A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity

Finch, Natalie; Zasowski, Evan J; Murray, Kathryn; Mynatt, Ryan P.; Zhao, Jing; Yost, Raymond; Pogue, Jason M.; Rybak, Michael J.

doi:10.1128/aac.01293-17

Cited by 201 publications

(201 citation statements)

References 34 publications

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“…Recent studies have provided support for the AUC‐guided, Bayesian approach to dosing for vancomycin . Compared with trough‐based concentration targets, the AUC‐guided approach was shown to lead to decreased nephrotoxicity, reduced per‐patient blood sampling, and shorter length of therapy, while maintaining efficacy …”

Section: Integration Of the Auc/mic Ratio Into Clinical Practicementioning

confidence: 99%

Reappraisal of Contemporary Pharmacokinetic and Pharmacodynamic Principles for Informing Aminoglycoside Dosing

2018

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Therapeutic drug management is regularly performed for aminoglycosides in an effort to maximize their effectiveness and safety. The ratio of maximum plasma drug concentration to minimum inhibitory concentration (Cmax/MIC) has long been regarded as the primary pharmacokinetic/pharmacodynamic (PK/PD) index of clinical efficacy for aminoglycosides due to their concentration‐dependent killing. In this review, however, we discuss why the area under the plasma concentration–time curve (AUC)/MIC ratio may be a more reliable indicator of bacterial killing and clinical efficacy for these agents. The definitive AUC/MIC efficacy targets for aminoglycosides are less clear, unlike those that exist for fluoroquinolones. Evaluation of available literature suggests that an AUC/MIC ratio of 30–50 for aminoglycoside therapy may provide optimal outcomes when targeting non–critically ill immunocompetent patients with low–bacterial burden gram‐negative infections such as urinary tract infections or in patients receiving additional gram‐negative therapy with good source control. However, an AUC/MIC target of 80–100 may be more prudent when treating patients with aminoglycoside monotherapy or in critically ill patients with high–bacterial burden infections, such as nosocomial pneumonia. Reappraisal of current antimicrobial susceptibility breakpoints for aminoglycosides against gram‐negative bacteria may also be necessary to achieve these AUC/MIC targets and ensure that current empiric doses are not grossly suboptimal in critically ill patients. Although it has been historically difficult to calculate AUCs in clinical practice, equation‐based and Bayesian approaches now can be used to estimate the AUC in clinical practice, with limited PK sampling. Additional research is needed to better define optimal AUC/MIC targets for efficacy, especially when drugs are used in combination, as well as PK/PD targets associated with suppression of resistance. It is also important to determine if AUC can predict nephrotoxicity of these agents or whether trough concentrations should be used instead.

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Section: Integration Of the Auc/mic Ratio Into Clinical Practicementioning

confidence: 99%

Reappraisal of Contemporary Pharmacokinetic and Pharmacodynamic Principles for Informing Aminoglycoside Dosing

2018

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“…Clinical data examining the impact of AUC‐guided dosing are limited and not the focus of this article. One study included 1280 patients (734 underwent AUC‐guided dosing with collection of two levels and utilization of equation 4) and found that AUC‐guided dosing resulted in lower daily vancomycin doses and reduced risk of nephrotoxicity . In agreement with other data, a large percentage of patients had adequate AUC with troughs lower than 15 mg/L.…”

Section: Discussionmentioning

confidence: 67%

Review and Validation of Bayesian Dose‐Optimizing Software and Equations for Calculation of the Vancomycin Area Under the Curve in Critically Ill Patients

