Date of Award

2021

Document Type

Thesis

Degree Name

Master of Science (M.S.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Myo-Kyoung Kim

First Committee Member

Linda Norton

Second Committee Member

Jered Arquiette

Third Committee Member

Jenana Maker

Fourth Committee Member

Miki S. Park

Abstract

A Bayesian-derived 24-hour area under the concentration-time curve over minimum inhibitory concentration from broth microdilution (AUC24h/MICBMD) ratio of 400 to 600 is recommended as the new monitoring parameter for vancomycin to optimize efficacy and minimize nephrotoxicity. The AUC24h threshold of 600 mg*h/L for nephrotoxicity was extrapolated from studies that assessed the general population. It is unclear if this upper threshold is consistent or varies when used in special populations such as critically ill patients, obese patients, patients with preexisting renal disease, and patients on concomitant nephrotoxins.The purpose of this study is to investigate the generalizability of the proposed vancomycin AUC24h threshold of 600 mg*h/L for nephrotoxicity. The objective is to determine the optimal Bayesian-derived AUC24h threshold to minimize vancomycin-associated nephrotoxicity in special populations such as critically ill patients, obese patients, patients with preexisting renal disease, and patients on concomitant loop diuretics, ACEIs, ARBs, NSAIDs, aminoglycosides, piperacillin-tazobactam, and IV contrast dyes.

The study design is a single-center, retrospective cohort study. For each patient, nephrotoxicity was assessed and the Bayesian-derived AUC24h was estimated. Using classification and regression tree (CART) analysis, the AUC24h threshold for nephrotoxicity was determined for each special population that had at least ten nephrotoxic patients. The predictive performances (e.g., positive predictive value [PPV], negative predictive value [NPV], sensitivity, specificity, and area under the receiver operating characteristic [ROC] curve) of each CART-derived threshold were then compared to the guideline threshold’s predictive performances. PPV and sensitivity were given greater weight when comparing the thresholds.

Of the 336 patients, 29 (8.6%) nephrotoxic patients were observed after initiating vancomycin. Among the special populations of interest, critically ill patients, obese patients, patients with preexisting renal disease, and patients on concomitant loop diuretics included at least ten nephrotoxic patients and thus were further analyzed to determine the CART-derived AUC24h thresholds. The CART-derived AUC24h thresholds were 544 mg*h/L for critically ill patients (n=116), 586 mg*h/L for obese patients (n=111), 539 mg*h/L for patients with preexisting renal disease (n=54), and 543 mg*h/L for patients on concomitant loop diuretics (n=126). Compared to the guideline threshold of 600 mg*h/L, the CART-derived thresholds for critically ill patients, patients with preexisting renal disease, and patients on concomitant loop diuretics had comparable PPVs but significantly higher sensitivities. On the other hand, the CART-derived threshold for obese patients did not have a significantly different PPV, NPV, sensitivity, specificity, and area under the ROC curve.

For critically ill patients, patients with preexisting renal disease, and patients on concomitant loop diuretics, a lower vancomycin AUC24h threshold for nephrotoxicity such as 544 mg*h/L, 539 mg*h/L, and 543 mg*h/L, respectively, may be considered to minimize the risk of nephrotoxicity. On the other hand, this study supports the continued use of the guideline threshold of 600 mg*h/L to minimize the risk of nephrotoxicity in obese patients.

Pages

76

Share

COinS