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 AND OBJECTIVE: Multidrug-resistant (MDR) Gram-negative infections pose significant therapeutic challenges, with limited evidence guiding optimal polymyxin B dosing in patients with renal impairment. This systematic review aimed to identify key covariates influencing polymyxin B pharmacokinetic and inform dosing strategies in this population. METHODS: A comprehensive search of PubMed, Scopus, Embase, and Cochrane library was conducted from inception to May 2025. Population-pharmacokinetic (pop-PK) studies evaluating polymyxin B in adult patients in adult patients with renal impairment, with or without renal replacement therapy (RRT) were included. Study quality was assessed using a validated critical appraisal of clinical pharmacokinetic studies tool (CACPK). RESULTS: Eleven pop-PK studies (603 patients) were included. Considerable interindividual variability in clearance and volume of distribution was noted. Creatinine clearance (CrCL), RRT modality, and disease severity were key covariates influencing drug exposure. Convective RRT modalities (CVVH, CVVHDF) were associated with increased clearance and lower exposure, whereas diffusive modalities (CVVHD) showed variable effects. However, the clinical relevance of CrCL-based dose adjustment alone remains uncertain and should be interpreted alongside other clinical factors. CONCLUSION: Polymyxin B dosing in renal impairment requires an individualized approach integrating renal function, RRT modality, and disease severity. While a loading dose of 150 mg is appropriate, maintenance dosing should be guided by clinical context, with higher doses in convective RRT and cautious dosing in diffusive modalities. Therapeutic drug monitoring (TDM), where available, is recommended to optimize efficacy and minimize toxicity.