et al. 2018

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Background Vancomycin area under the concentration‐time curve (AUC) has been linked to efficacy and safety. An accurate method of calculating the AUC is needed. Methods Bayesian dose‐optimizing software programs available for clinician use and first‐order pharmacokinetic equations were evaluated for their ability to estimate vancomycin AUC. A previously published rich pharmacokinetic data set of 19 critically ill patients was used for validation of the AUC estimation. The AUC estimated using subsets of the full data set by Bayesian software and equations was compared with the reference AUC. Accuracy (ratio of estimated AUC to the reference AUC) and bias (percentage difference of estimated AUC to reference AUC) were calculated. Results Five Bayesian dose‐optimizing software programs (Adult and Pediatric Kinetics [APK], BestDose, DoseMe, InsightRx, and Precise PK) and two first‐order pharmacokinetic equations were included. Of the Bayesian programs, InsightRx was the most adaptable, visually appealing, easiest to use, and had the most company support. Utilizing only the trough, accuracy (range 0.79–1.03) and bias (range 5.1–21.2%) of the Bayesian dose‐optimizing software were variable. Precise PK and BestDose had the most accurate estimates with the accuracy values of BestDose exhibiting the most variability of all the programs; however, both programs were more difficult to use. Precise PK was the least biased (median 5.1%). Using a single nontrough value produced similar results to that of the trough for most programs. The addition of a second level to the trough improved the accuracy and bias for DoseMe and InsightRx but not Precise PK and BestDose. APK did not reliably estimate the AUC with input of two levels. Using two levels, the pharmacokinetic equations produced similar or better accuracy and bias as compared with Bayesian software. Conclusion Bayesian dose‐optimizing software using one or more vancomycin levels and pharmacokinetic equations utilizing two vancomycin levels produce similar estimates of the AUC.

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“…Patients with normal renal function would require doses between 3500 and 4500 mg/day to maintain the conventional target trough goal compared with doses between 2250 and 3250 mg when targeting goal AUC 24 . As demonstrated in previous studies, reduced vancomycin doses targeting AUC may minimize the potential for nephrotoxicity …”

Section: Discussionmentioning

confidence: 99%

Vancomycin Pharmacokinetics in Obese Patients with Sepsis or Septic Shock

Masich

Kalaria

Gonzales³

et al. 2020

Pharmacotherapy

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Study Objectives Obese patients with sepsis or septic shock may have altered vancomycin pharmacokinetics compared with the general population that may result in improper dosing or inadequate drug concentrations. The objective of this study was to characterize vancomycin pharmacokinetics in obese patients with sepsis or septic shock, and to develop a novel pharmacokinetic dosing model based on pharmacokinetic‐pharmacodynamic target requirements. Design Prospective observational pharmacokinetic study. Setting Large quaternary academic medical center. Patients Sixteen obese (body mass index [BMI] 30 kg/m2 or higher) adults with sepsis and either a gram‐positive bacteremia or requiring vasopressor support (septic shock), who were receiving vancomycin between November 2016 and June 2018, were included. Patients were excluded if they were receiving renal replacement therapy or extracorporeal membrane oxygenation, treatment for central nervous system infections, pregnant, or receiving vancomycin for surgical prophylaxis. Intervention Four blood samples per patient were collected following a single dose of vancomycin: one peak serum vancomycin level (within 1–2 hrs of infusion completion), two random levels during the dosing interval, and one trough level (within 30–60 min of the next dose) were measured. Measurements and Main Results A population pharmacokinetic model was developed to describe vancomycin concentrations over time. Simulations to determine optimal dosing were performed using the pharmacokinetic model with different ranges of creatinine clearance (Clcr) and different vancomycin daily doses. Median age of the patients was 62 years; median BMI was 36.1 kg/m2, Acute Physiology and Chronic Health Evaluation II score was 26, and Sequential Organ Failure Assessment score was 11. Eleven patients (69%) had an acute kidney injury. Median initial vancomycin dose was 15 mg/kg; median vancomycin trough concentration was 17 mg/L. A one‐compartment model best characterized the pharmacokinetics of vancomycin in obese patients with sepsis or septic shock. Volume of distribution was slightly increased in this population (0.8 L/kg) compared with the general population (0.7 L/kg). Only Clcr effect on drug clearance was found to be significant (decrease in the objective function value by 16.4 points), confirming that it is a strong predictor of vancomycin clearance. Conclusion To our knowledge, this study provides the first population‐based pharmacokinetic model in obese patients with sepsis or septic shock. The nomograms generated from this pharmacokinetic model provide a simplified approach to vancomycin dosing in this patient population.

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A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity

Cited by 201 publications

References 34 publications

Reappraisal of Contemporary Pharmacokinetic and Pharmacodynamic Principles for Informing Aminoglycoside Dosing

Reappraisal of Contemporary Pharmacokinetic and Pharmacodynamic Principles for Informing Aminoglycoside Dosing

Review and Validation of Bayesian Dose‐Optimizing Software and Equations for Calculation of the Vancomycin Area Under the Curve in Critically Ill Patients

Vancomycin Pharmacokinetics in Obese Patients with Sepsis or Septic Shock

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