Overview of the PRN

The ACCP Adult Medicine PRN, founded in 1999, optimizes pharmacotherapy outcomes by promoting excellence and innovation in clinical practice, education, and research and improving the knowledge, skills, and productivity of its members. The PRN’s main objectives are to provide communication and informal networking among members, quality educational programming at national meetings, use of the internet to facilitate both access to timely educational updates and information exchange among adult medicine pharmacists, and opportunities for collaborative research. The PRN hosts a diverse group of members, including community, family medicine, internal medicine, geriatrics, and managed care pharmacists. Although most members practice in adult medicine, each also brings an individual expertise area to the PRN, with practitioners from areas such as infectious diseases, transitions of care, and cardiology. These diverse areas of expertise make this a well-rounded PRN, which affords a wide variety of educational and scholarship opportunities through both formal and informal collaborative settings. Collaboration among members further allows many mentorship and service opportunities within the PRN for students, residents, fellows, and both new and established adult medicine practitioners.

Opportunities and Resources for Trainee Members of the Adult Medicine PRN

The Adult Medicine PRN provides its resident and fellow members with many opportunities, and trainee programs have become a focus over the past few years. Postgraduate trainees are encouraged to join one of the PRN’s many committees during and after the ACCP Annual Meeting. PRN committees include External Affairs, Internal Affairs, Nominations, Programming, Research, Trainee Engagement, Training and Travel Awards, and Walk-Rounds. Committees blend those with a medley of experience to unite new and seasoned members in their efforts to support the PRN and ACCP. As part of the Internal Affairs Committee, trainee members hone their skills in medical writing by cowriting review articles published biannually in the PRN newsletter. The electronic journal club presented throughout the year pairs postgraduate trainees with a mentor from another institution to review and present a piece of recent literature. Resident and fellow members can apply for travel awards that help fund attendance at the ACCP Annual Meeting and deliver a presentation of their research to the membership. New this year, the PRN is offering a Trainee Poster Review service before the Annual Meeting. Trainees will receive feedback on their verbal presentation skills from a practicing pharmacist, setting them up for success at Annual Meeting poster sessions. By engaging its postgraduate trainees in so many activities, the ACCP Adult Medicine PRN provides a significant service to them.

Current Clinical Issues Important to Adult Medicine PRN Members

The Adult Medicine PRN is an amalgam of members with different practice backgrounds and expertise. Therefore, this is a preview of just a few of the clinical issues its members are paying attention to in 2021.

Current Clinical Issue: Update on Direct Oral Anticoagulants in Obesity

Author: Zachary Powers, Pharm.D. Candidate 2022

For the treatment of venous thromboembolism (VTE), the 2016 International Society on Thrombosis and Haemostasis (ISTH) guidelines raised some concerns for the use of direct oral anticoagulants (DOACs) in the morbidly obese population. This population was historically underrepresented in clinical trials, which led to uncertainty in the guideline recommendations. The 2016 ISTH guidance suggested that DOACs should not be used in patients with a BMI greater than 40 kg/m² and weight greater than 120 kg because of this lack of clinical evidence and concerns for underdosing; also, if DOACs were to be used in these patients, clinical decision-making should be guided by measured peak and trough concentrations.¹

Since 2016, more data have been published, prompting the ISTH to publish an updated guidance in 2021. Recommendations by the ISTH are now DOAC-specific. For the prevention and treatment of VTE, the ISTH suggests that standard doses of apixaban and rivaroxaban are appropriate options regardless of BMI and weight.² This is based on phase III and IV clinical data, systematic reviews/meta-analyses, and pharmacokinetic/pharmacodynamic (PK/PD) studies. Table 1 summarizes the evidence from phase III and IV trials for rivaroxaban and apixaban use in the treatment of VTE. Overall, the data from observational studies concluded at least similar efficacy and safety with rivaroxaban and apixaban, each compared with warfarin. Dabigatran, edoxaban, and betrixaban are still not suggested for VTE treatment and prevention in patients with a BMI greater than 40 kg/m² or weight greater than 120 kg, given the general lack of clinical evidence and PK/PD data to support their use. In addition, regularly following peak or trough drug-specific DOAC concentrations is not suggested because no research has yet shown a clinically significant relationship between laboratory values and disease outcomes.²

With the recent publication of clinical and PK/PD studies for DOAC use in obesity, the ISTH updated some of its recommendations, broadening the choice of anticoagulants in this population. Residents and fellows working on the frontlines of health care can make interventions using the latest guidelines, which may make treatment and prevention of VTE much more manageable in patients with obesity.

