In this article perspectives on AUC-guided vancomycin dosing and monitoring are provided.
Article Author: Sara Lee, Pharm.D.
Article Mentor: Monica Mehta, Pharm.D., MPH, BCPS
Article Posted 27 November 2021
Vancomycin is a glycopeptide antibiotic that has been used in clinical practice for over 50 years. Its early use was associated with nephrotoxicity and ototoxicity, and although it was discovered that these toxicities were related to the presence of impurities in the earlier formulations, vancomycin was relegated to a secondary role to antistaphylococcal penicillins (e.g., oxacillin) [1]. However, the worldwide emergence of methicillin-resistant staphylococci in the early 1980s ushered in a new era in the history of vancomycin use. Currently, vancomycin remains one of the most widely used antibiotics in the United States to treat various infections suspected to be our found to be caused by Gram positive bacteria, including methicillin-resistant staphylococcus aureus (MRSA).
Although newer formulations of vancomycin show fewer toxicities, therapeutic drug monitoring (TDM) for vancomycin was advocated to minimize its toxicities. Since then, the practice of routine vancomycin TDM has been the subject of intense debate. For antibiotics in general, we integrate pharmacokinetic (PK) parameters with the minimum inhibitory concentration (MIC) of the pathogen to determine drug targets. The activity of an antibiotic can be categorized into three buckets:
- Time above the MIC (i.e., T>MIC)
- Ratio of the peak concentration to the MIC (i.e., Cmax/MIC)
- The ratio of the area under the concentration-time curve (AUC) from 0-24 hours to the MIC (i.e., AUC/MIC)
Vancomycin’s dose-response relationship with Staphylococcuss aureus cannot be reduced to a simple time above the MIC [2]. By integrating overall concentration over time, the AUC provides a more accurate estimate of the overall drug exposure. Thus, AUC/MIC has been identified to be the best predictive PK parameter for vancomycin versus Staphylococcus aureus.
The recently revised SIDP/IDSA/ASHP/PIDS vancomycin guidelines pull from existing data on this topic and advocate for AUC-guided dosing and monitoring [3]. This reflects a paradigm shift to decades of clinical experience and routine performance of vancomycin TDM using a trough-based approach. As life-long learners, pharmacists are looking to become more familiar with AUC-based dosing for vancomycin. We pharmacists not only welcome the black-and-white but also the spectrum of gray found in advanced pharmacotherapy – we live in supplementary tables, in vitro studies from 1958, and extrapolated data to find answers to questions that lie along that spectrum. As pharmacists look to become more familiar with AUC-guided dosing for vancomycin the following is provided. Here is a quick summary of the revised guideline recommendations as well as some relevant literature and important considerations when making the change to AUC-guided vancomycin dosing and monitoring.
CURVE YOUR ENTHUSIASM
Although AUC was acknowledged to be the best predictive PK parameter for vancomycin for Staphylococcus aureus, this was not the guideline recommendation for patients with serious MRSA infections in 2009. The reason? Well, calculating the AUC requires a bit of work. In summary, it requires multiple serum concentrations to be drawn at different times in a world where a scheduled 3 pm dose is not always given at 3 pm. Highlighting this pragmatic issue, the guidelines offered a shortcut approach to guarantee clinical efficacy (i.e., AUC ≥400): maintain a trough of 15 to 20 mg/L [4].
Why a trough of 15-20 mg/L?
To put it simply, mathematically it makes sense. The graph below is a simplified visual representation of the rationale behind our well-known target for serious MRSA infections. Here, a steady-state trough concentration of 15 mg/L guarantees an AUC of 360 in 24 hours (dark blue) and because the trough is the lowest concentration of a drug, we can expect the corresponding AUC to be at least 400 thanks to the peak (light blue). Therefore, we can feel confident that vancomycin trough concentrations between 15 to 20 mg/L will achieve an AUC/MIC ≥400 for S. aureus isolates when the MIC is ≤1 mg/L [5].
Adapted from: https://emcrit.org/pulmcrit/vanco/
However, it is important to remember that the AUC represents the cumulative exposure of a drug over a defined time-period (e.g., 24 hours) whereas a trough measures a single point of exposure. Therefore, while a trough of 15 mg/L may ensure an AUC of at least 400, there is considerable variability in the upper range of AUC values.
This is shown in a Monte Carlo simulation by Pai and colleagues. A Monte Carlo simulation is a mathematical model used to simulate thousands of patients from smaller sample sizes to predict the likelihood of an event. This type of mathematical sampling can be used in various scenarios. Initially, the Monte Carlo simulation first gained momentum during the Manhattan project when it was used to estimate the probability of the chain reactions needed to develop the atomic bomb. In drug development, this type of mathematical modeling may be used to explore the consequences of PK/PD variabilities on the probability of achieving a given therapeutic target. Ultimately, this may help optimize dosing regimens or clinical trial designs such as sample size and study duration.
