One Year Later: Experience and Insights From One of The 2020 Vancomycin Guideline Authors

Dr Kristi Kuper, Director of Clinical Pharmacy, DoseMe

Dr. Lodise is an internationally known infectious diseases expert and is one of the most prolific researchers in vancomycin. Through these experiences, he has provided his perspectives on the evidence behind this shift to AUC dosing and shares some ideas that may assist institutions or clinical practice sites that are continuing to make the transition to AUC dosing.

What is the key evidence behind the recommendation to move away from trough-only monitoring to AUC-guided dosing and monitoring and maintaining the daily AUC between 400-600 mg*h/L?

The 2009 consensus guidelines ² recommended trough monitoring and maintaining trough concentrations between 15-20 mg/L as a surrogate for achieving an AUC to minimum inhibitory concentration (MIC) of >=400.

This was based, in part, on the historical difficulty in estimating AUC/MIC ratios in clinical practice and to facilitate ease of monitoring.

While this recommendation was widely integrated into vancomycin dosing protocols, the clinical benefits of maintaining higher vancomycin trough values have not been well established.

There have also been numerous reports of increased rates of vancomycin-associated AKI (VA-AKI), associated with maintaining vancomycin troughs between 15-20 mg/L, without any improvements in efficacy. ¹

As mentioned earlier, the trough values were intended to merely serve as a surrogate of the daily AUC value. However, data also shows that there is a therapeutic discordance between trough and daily AUC values.

A trough value of 15-20 mg/L will almost always ensure a daily AUC in excess of 400 mg*hr/L. However, the majority of patients will have daily AUCs of ≥ 600 mg*hr/L.3 The reason why this is so concerning is that there are a growing number of studies demonstrating that patients with a daily AUC of above 600 mg*hr/L are at an increased risk of VA-AKI. ¹

In further support of this shift to AUC-guided vancomycin dosing and monitoring, two recent studies by Neely et al., (2018) and Finch et al., (2017) have found AUC-guided dosing relative to trough-based monitoring is associated with less nephrotoxicity.^4,5

Most of the patients in the AUC-guided dosing group in these studies had a daily AUC of 400-600 mg*hr/L while many in the trough-based monitoring group had AUC in excess of 600 mg*hr/L^4,5.

In addition to mounting data establishing the upper end of the therapeutic AUC range, limited data show that efficacy outcomes are maintained when the daily AUC is above 400 mg*h/L for patients with serious MRSA infections.⁶

It may be possible to lower the daily AUC range (i.e., 300 mg*h/L) for patients with serious MRSA infections but little data exist at this time to support this practice. For these reasons combined, the guideline committee concluded AUC-guided dosing and monitoring is the most accurate and safest way to optimize vancomycin, and AUC should be maintained between 400-600mg*h/L to maximize efficacy and minimize the likelihood of VA-AKI. ⁷

Can you describe why clinicians should be concerned with VA-AKI?

It is important to recognize that VA-AKI cannot be avoided by simply monitoring a patient’s serum creatinine (Scr).

It is well described that Scr is an insensitive and delayed indicator of AKI and it is estimated that up to 50% of the kidney function is lost before there is any detectable increase in Scr. ⁸

This is so concerning because even mild cases of VA-AKI have been linked to a variety of adverse outcomes including increased in-hospital mortality, length of stay, and healthcare resource utilization. In a study of hospitalized patients with skin and skin structure infections (SSSIs) who received vancomycin, we found that each case of VA-AKI results in ~15,000 USD in excess cost. ⁹

Data also indicate that occurrence of AKI, regardless of cause, is often accompanied by remote organ dysfunction, which increases a patient’s susceptibility to a number of conditions (e.g., cardiovascular events, infections due to immunosuppression, etc.) over time.

Our group recently reported that adult hospitalized patients with SSSIs who experienced VA-AKI had considerably higher rates of 30-day readmissions and most re-admissions were consistent with the described consequences of AKI–remote organ “crosstalk”.¹⁰

What role does the Minimum Inhibitory Concentration (MIC) play when determining an optimal vancomycin dose?

The Committee did not believe it was necessary to factor in the vancomycin MIC value when determining dosing and to assume the MIC was 1 mg/L, unless it is known that the MIC, by the broth microdilution methods, is > 1 mg/L. The full guidelines ¹provide a great overview of the science behind this rationale.

What should be considered when looking to transition to vancomycin AUC-based dosing?

Evaluate AUC Calculation Approaches: I encourage everyone to read this paper I co-authored ⁴ for a detailed description regarding the use of first-order pharmacokinetic (PK) equations and Bayesian-derived approaches for vancomycin AUC-monitoring.
Review the 2020 Vancomycin Guidelines: The revised vancomycin consensus guidelines¹ also provides a detailed description of these two AUC approaches.
Trial AUC Dosing Methodologies: Both Bayesian dosing and first-order kinetics are acceptable methods to estimate the AUC with low bias and high precision. Of the two, I am more favorable to Bayesian-derived approaches to estimate the AUC. This is because, with Bayesian programs, vancomycin concentrations can be obtained at any time, even over different dosing intervals which offer more flexibility.

