, B., Louart, B., Friggeri, A., Knani, H., Evrard, A., Lavigne, J. P., Allaouchiche, B., Lefrant, J. Y., & Roberts, J. A. (2018). Impact of augmented renal clearance on the pharmacokinetics of linezolid in critically ill patients. Journal of Antimicrobial Chemotherapy, 73(12), 3401–3408.
Sime, F. B., Roberts, M. S., & Roberts, J. A. (2016). Optimization of dosing regimens for antibiotics in the critically ill using population pharmacokinetic modeling. Journal of Antimicrobial Chemotherapy, 71(1), 5–12.
Schrader, N., Riese, T., Kurlbaum, M., Meybohm, P., Kredel, M., Surat, G., Scherf-Clavel, O., Strate, A., Pospiech, A., & Hoppe, K. (2021). Personalized antibiotic therapy for the critically ill: Implementation strategies and effects on clinical outcome of piperacillin therapeutic drug monitoring—a descriptive retrospective analysis. Antibiotics, 10(12), 1452. https://doi.org/10.3390/antibiotics10121452
Tabah, A., De Waele, J. J., Lipman, J., Zahar, J. R., & Timsit, J. F. (2022). Antimicrobial stewardship in the intensive care unit: An international survey. Journal of Hospital Infection, 119, 123–131.
Taccone, F. S., Laterre, P. F., Spapen, H., Dugernier, T., Delattre, I., Wittebole, X., De Backer, D., & Vincent, J. L. (2010). Revisiting amikacin dosing in patients with severe sepsis and septic shock. Critical Care, 14(6), R213.
Udy, A. A., Roberts, J. A., Boots, R. J., & Lipman, J. (2010). Augmented renal clearance in the ICU: Secrets, pitfalls, and dosing solutions. Intensive Care Medicine, 36(10), 1630–1632.
Vale, C., Sime, F., Cotta, M. O., Roberts, J. A., & Horvarth, R. (2026). Therapeutic drug monitoring and the role of pharmacokinetics/pharmacodynamics in optimizing beta-lactam antibiotic dosing for deep-seated infections: a systematic review. Journal of Antimicrobial Chemotherapy, 81(5), dkag142.
van Hest, R. M., Haringman, J. J., & Koch, B. C. P. (2024). Model-informed precision dosing of antimicrobials in the intensive care unit: Clinical benefits and operational barriers. Clinical Pharmacokinetics, 63(1), 15–28.
Varghese, J. M., Roberts, J. A., & Lipman, J. (2020). Antimicrobial dosing in ECMO: Navigating the unknown. Critical Care, 24(1), 312.
Wicha, S. G., Kees, M. G., Solms, A., Kloft, C., & Kees, F. (2015). TDMx: A software tool for model-informed precision dosing of antibiotics. Journal of Pharmacokinetics and Pharmacodynamics, 42(4), 455–464.
Wieringa, A., Ewoldt, T. M. J., Gangapersad, R. N., Gijsen, M., Parolya, N., Kats, C. J. A. R., Spriet, I., Endeman, H., Haringman, J. J., van Hest, R. M., Koch, B. C. P., & Abdulla, A. (2023). Predicting Beta-Lactam Target Non-Attainment in ICU Patients at Treatment Initiation: Development and External Validation of Three Novel (Machine Learning) Models. Antibiotics, 12(12), 1674. https://doi.org/10.3390/antibiotics12121674
Wong, G., Briscoe, S., McWhinney, B., Ally, M., Ungerer, J., & Lipman, J. (2014). Therapeutic drug monitoring of beta-lactam antibiotics in the ICU: Efficiency and practical implications. Journal of Infection and Chemotherapy, 20(9), 561–566.
Zoller, M., Maier, B., Liebchen, U., & Michels, A. (2020). Continuous versus intermittent infusion of meropenem in critically ill patients: A randomized clinical trial. Critical Care, 24(1), 118.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Ajit Das, Tusar Mishra
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
10.55544/jrasb
editor@jrasb.com or mailtojrasb@gmail.com | 
+91-8874396939
This work is licensed under a 