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Despite the common use, there is a poor understanding of the mechanistic drivers and potential modifiers of vancomycin\u2010mediated kidney injury. In this review, historic and contemporary rates of vancomycin\u2010induced kidney injury (VIKI) are described, and toxicodynamic models and mechanisms of toxicity from preclinical studies are reviewed. Aside from known clinical covariates that worsen VIKI, preclinical models have demonstrated that various factors impact VIKI, including dose, route of administration, and thresholds for pharmacokinetic parameters. The degree of acute kidney injury (AKI) is greatest with the intravenous route and higher doses that produce larger maximal concentrations and areas under the concentration curve. Troughs (i.e., minimum concentrations) have less of an impact. Mechanistically, preclinical studies have identified that VIKI is a result of drug accumulation in proximal tubule cells, which triggers cellular oxidative stress and apoptosis. Yet, there are several gaps in the knowledge that may represent viable targets to make vancomycin therapy less toxic. Potential strategies include prolonging infusions and lowering maximal concentrations, administration of antioxidants, administering agents that decrease cellular accumulation, and reformulating vancomycin to alter the renal clearance mechanism. Based on preclinical models and mechanisms of toxicity, we propose potential strategies to lessen VIKI.<\/jats:p>","DOI":"10.1002\/phar.2388","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T04:08:09Z","timestamp":1585800489000},"page":"438-454","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Vancomycin\u2010Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4961-0048","authenticated-orcid":false,"given":"Gwendolyn M.","family":"Pais","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice Chicago College of Pharmacy Midwestern University Downers Grove Illinois"},{"name":"Pharmacometrics Center of Excellence Midwestern University Chicago College of Pharmacy Downers Grove 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