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Polymyxin Antibiotics: From Laboratory Bench to Bedside pp 305–319Cite as

Mechanisms of Polymyxin-Induced Nephrotoxicity

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1145))

Abstract

Polymyxin-induced nephrotoxicity is the major dose-limiting factor and can occur in up to 60% of patients after intravenous administration. This chapter reviews the latest literature on the mechanisms of polymyxin-induced nephrotoxicity and its amelioration. After filtration by glomeruli, polymyxins substantially accumulate in renal proximal tubules via receptor-mediated endocytosis mainly by megalin and PEPT2. It is believed that subsequently, a cascade of interconnected events occur, including the activation of death receptor and mitochondrial apoptotic pathways, mitochondrial damage, endoplasmic reticulum stress, oxidative stress and cell cycle arrest. The current literature shows that oxidative stress plays a key role in polymyxin-induced kidney damage. Use of antioxidants have a potential in the attenuation of polymyxin-induced nephrotoxicity, thereby widening the therapeutic window. Mechanistic findings on polymyxin-induced nephrotoxicity are critical for the optimization of their use in the clinic and the discovery of safer polymyxin-like antibiotics.

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Authors and Affiliations

  1. Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC, Australia

    Mohammad A. K. Azad & Jian Li

  2. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Melbourne, VIC, Australia

    Roger L. Nation

  3. Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia

    Tony Velkov

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  4. Jian Li
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Correspondence to Jian Li .

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  1. Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC, Australia

    Jian Li

  2. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Melbourne, VIC, Australia

    Roger L. Nation

  3. Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI, USA

    Keith S. Kaye

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Azad, M.A.K., Nation, R.L., Velkov, T., Li, J. (2019). Mechanisms of Polymyxin-Induced Nephrotoxicity. In: Li, J., Nation, R., Kaye, K. (eds) Polymyxin Antibiotics: From Laboratory Bench to Bedside. Advances in Experimental Medicine and Biology, vol 1145. Springer, Cham. https://doi.org/10.1007/978-3-030-16373-0_18

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