Can Model-Informed Precision Dosing of Beta-Lactams in Critical Care Improve Clinical Outcomes?

Critically ill patients exhibit acute physiological changes leading to marked antibiotic exposure variability and an increased probability of either subtherapeutic or potentially toxic exposures. Beta-lactam antibiotics are often affected by these physiological changes, leading to variable and often subtherapeutic exposures. Therefore, methods to increase the probability of a therapeutic exposure may be beneficial for critically ill patients. Model Informed Precision Dosing (MIPD) is an emerging strategy using advanced computer models to individualise dosing in this vulnerable population with or without therapeutic drug monitoring (TDM). By tailoring therapy to the individual patient scenario, MIPD aims to improve clinical outcomes by enhancing the likelihood of effective and safe therapy.

MIPD-guided beta-lactam antibiotic dosing may improve the probability of attaining target therapeutic exposures and clinical cure rates compared to standard fixed dosing in critically ill patients. Moreover, MIPD allows clinicians to target higher beta-lactam antibiotic exposures while minimising the risk of toxicity, when the goal of treatment is both improving clinical cure rates and suppressing the probability of antibiotic resistance emergence. No differences in mortality and adverse event reduction compared to standard dosing have been currently identified in the literature. However, the exact potential of MIPD has yet to be determined given the significant limitations in the current evidence base, including heterogeneous study designs, small sample sizes, inconsistent implementation strategies, and variable outcome definitions. Clinical practice and future research should optimise MIPD performance by selecting appropriate and innovative beta-lactam antibiotic exposure models, as well as identify methods to instigate early MIPD dosing and timely TDM dose adjustments. This may further improve clinical and economic outcomes for critically ill patients.

MIPD is a clinical decision making tool that uses pharmacokinetic modelling to guide beta-lactam dosing, with or without TDM input. A small number of observational and randomised beta-lactam MIPD intervention studies suggest that clinical outcomes for critically ill patients are improved. Technical, casemix, implementation, and study design limitations likely contribute to inconsistent findings in studies comparing MIPD to standard care. Stronger signals in improved outcomes are correlated with appropriate pharmacokinetic model and pharmacokinetic/pharmacodynamic (PK/PD) target selection, accompanied with timely dose adjustments in critically ill patients with significant pharmacokinetic variability and/or complex pharmacodynamic profiles. Future studies should more robustly define key features that will optimise patient outcomes including: optimal target exposure, characteristics of patients most likely to benefit, preferred minimum inhibitory concentration (MIC) parameter, favoured beta-lactam infusion duration, MIPD technical and implementation factors, and study design elements.