Impact of Higher Vancomycin Troughs on Vancomycin-Induced Nephrotoxicity Marilyn Novell Bulloch, PharmD, BCPS,*† Lyndsi Paumen, MD,‡ Stephen Eure, RPh, BCPS,§ and Joseph Grier Stewart, MD† Background: Guidelines published in 2009 by the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists recommended targeting vancomycin troughs of 15 to 20 mg/L. No previous studies exist examining the effect of implementing these guidelines on kidney function. The objective of this study was to evaluate the effect of a dosing nomogram that incorporated recommendations for higher vancomycin goal trough vancomycin-induced nephrotoxicity (VIN). Methods: This study evaluated 300 adult inpatients with a pharmacoki- netics consultation for vancomycin dosing. Two periods were evaluated: phase I (2008) assessed practice preguideline vancomycin dosing nomo- gram change, and phase II (2012) assessed practice postguideline vancomy- cin dosing nomogram change reflecting the higher trough targets. Groups were compared using χ 2 or Fisher exact tests for categorical variables and Mann-Whitney U tests for continuous variables. The a priori level of signif- icance was set at 0.05. Results: A total of 300 inpatients (150 in 2008 and 150 in 2012) were in- cluded in the analysis. More patients from the 2012 group experienced VIN, according to the guideline definition (P = 0.03), but not per the 2007 Acute Kidney Injury Network definition (P = 0.88). There was no change in other adverse outcomes, including dialysis initiation (2 vs 0; P = 0.16), dis- charge on dialysis (1 vs 0; P = 0.32), transfer to another hospital for higher level of care (33 vs 34; P = 0.89), or death (15 vs 11; P = 0.41). Conclusions: Targeting higher vancomycin troughs resulted in transient VIN but did not cause adverse sequelae. Key Words: vancomycin, pharmacokinetics, antimicrobial resistance, acute renal failure, drug safety (Infect Dis Clin Pract 2017;25: 203–208) V ancomycin has been used for decades to treat serious infections caused by gram-positive organisms. There have been concerns about the development of resistance. In 2009, new consensus rec- ommendations for the use and monitoring of vancomycin were published by the Infectious Diseases Society of America (IDSA), the American Society of Health-System Pharmacists (ASHP), and the Society of Infectious Diseases Pharmacists (SIDP). Based on a thorough review of literature available at the time, these or- ganizations recommended increasing vancomycin dosages to target a trough of 15 to 20 mg/L to minimize both treatment fail- ure and toxicity. 1 Vancomycin kills susceptible bacteria in a time-dependent, concentration-independent manner. The pharmacodynamic parameter that has been shown to be predictive of vancomycin ef- fectiveness is the ratio of the area under the serum concentration curve (AUC) to the mean inhibitory concentration (MIC). Based on a review of AUC/MIC as a predictor of clinical and microbio- logical success of vancomycin treatment, the 2009 guidelines suggest a target AUC/MIC value of 400 to achieve clinical effec- tiveness. 2,3 Because the determination of this parameter requires multiple serum vancomycin concentrations, the guidelines sug- gest that a trough obtained at steady state be used as a surrogate. The target trough range recommended by these guidelines to maintain the recommended AUC/MIC of 400 is 15 to 20 mg/L. Troughs within this range have been associated with fewer treat- ment failures than that with lower troughs. 4 The emergence of vancomycin-heteroresistant, vancomycin intermediate–susceptible, and vancomycin-resistant Staphylococcus aureus strains poses a threat to the use of the vancomycin and is associated with more treatment failure and poorer outcomes. 5 The emergence of these bacteria seems to be directly correlated with low-serum vancomycin concentrations, perhaps because of reduced tissue penetration or because of selection pressure favor- ing heteroresistant strains. A serum concentration of greater than or equal to 10 mg/L has been demonstrated to be sufficient to pre- vent selection of intermediately susceptible organisms. 6 As a re- sult, the 2009 guidelines state that vancomycin troughs should always be maintained at greater than or equal to 10 mg/L to avoid bacterial resistance and treatment failures. 2 Although it has long been recognized that vancomycin has the potential to cause nephrotoxicity, at least some of the toxic ef- fects have been attributed to impurities that were present in its early formulations. 7 With modern manufacturing, the severity of vancomycin-associated toxicity has declined. 7,8 When nephrotox- icity does occur, it tends to be reversible when recognized and ad- dressed promptly. 9,10 Given the threat of vancomycin resistance, the authors of the 2009 guidelines felt that the modest risk of toxicity was worth lower treatment failure rates associated with higher serum vancomycin concentrations. The risk of nephro- toxicity still warrants further evaluation with the change to more aggressive dosing. Greater exposure to vancomycin has been associated with in- creased incidence of nephrotoxicity. 4,11–14 Lodise et al 11,12 and Cano et al 13 found statistically significant relationships between vancomycin troughs and both the incidence as well as the time to nephrotoxicity. Kullar et al 4 showed that supratherapeutic trough levels were associated with higher incidence of nephrotoxicity, but the incidence was not significantly different with troughs less than 10 mg/L, 10 to 14.9 mg/L, and 15 to 20 mg/L. The incidence of vancomycin-induced nephrotoxicity (VIN) has also been shown to be associated with an increased duration of exposure to vanco- mycin. 9 Other risk factors for VIN, such as intensive care unit (ICU) stay, comorbidities, and use with other nephrotoxic medica- tions, have been identified; however, the risk factors have not been entirely consistent across studies. 7,9 The purpose of this study was to evaluate the effects of more aggressive vancomycin dosing that reflected recommendations of the 2009 therapeutic monitoring of vancomycin published by the From the *Department of Pharmacy Practice, Auburn University, Harrison School of Pharmacy, Auburn; †Department of Family, Internal, and Rural Med- icine, ‡University of Alabama College of Community Health Sciences; §De- partment of Pharmacy, DCH Regional Medical Center, Tuscaloosa, AL. Correspondence to: Marilyn Novell Bulloch, PharmD, BCPS, Northeast Medical Center, PO Box 3611 Tuscaloosa, AL 35487. E‐mail: novellm@gmail.com. The authors have no funding or conflicts of interest to disclose. Presented at the Society of Critical Care Medicine Annual Congress in February 2016 in Orlando, FL. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1056-9103 ORIGINAL ARTICLE Infectious Diseases in Clinical Practice • Volume 25, Number 4, July 2017 www.infectdis.com 203 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.