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

Background
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. Furthermore, although this medication class is associated with minimal concentration-related adverse effects, recent evidence suggests that beta-lactams may be associated with neurotoxicity and nephrotoxicity. 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.

Summary
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 whilst 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 has 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.