Critical Care Medicine www.ccmjournal.org 2527 Objectives: To evaluate the influence of vancomycin dose, serum trough concentration, and dosing strategy on the evolution of acute kidney injury in critically ill patients. Design: Retrospective, single-center, observational study. Setting: University Hospital ICU, Birmingham, UK. Patients: All critically ill patients receiving vancomycin from December 1, 2004, to August 31, 2009. Intervention: None. Measurements and Main Results: The prevalence of new onset nephrotoxicity was reported using Risk, Injury, Failure, Loss, End-stage renal disease criteria, and independent factors pre- dictive of nephrotoxicity were identified using logistic regression analysis. Complete data were available for 1,430 patients. Con- comitant vasoactive therapy (odds ratio = 1.633; p < 0.001), median serum vancomycin (odds ratio = 1.112; p < 0.001), and duration of therapy (odds ratio = 1.041; p ≤ 0.001) were sig- nificant positive predictors of nephrotoxicity. Intermittent infusion was associated with a significantly greater risk of nephrotoxicity than continuous infusion (odds ratio = 8.204; p ≤ 0.001). Conclusions: In a large dataset, higher serum vancomycin con- centrations and greater duration of therapy are independently associated with increased odds of nephrotoxicity. Furthermore, continuous infusion is associated with a decreased likelihood of nephrotoxicity compared with intermittent infusion. This large dataset supports the use of continuous infusion of vancomycin in critically ill patients. (Crit Care Med 2014; 42:2527–2536) Key Words: acute kidney injury; glycopeptide; infection; intensive care unit; sepsis; vancomycin M ethicillin-resistant Staphylococcus aureus (MRSA) is associated with significant morbidity and mor- tality in the ICU. MRSA is responsible for 10% of all infections (1) and 14% of all instances of sepsis (2). Fur- thermore, MRSA is associated with a 50% greater likelihood of mortality than methicillin-susceptible Staphylococcus aureus (3). Given that between 19% and 25% of patients colonized with MRSA develop infection, with an overall mortality rate as high as 6.3 per 100,000 infections (4), effective antibiotic treat- ment is critical to treatment success. Vancomycin is the antibiotic most widely used for the treatment of infections mediated by MRSA (5). Of concern, MRSA with reduced susceptibility to vancomycin is increasing in prevalence with studies suggesting trough serum concen- trations less than 10 mg/L are associated with the emergence of vancomycin-resistant S. aureus (6, 7). Subsequently, clini- cal practice guidelines now advocate targeting trough serum concentrations of 15–20 mg/L, which is much higher than the previous target of 5–10 mg/L (8–10). This increase in the target exposure is considered to increase the likelihood of concentra- tion-related adverse effects, including nephrotoxicity. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000514 *See also p. 2635. 1 Burns Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia. 2 Department of Intensive Care Medicine, The Royal Brisbane and Wom- en’s Hospital, Brisbane, Queensland, Australia. 3 Department of Anaesthesia and Critical Care, University Hospital Bir- mingham, Birmingham, United Kingdom. This work was performed at Department of Intensive Care Medicine, Level 3 Ned Hanlon Building, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia; and Department of Anaesthesia and Critical Care, Univer- sity Hospital Birmingham, Birmingham, United Kingdom. Dr. Hanrahan received grant support from the University of Queensland Research Scholarship (Master of Philosophy Research scholarship, liv- ing allowance). Dr. Lipman served as board member for Bayer European Society of Intensive Care Medicine Advisory Board; consulted for Janssen- Cilag, Merk Sharp Dohme (Australia), Pfizer Australia, and AstraZeneca; received grant support from AstraZeneca; and lectured for Wyeth Austra- lia, AstraZeneca, and Pfizer Australia. Dr. Roberts’ institution received grant support from Janssen-Cilag, and he served as a board member for Pfizer and AstraZeneca and lectured for AstraZeneca. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Timothy Hanrahan, BSc, Burns Trauma and Critical Care Research Centre, The University of Queensland, Level 3 Ned Hanlon Building, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia, 4029. E-mail: timothy.hanrahan@uqconnect.edu.au Vancomycin-Associated Nephrotoxicity in the Critically Ill: A Retrospective Multivariate Regression Analysis* Timothy P. Hanrahan, BSc, MBBS 1,2 ; Georgina Harlow, MB BCh, MRCPCH 3 ; James Hutchinson, MB BCh, FRCA 3 ; Joel M. Dulhunty, PhD, FRACMA 2 ; Jeffrey Lipman, MD, FCICM 1,2 ; Tony Whitehouse, MD, FRCA 3 ; Jason A. Roberts, PhD, FSHP 2