Vancomycin TDM: the past
Monitoring vancomycin trough serum concentrations has historically been the standard method for performing vancomycin TDM, as was recommended in the ASHP, IDSA and SIDP 2009 Vancomycin Therapeutic Drug Monitoring Consensus Guidelines . For complicated infectious caused by S. aureus, such as bacteremia, endocarditis, and pneumonia, target trough serum concentrations of 15 – 20 mg/L were recommended, a range that was considered sufficient to achieve of an AUC/MIC of at least 400 mg*h/L while minimizing adverse events .
Performing vancomycin trough TDM is relatively straightforward: trough values should be obtained just prior to the next dose while at stead-state conditions, which is typically achieved after three to five consecutive doses. The dose of vancomycin may then be adjusted up or down depending on obtained serum trough concentration in an effort to achieve the goal trough range.
Although it is simple to execute vancomycin trough monitoring in clinical practice, some issues were raised over time. First, there was minimal safety and efficacy data to support targeted trough concentrations of 15–20 mg/L . Second, although initially thought that these trough ranges would yield successful achievement of AUC/MIC values of >400 mg*h/L, data was presented that suggested no difference in attainment of AUC/MIC values of ≥400 mg*h/L between trough ranges of 15–20 mg/L and 10–14.9 mg/L, and that trough values of 15–20 mg/L may increase nephrotoxicity risk . Lastly, methods for calculating AUC values, rather than performing trough-only analyses, became more widely practical to perform in real-time, leading to a shift in vancomycin TDM.
Vancomycin TDM: the present
Vancomycin TDM guidelines were updated in March 2020, where the recommendations for TDM moved away from serum trough
levels and moved towards an AUC/MIC ratio . This update was secondary to further data suggesting that trough values may not be an optimal surrogate for AUC values for vancomycin, further safety and efficacy data associated with AUC/MIC ratios between 400–600 mg*h/L, and feasibility of performing these calculations in clinical practice.
The new guidelines recommend two methods to calculate AUC/MIC: Bayesian-derived AUC24 monitoring or first-order pharmacokinetic equations. The Bayesian software programs involve estimating the vancomycin AUC value with minimal pharmacokinetic sampling, whereas the first-order pharmacokinetic equations estimate AUC values by using two vancomycin concentrations .
Bayesian-guided dosing offers certain benefits over the first-order equation approach as vancomycin concentrations can be obtained at any time, rather than at steady-state or during the same dosing interval. The Bayesian approach incorporates pathophysiologic changes that occur in patients, which can allow providers to optimize vancomycin dosing and assist in predicting future dosing. This approach utilizes software programs integrated into the electronic medical record, that can require extensive training. Disadvantages of this method include that this software is costly and may not readily be available at some institutions .
First-order pharmacokinetic equations can be utilized to estimate the AUC, based on the collection of two steady-state serum vancomycin concentrations. A post-distributional peak obtained one to two hours after the end of the infusion, and a trough concentration obtained within the same dosing interval is recommended to be used in these equations. This approach is most commonly used in clinical practice, given less complexity over the Bayesian method, and is easily performed utilizing home-grown calculators (Fig. 2). In comparison to the Bayesian approach, the equations are less complex. Disadvantages of the pharmacokinetic equation method include that it requires the obtainment of two vancomycin concentrations and more time is required for this method of estimating AUC in comparison to the Bayesian method .
Vancomycin TDM: the future
With the update in the vancomycin TDM guidelines, there was a need for less complex methods to estimate vancomycin AUC. This sparked the development of several free online vancomycin dosing calculators from multiple organizations . There are free, open access online calculators that utilize patient demographics and a single vancomycin concentration in order to estimate AUC. These calculators are being used by many institutions, although these calculators may be associated with a meaningful degree of imprecision compared to first-order pharmacokinetic equations, which may preclude their use at this time until further validation is pursued .
Vancomycin remains the gold-standard therapy for patients with severe MRSA infections, and AUC-based TDM is critical to optimizing vancomycin efficacy and minimizing toxicities. First-order pharmacokinetics may be the most practical method for performing AUC-
based TDM for vancomycin at this time, although other methods such as the utilization of Bayesian software as well as online, open-
access single-concentration calculators may become more widely adopted as access to software increases and calculators become more refined/validated in larger patient populations, respectively.