Therapeutic drug monitoring for vancomycin: past, present and future

Nicole M. Ondrush, PharmD, AAHIVP ; Bryan T. Mogle, PharmD, BCPS

Vancomycin remains a mainstay of treatment for invasive infections caused by methicillin-resistant Staphylococcus aureus, and requires therapeutic drug monitoring (TDM) for optimal drug delivery. Herein, we discuss various methods of performing TDM for vancomycin, challenges associated with each method, and future directions for vancomycin TDM.

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) continues to persist as a global health concern. The USA Centers for Disease Control and Prevention (CDC) lists MRSA as a serious threat, based on factors such as the clinical and economic impacts, incidence of infection, as well as availability of antimicrobials [1]. This resistant, gram-positive organism causes significant numbers of both healthcare-associated and community-associated infections and remains associated with poor clinical outcomes with high rates of morbidity and mortality [2]. In 2017, the CDC reported an estimated 10 600 deaths due to MRSA infections [1].

Vancomycin, a glycopeptide antimicrobial, was approved in 1958 as an alternative to treat penicillinase-producing strains of Staphylococcus aureus [3]. Since this time, it is one of the most widely used antimicrobial agents and has remained as the mainstay of treatment for MRSA infections [4].

Fifty years since this antimicrobial’s discovery, methods to adequately monitor serum concentrations to optimize drug efficacy and minimize adverse events, such as nephrotoxicity, continue to evolve [4]. The therapeutic effect of vancomycin is best predicted through a ratio of area under the concentration-time curve to the minimum inhibitory concentration (AUC/MIC) (Fig. 1). The pharmacodynamic parameter of AUC/MIC describes the drug exposure over a 24-hour time period and optimizes both dosing and frequency parameters [5].

Therapeutic drug monitoring for vancomycin

Therapeutic drug monitoring (TDM) refers to the individualization of drug dosage by maintaining a certain concentration within a targeted therapeutic range. This range is the concentration range in which the medication provides its clinical effect with minimal adverse events [6]. For certain medications, such as vancomycin, obtaining therapeutic concentrations while minimizing adverse events may be difficult. This is attributed to the wide variety of pharmacokinetic profiles among patients. The way in which patients eliminate vancomycin can be drastically different, especially in certain clinical scenarios, such as with impaired renal function, critical illness and obesity. Patients will require different doses, and different frequencies of dosing, which may alter how their vancomycin therapy is monitored and adjusted. Lastly, drug clearance rates may constantly change, depending on the patient’s clinical status, disease states and potential interactions with other medications [7].

TDM is recognized as an important part of vancomycin therapy management. Inappropriate vancomycin dosing is associated with therapeutic failure, bacterial resistance and toxicity. Subtherapeutic vancomycin has been associated with the emergence of vancomycin-resistant Enterococci and vancomycin-resistant S. aureus, where management becomes more difficult due to the limitation of other antimicrobial agents [3].

Figure 1. Area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) ratio

Figure 2. Example first-order pharmacokinetic calculator to estimate AUC values in clinical practice

CL, clearance; Cmax, maximum concentration; Cmin, minimum concentration; Ke, elimination rate; Vd, volume of distribution.

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 [3]. 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 [3].

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 [8]. 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 [8]. 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 [9]. 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 [9].

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 [10].

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 [9].

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 [11]. 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 [12].

Summary

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.

The authors

Nicole M. Ondrush*1, PharmD, AAHIVP ; Bryan T. Mogle2, PharmD, BCPS
1 The Mount Sinai Hospital, New York, NY 10029, USA
2 Upstate University Hospital, Syracuse, NY 13210, USA

*Corresponding author
E-mail: Nicole.ondrush@mountsinai.org

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Forum Labo Paris March 2023