Are vancomycin trough concentrations adequate for optimal dosing?

Abstract

The 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 trough-only 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.

FIG 1

Use of the data. We used three versions of the data set (row 1). The full data set consisted of all 47 subjects with rich sampling for vancomycin concentration measurements. The trough concentration data set was the full data set with all nontrough concentrations, as defined in Materials and Methods, set as missing. The peak-trough concentration data set also included peak concentrations, as defined in Materials and Methods. We used each version of the data to construct population models (row 2) that differed only in the parameter value distributions based on the data. From each population model, we calculated all 47 subjects' Bayesian posterior AUCs (row 3) and compared these AUCs (=) by using the AUC_F from Model_F as the gold standard (row 3, column 1). We also used Model_F and Model_PT as Bayesian priors to estimate AUCs in the trough concentration data set (diagonal arrows), comparing these to the gold standard as well. Dotted arrows indicate AUCs significantly different from the AUC_F. Finally, we used Model_F for simulations.

FIG 2

Linear regression of AUCs predicted from full data (AUC_F) versus depleted data. Data were depleted to trough concentrations only (AUC_T, triangles) or peak and trough concentrations (AUC_PT, crosses). The solid line is the line of identity, i.e., perfect agreement.

FIG 3

Distribution of steady-state vancomycin trough concentrations among 5,000 simulated adult patients who received 1,000 mg (black) or 1,500 mg (gray) of vancomycin by a 1-h infusion every 12 h and who had a 24-h AUC of ≥400 mg · h/liter (A) or ≥700 mg · h/liter (B). Each panel shows the probability densities of the trough concentration distributions, which are normalized to the number of sample trough concentrations. The vertical dotted lines are the median trough concentrations for the two doses. Note that the median trough concentration in both panels is higher for the lower dose (1,000 mg) because lower clearance is required to achieve a given AUC for a lower dose (AUC = Dose/Clearance), which results in higher trough concentrations. The effect is more pronounced at the higher AUC target in panel B.