Polymyxins are vital antibiotics for the treatment of multiresistant Gram-negative ESKAPE pathogen infections. However, their clinical value is limited by their high nephrotoxicity and neurotoxicity, as well as their poor permeability and absorption in the gastrointestinal tract. This review focuses on various polymyxin delivery systems that improve polymyxin bioavailability and reduce drug toxicity through targeted and controlled release. Currently, the most suitable systems for improving oral, inhalation, and parenteral polymyxin delivery are polymer particles, liposomes, and conjugates, while gels, polymer fibers, and membranes are attractive materials for topical administration of polymyxin for the treatment of infected wounds and burns. In general, the application of these systems protects polymyxin molecules from the negative effects of both physiological and pathological factors while achieving higher concentrations at the target site and reducing dosage and toxicity. Improving the properties of polymyxin will be of great interest to researchers who are focused on developing antimicrobial drugs that show increased efficacy and safety.
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