ICD = International Classification of Diseases; VKA = vitamin K antagonist.

References

1. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016;14:1308-13.
2. Martin KA, Beyer-Westendorf J, Davidson BL, et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost 2021;19:1874-82.
3. Di Nisio M, Vedovati MC, Riera-Mestre A, et al. Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies. Thromb Haemost 2016;116:739-46.
4. Costa OS, Beyer-Westendorf J, Ashton V, et al. Effectiveness and safety of rivaroxaban versus warfarin in obese patients with acute venous thromboembolism: analysis of electronic health record data. J Thromb Thrombolysis 2021;51:349-58.
5. Perales IJ, San Agustin K, DeAngelo J, et al. Rivaroxaban versus warfarin for stroke prevention and venous thromboembolism treatment in extreme obesity and high body weight. Ann Pharmacother 2020;54:344-50.
6. Kushnir M, Choi Y, Eisenberg R, et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haematol 2019;6:e359-65.
7. Spyropoulos AC, Ashton V, Chen YW, et al. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: comparative effectiveness, safety, and costs. Thromb Res 2019;182:159-66.
8. Cohen A, Sah J, Lee T, et al. Effectiveness and safety of apixaban vs. warfarin in venous thromboembolism patients with obesity and morbid obesity. J Clin Med 2021;10:200.

Current Clinical Issue: Vancomycin Therapeutic Drug Monitoring

Author: Amy R. Chan, Pharm.D. Candidate 2022

The 2020 vancomycin dosing guidelines published in the American Journal of Health-System Pharmacy contain some notable differences from the previous iteration. One change in particular is that the 2020 guidelines no longer recommend trough-based management of vancomycin for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. The definition of serious MRSA infection includes bacteremia, infective endocarditis, meningitis, osteomyelitis, pneumonia, and sepsis. Previously, the 2009 guidelines recommended that serum trough concentrations of 15–20 mg/L be used as a surrogate marker for monitoring the ratio of AUC to MIC.¹ However, trough concentrations only ensure a minimum cumulative exposure at a single exposure point, whereas AUC is the integrated quantity of cumulative drug exposure over a defined interval and the primary PK/PD predictor of vancomycin efficacy.² With the revised guidelines, an individualized target AUC/MIC_BMD ratio of 400:600 (assuming a vancomycin MIC_BMD of 1 mg/L) should be reached early, within 24–48 hours, to achieve clinical efficacy while improving patient safety.² Until now, there has been no well-described evidence that attainment of therapeutic trough values is linked with clinical success, though the practice of monitoring troughs has widely been implemented since its recommendation in 2009.³

The range of 15–20 mg/L was recommended in the 2009 guidelines because trough values over 15 mg/L always achieve a 24-hour AUC value (AUC₂₄) of      400 mg·× hour/L or greater, the threshold where vancomycin is considered to have near-maximal bactericidal activity against MRSA that has a MIC of 1 mg/L or less.^3,4 However, trough-based monitoring is problematic because trough values of 15–20 mg/L have considerable interpatient variability in the upper bound of the AUC, reaching concentrations upward of 1200 mg·× hour/L.⁴ This upper bound of AUC falls well in the range of 650–1300 × mg × hour/L, where there is an increased risk of nephrotoxicity.² Thus, trough concentrations are not entirely indicative of the relationship between vancomycin AUC and exposure-related nephrotoxicity, which makes them a poor clinical surrogate marker for monitoring therapy.

