Vancomycin

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351

eThe current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P ‫؍‬ 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with troughonly data allowed 97% (93 to 102%; P ‫؍‬ 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of >400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter.

Section: Discussionmentioning

confidence: 99%

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Neely

Youn

Jones

et al. 2014

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351

“…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).…”

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confidence: 99%

“…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)(4)(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).…”

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confidence: 99%

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

Pai

Hong

Krop

2017

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-

“…The pharmacokinetics of vancomycin has shown large interindividual variability, primarily linked to a patient's age, clinical condition, and disease (3,4). Patients in oncology represent a critical population in whom inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality.…”

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confidence: 99%

Population Pharmacokinetics and Dosing Optimization of Vancomycin in Children with Malignant Hematological Disease

Zhao

Zhang

Fakhoury

et al. 2014

e An increase in vancomycin dose has been proposed in adults with malignant hematological disease. As pediatric data are limited, our aim was to evaluate the population pharmacokinetics of vancomycin in order to define the appropriate dosing regimen in children with malignant hematological disease. Vancomycin concentrations were collected prospectively during therapeutic monitoring. Population pharmacokinetic analysis was performed using NONMEM software. Seventy children (age range, 0.3 to 17.7 years) were included. With the current recommended dosing regimen of 40 to 60 mg/kg/day, 53 children (76%) had subtherapeutic steady-state trough concentrations (C ss/min of <10 mg/liter). A one-compartment model with first-order elimination was developed. Systematic covariate analysis identified that weight significantly influenced clearance (CL) and volume of distribution (V) with power functions of 0.677 for CL and 0.838 for V. Vancomycin CL also significantly increased with increases in creatinine clearance and seemed to be higher in children with malignant hematological disease than in the general pediatric population. The model was validated internally. Its predictive performance was further confirmed in an external validation by Bayesian estimation. A patient-tailored dosing regimen was developed based on the final pharmacokinetic model and showed that a higher proportion of patients reached the target C ss/min than with the traditional mg/kg-basis dose (60% versus 49%) and that the risks associated with underdosing or overdosing were reduced. This is the first population pharmacokinetic study of vancomycin in children with malignant hematological disease. An optimized dosing regimen, taking into account patient weight, creatinine clearance, and susceptibility of the pathogens involved, could routinely be used to individualize vancomycin therapy in this vulnerable population.