(B-304) Factors affecting pharmacokinetics and dosing strategies of polymyxin B in multidrug-resistant gram-negative infected patients with renal impairment: A systematic review with expert opinion

Background: Multidrug-resistant (MDR) gram-negative infections pose significant clinical challenges. Still evidence is lacking to determine the appropriate dosing regimen for polymyxin B, though it has emerged as an effective treatment option, especially in patients with renal impairment.

Objectives: This systematic review aims to identify key covariates influencing the pharmacokinetic parameters of polymyxin B with an expert opinion that facilitates dosing recommendations in this set of patients.

Methods: A comprehensive search was conducted in PubMed/Medline, Scopus, Embase and Cochrane library from inception till November 2024. Studies reporting factors affecting pharmacokinetics of polymyxin B in adult renal impaired patients with or without renal replacement therapy (RRT) were considered. A clinical pharmacokinetic critical appraisal tool was used to assess methodological quality of the included studies.

Results: Our systematic review based on the recent literature evidence from 11 studies including 603 patients found that CrCL significantly impacts polymyxin B clearance. CRRT techniques, especially CVVHDF and CVVH, substantially increase polymyxin B clearance. Body weight influences volume of distribution, but not clearance. Individualized dosing strategies are crucial, considering factors such as renal function, RRT modality and disease severity. Loading doses are essential for rapidly achieving therapeutic levels, regardless of renal function. TDM, when available, is vital for optimizing treatment and minimizing toxicity.

Conclusions: Expert Opinion: This review provides insights into polymyxin B dosing for patients with renal impairment. Compared to guideline-recommended doses, higher loading (>150mg) and maintenance doses (>100mg, BD) are recommended for patients on CVVHDF and CVVH, while lower doses are suggested for those on CVVHD. A loading dose is essential for achieving effective drug levels, irrespective of the renal function of the patients. Individualized dosing based on CrCL, RRT modalities and severity of illness is crucial for optimal therapy. Further research is needed to correlate these dosing strategies with clinical outcomes to refine dosing recommendations.