How can Bayesian dosing be used to optimize vancomycin dosing?

Bayesian dosing using Bayesian software starts by using a well-developed vancomycin population PK model as the “Bayesian” PK prior. Based on a patient’s dosing history and collected PK data, the software estimates the Bayesian posterior parameter values for that patient (i.e., individualized PK parameter estimates). The dose optimization software then calculates the optimal dosing regimen based on the specified exposure target. In the case of vancomycin, the exposure target is a daily AUC of 400-600 mg*h/L.

Flexible Timing of Vancomycin Levels

What is interesting is that vancomycin concentrations do not need to be collected at steady-state conditions. In contrast, it is highly preferred that concentrations are collected during the same interval at steady-state conditions when computing the AUC with first-order equation-based methods.

Earlier Achievement of a Target AUC

Bayesian dosing programs are extremely flexible and adaptive. For example, Bayesian dosing programs can be used to calculate innovative treatment schemes such as front-loading doses with a transition to a lower maintenance dosing regimen. This allows the clinician to achieve target concentrations within the first 24 to 48 hours in critically ill patients. The Bayesian approach also provides the ability to include covariates, such as creatinine clearance, into the pharmacokinetic models to account for the pathophysiological changes that readily occur in critically ill patients.

These inputs/outputs are not possible with first-order equation-based methods. First-order equation-based methods only provide a “snapshot” of the AUC for the sampling period. However, programs can be created to compute the daily AUC in patients stabilized on multiple daily dosing regimens, and provide dosing recommendations that are projected to achieve the daily AUC target.

Estimate AUC using a Trough Value

Lastly, while it is preferred to have two concentrations, Bayesian software programs can accurately estimate the vancomycin AUC value with trough values in hemodynamically stable, normal weight patients. For obese patients, the guidelines recommend to obtain two concentrations (a post infusion peak and a pre-infusion trough) when determining initial dosing regimens. Once a reliable PK estimate of vancomycin elimination is determined by using these two concentration measurements, subsequent vancomycin AUC estimation is achievable with trough-only measurements by Bayesian methods in physiologically stable patients. In contrast, two concentrations (peak and trough) are always recommended when using first-order PK equation-based methods to estimate AUC values.

A Note About First-order PK equations

In short, first-order PK equations used to compute AUCfrom two samples collected during the same dosing interval are based in part on an original approach proposed by Begg, Barclay, and Duffull ¹¹ for aminoglycosides and modified by Pai and Rodvold.⁴

Although it is possible to estimate individualized PK parameters after the first vancomycin dose, it is preferred that the first-order PK equation-based method is used when a patient is stabilized on a regimen at near steady-state conditions. It is also extremely difficult to estimate the vancomycin AUC₂₄with first-order PK equation-based method in patients who receive multiple dosing regimens within the recent 24-hour period.

What key factors should pharmacists consider when deciding between vancomycin AUC-guided dosing approaches?

Clinical requirements: Clinicians who routinely use vancomycin must ultimately decide upon the best solution for their clinical practice.
Experience of your pharmacy staff: Both are reasonable approaches and both estimate the AUC with low bias and high precision.
Review advantages of Bayesian method: Bayesian programs offer numerous clinical advantages over the traditional first-order equation approach as detailed above for optimizing the use of vancomycin in practice.

About the Interviewee

Dr. Lodise, is an internationally known expert in antimicrobial pharmacokinetics and pharmacodynamics and co-author of the revised consensus guideline and review for monitoring vancomycin in the treatment of serious methicillin-resistant Staphylococcus aureus infections published last year. He is the Chair of the Clinical Advisory Board advising DoseMeRx and Tabula Rasa HealthCare’s hospital and acute-care solutions.

Dr. Lodise was selected to serve on the committee responsible for reviewing the dosing and monitoring guidelines of vancomycin due to his publication track record on MRSA, vancomycin PK/PD, and vancomycin exposure-related outcomes (efficacy and toxicity). He was one of 13 experts from the United States to revise the clinical guidelines for using the antibiotic Vancomycin to treat MRSA patients. The panelists, who were chosen by The American Society of Health-System Pharmacists (ASHP), include members of the Infectious Disease Society of America, Society of Infectious Disease Pharmacists, and the Pediatric Infectious Disease Society.

In the past 15 years, he has published over 70 manuscripts related to the management of patients with infections due to MRSA infections; 59 of these manuscripts are specifically focused on vancomycin. Dr. Lodise has also published over 70 manuscripts related to the management of patients with infections due to MRSA infections.

Most recently, he was the Principal investigator of the multi-center, prospective study that determined the day 2 vancomycin exposure profile associated with maximal response among patients with bloodstream infections due to MRSA, entitled “Prospective Observational Evaluation of the Association Between Initial Vancomycin Exposure and Failure Rates Among Adult Hospitalized Patients With Methicillin-resistant Staphylococcus aureus Bloodstream Infections”. This is the largest prospective analysis of vancomycin pharmacokinetics and pharmacodynamics available in the literature at present.