Precision Dosing of Antibiotics in Critically Ill Patients: Role of Pk/Pd Modelling and Therapeutic Drug Monitoring

Patients with critical illnesses admitted to the intensive care unit (ICU) suffer severe physiological derangements, changes in the pharmacokinetics and pharmacodynamics of antibiotics (PK/PD) resulting in significant inter-patient variability and intra-patient variations in drug exposure, and conventional dosing regimens may not achieve optimal therapeutic outcomes. All these changes, which are predetermined by factors as capillary leak syndrome, increased volume of distribution due to aggressive fluid resuscitation, hypoalbuminemia, organ dysfunction, augmented renal clearance, and the use of extracorporeal support therapies, lead to poor clinical outcomes, toxicity, and the development of antimicrobial resistance. Model-informed precision dosing (MIPD), therapeutic drug monitoring (TDM), precision dosing, which now includes PK/PD principles, and precision dosing in critically heterogeneous populations, has become the new focus of realizing the best use of antibiotic therapy in this heterogeneous population. The review presents a critical synthesis of current evidence on PK/PD targets within major classes of antibiotics, an assessment of modern approaches involving extended and continuous infusion, AUC-based TDM, Bayesian forecasting, population PK modeling, and Monte Carlo simulation, and an evaluation of personalized dosing strategies of special patients in the ICU. The clinical effects of precision dosing on therapeutic target achievement, clinical cure, reduction of mortality, reduction of toxicity, and antimicrobial stewardship are addressed. This review identifies accuracy of antibiotic dosing as one of the main pillars of personalized medicine in critical care and as a necessity to enhance the therapeutic effect and fight antimicrobial resistance in critically ill patients by combining mechanistic knowledge with technological and innovative approaches.