Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Abstract

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.

Establishment of an AUC 0–24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia

“…This is partly because of evidence showing a poor correlation between established pharmacodynamic (AUC 0 -24 ) target attainment and measured trough concentrations (6,8). Similar to others, a substantial number of our patients achieved an AUC 0 -24 of Ͼ400 despite having vancomycin trough concentrations below guideline recommendations (Յ15 mg/liter) (6). Of note, we observed that clinicians increased the total vancomycin dose prescribed in these patients, resulting in higher exposures and increasing the risk of AKI.…”

“…However, current dosing regimens and targets (vancomycin trough concentrations) are an area of great controversy with respect to efficacy. This is partly because of evidence showing a poor correlation between established pharmacodynamic (AUC 0 -24 ) target attainment and measured trough concentrations (6,8). Similar to others, a substantial number of our patients achieved an AUC 0 -24 of Ͼ400 despite having vancomycin trough concentrations below guideline recommendations (Յ15 mg/liter) (6).…”

“…Of note, we observed that clinicians increased the total vancomycin dose prescribed in these patients, resulting in higher exposures and increasing the risk of AKI. Therefore, ideally vancomycin dosing should be directly tailored toward established AUC 0 -24 targets rather than trough concentration ranges (6,13).…”

“…been criticized, as trough concentrations underestimate the true AUC by about 25% on average, with such significant interpatient variability that a single patient may end up being either over-or underexposed (6). The consequence of underexposure is treatment failure, while overexposure may lead to increased toxicity, especially acute kidney injury (AKI) (7,8).…”

“…In a population pharmacokinetic (PK) modeling and simulation study, an AUC 0 -24 value of 700 mg · h/liter at steady state was proposed as the threshold for nephrotoxicity. However, this has not been extensively studied or validated in a clinical setting (6). We therefore undertook this study to objectively determine a threshold for vancomycin AUC 0 -24 and increased risk of nephrotoxicity or AKI.…”