This is shown in a Monte Carlo simulation, which is a mathematical model used to simulate thousands of patients from smaller sample sizes to predict the likelihood of an event. This type of mathematical modeling may be used to explore the consequences of PK/PD variabilities on the probability of achieving a given therapeutic target. Ultimately, this may help optimize dosing regimens or clinical trial designs such as sample size and study duration. The mathematic relationship between trough and AUC was explored was Pai et al (2014) through a Monte Carlo simulation of the vancomycin concentration-time profile using a well-established population PK model (n=5000) [5]. The 5000 subject simulation showed that while maintaining a trough of 15-20 mg/L ensured an AUC of at least 400, there was considerable variability in the upper range of AUC values, with most patients having an AUC of 600 or greater. There was also a high degree of inter-individual variability seen with an AUC of 400-600, with patients reaching this target with a trough concentration as low as 5 mg/L and as high as 20 mg/L.
In addition to discrepancies between trough and AUC values, as the 2009 recommendations were widely integrated into practice, there were also increased reports of nephrotoxicity among patients. In a systematic review by Hal et al which included 15 studies published between 1996 and 2012, the odds of vancomycin-induced nephrotoxicity were nearly three times higher with trough concentrations maintained between 15-20 mg/L [6]. This persisted after adjusting for covariates known to independently increase the risk of nephrotoxicity such as ICU admission and concomitant nephrotoxins.
AUC FINALLY GETS ITS DAY
Over 30 years after S. Ebert presented an experimental mouse model at the 1987 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) that identified AUC to be the best predictive parameter of vancomycin in S. aureus infections [7], the 2020 IDSA guidelines no longer recommend trough-only monitoring of vancomycin in patients with serious MRSA infections. Instead, an individualized target AUC/MIC of 400 to 600 (assuming an MIC of 1 mg/L) is advocated to achieve clinical efficacy while improving patient safety.
It is important to highlight that the current data only demonstrates improved patient safety with AUC-guided dosing, and we do not have the data to suggest improved efficacy compared to troughs ≥15 mg/L. Further studies are also needed to support AUC-guided vancomycin dosing in other types of infections (e.g., skin and soft tissue and urinary tract infections) as well as other gram-positive pathogens, including coagulase-negative Staphylococcus and Streptococcus species. However, independent of MRSA infection, the guidelines recommend monitoring to be performed in patients with unstable renal function and those receiving prolonged courses of therapy. The guidelines recommend accomplishing this in one of two ways:
(1) Equation-based pharmacokinetic modeling: Sawchuck-Zaske (peak & trough method)
Vancomycin dosing may be modeled using 2-level pharmacokinetics assuming a 1-compartment model, as described by Sawchuck and Zaske in 1976 [8]. Using two levels drawn during the same dosing interval, a patient-specific AUC is estimated by calculating the area of the linear and logarithmic trapezoids of the concentration time curve. Although initially believed to be more labor-intensive than simply measuring a trough, electronic medical record (EMR)-based or free online dosing calculators have allowed this Sawchuck-Zaske method to be achievable for many institutions.
The basic principles of pharmacokinetic equations may not have changed over the past 40 years, but there are newer studies supporting the use of the Sawchuck-Zaske method in clinical settings. Finch et al performed a retrospective, quasi-experimental study evaluating the incidence of vancomycin-induced nephrotoxicity following the transition from trough- to AUC-guided monitoring at their institution [9]. Although the patients were sicker (e.g., higher comorbidity and APACHE-II scores), AUC-guided dosing was independently associated with lower nephrotoxicity by both multivariable logistic and Cox proportional hazards regression.
(2) Alternative to pharmacokinetic calculations: Bayesian method
The Bayesian approach uses a statistical method derived from the Bayesian Theorem which stipulates that one can describes the probability of an event based on prior knowledge of conditions that might be related to the event. In other (simpler) words: Initial belief (Bayesian prior) plus new evidence = New and improved belief (Bayesian conditional posterior) [10]. For example, imagine it’s a rainy season. Suppose you want to go out, but the morning looks cloudy. Do you need to take an umbrella? To answer this question, you can check past data (it rained 9 out of 30 days this month) and additional related probabilities (how common are cloudy mornings and how many rainy days start cloudy) to update your estimate on the probability of rain provided that the day started with clouds. When applying this principle to dosing and monitoring of vancomycin, the patient’s PK parameters (e.g., drug clearance or volume of distribution) are first estimated using a pre-existing population database (Bayesian prior). Following drug administration, the patient’s vancomycin serum concentrations are measured to provide a revised estimate of the patient’s PK parameters (Bayesian posterior).
