Peak Measurement for Vancomycin AUC Estimation in Obese Adults Improves Precision and Lowers Bias

Abstract

Vancomycin area under the curve (AUC) estimates may be skewed in obese adults due to weight-dependent pharmacokinetic parameters. We demonstrate that peak and trough measurements reduce bias and improve the precision of vancomycin AUC estimates in obese adults (n ϭ 75) and validate this in an independent cohort (n ϭ 31). The precision and mean percent bias of Bayesian vancomycin AUC estimates are comparable between covariate-dependent (R 2 ϭ 0.774, 3.55%) and covariate-independent (R 2 ϭ 0.804, 3.28%) models when peaks and troughs are measured but not when measurements are restricted to troughs only (R 2 ϭ 0.557, 15.5%).KEYWORDS MRSA, obese, obesity, peak, pharmacodynamics, pharmacokinetics, population pharmacokinetics, trough, vancomycin V ancomycin is an essential methicillin-resistant Staphylococcus aureus (MRSA) active antimicrobial dosed on the basis of total body weight (TBW) and kidney function, with maintenance dose adjustments guided by therapeutic drug monitoring (TDM) (1). The recommended TDM approach includes measurement of a trough concentration with dosage adjustments to a target value based on the seriousness of the MRSA infection (1). This trough target range serves as a surrogate for the vancomycin area under the concentration-time curve (AUC) that, coupled with the MIC (AUC/MIC), best predicts clinical success (1). As expected, the translation of single trough concentration measurements into an integrated concentration-time profile for AUC estimation is achievable but requires parameter assumptions and mathematical modeling (2). These assumptions include a population estimate of a weight-based volume of distribution (V) and clearance (CL), which is based on creatinine clearance (CLcr) (3).A major assumption, and the focus of the manuscript, is the widely utilized vancomycin V population value estimate of 0.5 to 1.0 liters/kg of body weight and the use of CLcr to estimate CL (2). Several studies have benchmarked the relationship between vancomycin V and TBW but have also suggested that the vancomycin V estimate per kilogram diminishes with increasing TBW (3-5). Bauer et al. demonstrated that the mean vancomycin V values were 0.32 liters/kg and 0.68 liters/kg in morbidly obese (165 kg) and normal-weight (68 kg) subjects, respectively (4). The mean absolute vancomycin V values were 52.8 liters (165-kg subject) and 46.2 liters (68-kg subject), which represent marginal differences relative to the average TBW of their two cohorts (4). Likewise, multiple approaches to estimate CLcr in obese patients exist, which can confuse dose selection (6, 7). As a consequence, the usefulness of TBW and CLcr as covariates to aid computation of vancomycin AUC values is not well characterized in the setting of single trough measurements.We implemented a peak and trough measurement clinical protocol in obese patients and sought to compare the precision and bias of vancomycin AUC estimations using our obese-population-derived parameter estimates (covariate independent) com-

Relationships of Vancomycin Pharmacokinetics to Body Size and Composition Using a Novel Pharmacomorphomic Approach Based on Medical Imaging

“…The mean (SD) Vc of vancomycin was 69.8 (16.9) liters in normal weight subjects compared with 74.7 (15.7) liters in obese subjects. This finding is consistent with studies that suggest improved prediction of vancomycin Vc with use of a traditional body-size-independent model (16,17). This classical error is also illustrated in Fig.…”

“…Our previously published vancomycin pharmacokinetic model and covariance matrix was used as the Bayesian prior to compute 1-compartment and 2-compartment parameter estimates (17). The Bayesian analyses were accomplished using the maximum a posteriori (MAP) function in ADAPT 5 (BMSR, University of Southern California, Los Angeles, CA) (20).…”

Comprehensive Guidance for Antibiotic Dosing in Obese Adults

“…Results from a pilot study in 12 obese patients recently suggested that use of Bayesian software tools with peak and trough data provided more accurate AUC predictions than trough‐only data . If Bayesian tools are not available to perform dose revisions, use of two point measurements (peaks and troughs) should still be considered because it improves precision and lowers the bias of AUC estimates in obese adults …”

“…66 If Bayesian tools are not available to perform dose revisions, use of two point measurements (peaks and troughs) should still be considered because it improves precision and lowers the bias of AUC estimates in obese adults. 14,67 Summary A reasonable approach to initial vancomycin dosing in obese patients would be to reduce the loading dose (if indicated) to 20-25 mg/kg TBW and to reduce the starting maintenance dose, then adjust according to TDM. Software capable of Bayesian analysis should be used, if available, and/or peak and trough measurements (using Sawchuck and Zaske methods) 14 because it provides greater accuracy of AUC-guided dose revisions in obese patients.…”

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

“…8,14 In contrast, the Bayesian software evaluated had a correlation (AUC T to AUC REF ) of 70-85% (r 2 of 0.70-0.85; data not shown) when using the trough only; these values are similar to other published literature with trough-only Bayesian estimation. 26 Although some methodologies produced more accurate estimates, all methodologies produced average accuracy ratios of 0.80 or higher and bias of less than 20% (with the exception of DoseMe with AUC T ). This degree of accuracy is likely adequate when targeting an AUC of 400-600 hrÁmg/L.…”