Several studies have validated the necessity for AUC-guided dosing in minimizing nephrotoxicity. Finch et al. found that AUC monitoring decreased rates of acute kidney injury (AKI) by about 50% compared with trough monitoring (95% CI, 0.34–0.80; p=0.003).⁵ The trough-guided group had a mean trough of 14.2 mg/L and a mean AUC_0-24 of 705 mg·× hour/L⁵. Of note, the mean trough was not in the target range of 15–20 mg/L, yet the mean AUC_0-24 was in the AUC range associated with nephrotoxicity. These investigators also showed that therapeutic AUC values can still be achieved at trough concentrations lower than those recommended in the 2009 guidelines, given that the AUC-guided dosing group had a mean trough of 12.5 mg/L yet a therapeutic mean AUC_0-24 at 474 mg ×·hour/L.⁵ In a 3-year prospective study, Neely et al. showed that transitioning from targeting trough concentrations of 10–20 mg/L in year 1 to targeting AUC/MIC ratios of      400 and greater using Bayesian software in years 2 and 3 led to a marked benefit with reduced nephrotoxicity, less patient drug sampling, and decreased overall length of therapy while maintaining efficacy in eradicating infection. Their institution went from 19% therapeutic trough concentrations to 70% therapeutic AUCs (p<0.0001) during the conversion and reduced nephrotoxicity rates from 8% with trough-based dosing to 0% and 2% with AUC-guided dosing in years 2 and 3.⁶ These two pivotal studies informed us that shifting to AUC-guided dosing results in fewer cases of vancomycin-associated AKI while maintaining efficacy, which led to the revised recommendation in the 2020 consensus statement.

A key factor contributing to the previous recommendation to use a surrogate marker was the impracticality of AUC monitoring. AUC monitoring used to require the collection of several concentrations during a single dosing interval, which was simply too difficult to do in clinical practice. Two methods are now used to estimate AUC that require limited PK sampling and are more clinically feasible than ever before. The first involves using Bayesian software programs to estimate the vancomycin AUC using one or two vancomycin concentrations. This method, shown to be effective in the Neely et al. study, allows for rapid, real-time monitoring within the first 24–48 hours of beginning treatment, given that it does not require steady-state serum vancomycin concentrations for AUC assessment.² The second approach involves collecting two concentrations (usually a peak and a trough) and using first-order analytic PK equations to estimate AUC values. Regardless of which method is used, transitioning from trough-based to AUC-guided dosing and monitoring will require institutions to overcome many logistical barriers. Multidisciplinary education involving pharmacists, prescribers, nurses, phlebotomy, and laboratory staff on the rationale and required procedural changes for AUC/MIC-based monitoring is critical for therapeutic drug monitoring to continue to improve and follow updated guidelines.⁷ As AUC-guided dosing and monitoring become more common, residents and fellows may present continuing education, support implementation efforts, and conduct quality improvement projects to support their institution and ultimately benefit their patients.

References

1. 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;66:82-98.
2. 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;77:835-64.
3. Pai MP, Neely M, Rodvold KA, et al. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev 2014;77:50-7.
4. Patel N, Pai MP, Rodvold KA, et al. Vancomycin: we can’t get there from here. Clin Infect Dis 2011;52:969-74.
5. Finch NA, Zasowski EJ, Murray KP, et al. A quasi-experiment to study the impact of vancomycin area under the concentration-time curve-guided dosing on vancomycin-associated nephrotoxicity. Antimicrob Agents Chemother 2017;61:e01293-17.
6. Neely MN, Kato L, Youn G, et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother 2018;62:e02042-17.
7. Heil EL, Claeys KC, Mynatt RP, et al. Making the change to area under the curve–based vancomycin dosing. Am J Health Syst Pharm 2018;75:1986-95.
8. Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 2006;42(suppl 1):S35-9.

Prepared by:

Amy R. Chan, Pharm.D. Candidate 2022, Virginia Commonwealth University School of Pharmacy; National Student Network Advisory Committee Member-at-Large 2021–2022; Pharmacy Intern, University of Virginia Health System

Zachary Powers, Pharm.D. Candidate 2022, Virginia Commonwealth University School of Pharmacy

Rachel W. Flurie, Pharm.D., BCPS; Adult Medicine PRN Secretary/Treasurer 2019–2020; Assistant Professor, Virginia Commonwealth University School of Pharmacy; Internal Medicine Clinical Pharmacist, VCU Health