Similar to equation-based PK modeling, the Bayesian method is also supported by newer vancomycin studies. Lodise et al performed a prospective, observational study to evaluate the impact of vancomycin AUC/MIC exposure on treatment failure using a Bayesian software program in patients with MRSA bacteremia [11]. The study found that patients with a day-2 AUC value of ≤515 experienced the best global outcomes (no treatment failure and no acute kidney injury) in a risk-benefit analysis. In addition, the Bayesian-guided approach allows for quicker predictions as vancomycin levels can be sampled early (first 24-48 hours) to rapidly provide an appropriate vancomycin dose. It is also adaptive to physiologic changes (e.g., renal dysfunction) and only a single level is required to obtain an AUC estimate. However, there are several factors that cannot be captured by Bayesian priors (e.g., bacterial inoculum, immune response, extent of source control, ancillary care), especially as these characteristics are patient-specific and may change over the course of their disease [12]. Also, the price of software programs typically makes it more expensive to implement compared to traditional trapezoidal methods, as well as an increased concern for patient data security.
A BRAVE NEW WORLD
Vancomycin remains a cornerstone in the management of Gram positive infections. For the first time, the guidelines not only acknowledge AUC to be its best predictive parameter, but also advocate an individualized AUC/MIC target of 400 to 600 to achieve clinical efficacy while improving safety in patients with serious MRSA infections. However, there are limitations with AUC-based monitoring. First, most studies regarding vancomycin AUC have been retrospective and in patients with MRSA bacteremia. The available studies also report a wide range of target AUC/MIC values for safety and there is limited evidence correlating vancomycin AUC/MIC with clinical efficacy. Lastly, while valuable literature as has emerged reviewing AUC-guided dosing in certain patient populations, further studies are needed to address existing gaps, including other gram-positive pathogens causing different types of serious infections.
ABOUT THE AUTHOR
Sara Lee, Pharm.D., is a Philadelphia native who received her Doctor of Pharmacy degree from Temple University School of Pharmacy in 2020. Following graduation, she completed a post-graduate year 1 (PGY-1) pharmacy residency at NewYork-Presbyterian Hospital where she is currently continuing her PGY-2 training in infectious diseases and serving as the co-chief resident for her residency class.
After her PGY2, Dr. Lee hopes to work as a clinical pharmacy specialist at an academic medical center. Her professional interests include PK/PD, antimicrobial stewardship, and multidisciplinary education.
You can find her on Twitter @SLeePharmDee and you can find her mentor for this article on Twitter @Nica_NYC
REFERENCES
1. Levine DP. Vancomycin: a history. Clin Infect Dis. 2006;42 Suppl 1:S5-12. doi:10.1086/491709
2. pharmacokinetics and pharmacodynamics of vancomycin in clinical practice: evidence and uncertainties | Journal of Antimicrobial Chemotherapy | Oxford Academic. Accessed November 14, 2021. https://academic.oup.com/jac/article/68/4/743/705696
3. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2020;77(11):835-864. doi:10.1093/ajhp/zxaa036
4. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1):82-98. doi:10.2146/ajhp080434
5. Pai MP, Neely M, Rodvold KA, Lodise TP. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Advanced Drug Delivery Reviews. 2014;77:50-57. doi:10.1016/j.addr.2014.05.016
6. van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57(2):734-744. doi:10.1128/AAC.01568-12
7. Ebert S. In vivo cidal activity and pharmacokinetic parameters for vancomycin against methicillin-susceptible and -resistant S. aureus. Presented at: Program and abstracts of the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1987; New York.
8. Sawchuk RJ, Zaske DE. Pharmacokinetics of dosing regimens which utilize multiple intravenous infusions: gentamicin in burn patients. J Pharmacokinet Biopharm. 1976;4(2):183-195. doi:10.1007/BF01086153
9. A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity – PubMed. Accessed November 14, 2021. https://pubmed.ncbi.nlm.nih.gov/28923869/
10. What Is Bayes’ Theorem? A Friendly Introduction. Probabilistic World. Published February 22, 2016. Accessed November 14, 2021. https://www.probabilisticworld.com/what-is-bayes-theorem/
11. Lodise TP, Rosenkranz SL, Finnemeyer M, et al. The Emperor’s New Clothes: PRospective Observational Evaluation of the Association Between Initial VancomycIn Exposure and Failure Rates Among ADult HospitalizEd Patients With Methicillin-resistant Staphylococcus aureus Bloodstream Infections (PROVIDE). Clin Infect Dis. 2020;70(8):1536-1545. doi:10.1093/cid/ciz460
12. Jorgensen SCJ, Spellberg B, Shorr AF, Wright WF. Should Therapeutic Drug Monitoring Based on the Vancomycin Area Under the Concentration-Time Curve Be Standard for Serious Methicillin-Resistant Staphylococcus aureus Infections?-No. Clin Infect Dis. 2021;72(9):1502-1506. doi:10.1093/cid/ciaa1743
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