• 06 Apr 2022 11:17 AM | Anonymous

    Authors: Stephanie Chau PharmD and Sarah Billings PharmD, BCACP, CDCES

    Program Number: 2202-02-03
    Approved Dates:  April 1, 2022 - October 1, 2022
    Approved Contact Hours:  One Hour(s) (1) CE(s) per session


    1. Compare the difference between the nonsteroidal mineralcorticoid receptor antagonist finerenone to steroidal mineralocorticoid receptor antagonists
    2. Assess literature on cardiovascular and renal effects of finerenone in type 2 diabetics with diabetic kidney disease
    3. Review other medications with cardiovascular and renal benefits used in type 2 diabetics


    Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) and is associated with an increase in mortality in diabetics1. Chronic kidney disease (CKD) and diabetes mellitus lead to an additive effect that increases the cardiovascular mortality rate. The current mainstay of therapy used to reduce the progression of DKD are angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Sodium-glucose co-transporter-2 (SGLT2) inhibitors further decrease the progression of DKD, incidence of major adverse cardiovascular events, and heart failure hospitalizations.

    Mineralocorticoid receptor antagonists (MRA) have been shown to reduce albuminuria in patients with CKD when given alone or with renin-angiotensin system (RAS) blockers and reduce overall mortality in patients with heart failure. Albuminuria reduction is a main factor of improving renal outcomes in patients with CKD. A 30% or greater reduction in albumin that is sustained for at least 2 years is considered to be a validated surrogate for slowing down CKD progression1. The addition of spironolactone or eplerenone to RAS blockers to improve renal outcomes is unclear in patients with DKD since there is limited renal outcome data. An issue with steroidal MRAs such as spironolactone and eplerenone is they are associated with an increase in serum potassium. The potential benefits and adverse events of steroidal and non-steroidal MRAs in DKD patients will be compared.

    Non-steroidal vs Steroidal Mineralocorticoid Receptor Antagonists

    While both non-steroidal and steroidal MRAs block aldosterone activity, the effects on potassium levels are different. Spironolactone is a potent steroidal MRA, has a long half-life, and relatively low selectivity since it also acts on progesterone and androgen receptors as well. One of the most important side effects of spironolactone is hyperkalemia. Eplerenone is another steroidal MRA with higher receptor specificity, but is still associated with hyperkalemia especially at a higher dose of 200 mg1. Both spironolactone and eplerenone are associated with a three-to-eight-fold increased risk of hyperkalemia in stage 3 CKD or higher patients1.

    Non-steroidal MRAs include the agents apararenone, esaxerenone, and finerenone. Finerenone has a high potency and selectivity for mineralocorticoid receptors and acts as an inverse agonist. It has a greater receptor selectivity compared to spironolactone. Finerenone has stronger mineralocorticoid receptor binding affinity compared to eplerenone and a lower affinity for androgen, progesterone, and glucocorticoid receptors similar to eplerenone. Compared to steroidal MRAs, finerenone has a reduced blood pressure lowering effect since it is unable to cross the blood-brain barrier and does not inhibit central mineralocorticoid receptors. However, finerenone is expected to have a lower risk of hyperkalemia compared to steroidal MRAs. This is thought to be due to a balanced kidney and heart distribution of finerenone while spironolactone and eplerenone are mostly distributed in the kidney compared to the heart. Also finerenone has no active metabolites and a shorter half-life of 2 hours compared to spironolactone which has a half-life of 14-16 hours with active metabolites. Eplerenone has no active metabolites, but has a slightly longer half-life of 4-6 hours2. However, finerenone is still dosed based potassium levels, which requires routine monitoring.

    Table Finerenone vs Traditional Steroidal Mineralocorticoid Receptors Antagonists1

    Table 2 Dosing of Finerenone3

    Finerenone Tolerability

    The ARTS studies looked at the tolerability of MRAs in heart failure in DKD. The study included patients with chronic systolic heart failure and stage 3 CKD who received finerenone, placebo, or open-label spironolactone. Finerenone was associated with smaller increases in serum potassium levels compared to spironolactone and a reduced incidence of hyperkalemia. The ARTS-DN trial and ARTS-HF trial looked at tolerability of finerenone in DKD and heart failure, which showed that finerenone was safe and efficacious.

    The ARTS-DN study was a randomized, double-blind, parallel-group placebo-controlled trial that compared efficacy and safety of different once-daily doses of finerenone compared to placebo for 90 days in patients with type 2 diabetes who had high or very high albuminuria. High albuminuria is defined as a urine to albumin creatinine ratio (UACR) 30 mg/g and very high albuminuria is defined as UACR 300 mg/g. This study had all patients receive an ACE inhibitor or ARB, have albuminuria (UACR 30 mg/g), have an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m2 with serum potassium levels less than or equal to 4.8 mmol/L. The doses of finerenone varied from 1.25, 2.5, 5, 7.5, 10, 15, and 20 mg daily. The primary outcome of the study was the ratio of UACR at day 90 vs at baseline. Finerenone doses of 7.5-20 mg daily showed a dose-dependent reduction in the UACR with the largest reduction in the 20 mg daily group at day 904. The study observed a mean change in serum potassium of 0.2-0.25 mmol/L in the 20 mg daily finerenone group4. Hyperkalemia and discontinuation of finerenone was observed in 1.8% of patients who received 7.5-20 mg daily compared to zero patients in the placebo group4. There were two cases of serum potassium levels greater than 6 mmol/L in the finerenone 1.25 mg group, and 1 in the 15 mg group only4. There was not a difference in the incidence of an eGFR decrease of at least 30% between finerenone and placebo4. There was also no difference in the overall difference in the incidence of adverse events between both groups4.

    The ARTS-HF study evaluated the effectiveness and safety of finerenone in heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes and/or CKD stage 3 or higher patients compared to eplerenone. The patients also had to require hospitalization and treatment with emergency intravenous diuretics. In this study patients received finerenone 2.5 to 20 mg daily and eplerenone 25 to 50 mg daily. The primary outcome of this study was the percent of patients who had a decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of >30% from baseline to day 90. About 30.9% to 38.8% of patients in the finerenone group compared to 37.2% of patients in the eplerenone group had a >30% decrease in NT-proBNP levels from baseline to day 905. Finerenone had a greater benefit in the composite endpoint of cardiovascular hospitalization, death from any cause, and emergency presentation for worsening heart failure at day 90. The most benefit was seen with a finerenone dose of 10-20 mg daily (HR: 0.56, 95% CI: 0.35-0.90, P=0.02) mostly due to a reduction in cardiovascular hospitalization5. Overall there were a total of 44 patients with hyperkalemia ( 5.6 mmol/L) and these were balanced between the finerenone and eplerenone group5. There were 5 patients in the eplerenone group and 4 in the finerenone group who had potassium concentrations >6.0 mmol/L at any point after baseline. The mean change in potassium from baseline to day 90 was greater in the epelerenone group (0.262 mmol/L) compared to the finerenone groups (0.119-0.202 mmol/L)5.

    Finerenone Trials on Progression of Diabetic Kidney Disease

    The FIDELIO-DKD trial evaluated the efficacy and safety of finerenone, in addition to the standard of care, on the progression of CKD in type 2 diabetics and advanced CKD. The study included patients who were at least 18 years old or older with type 2 diabetes with an established clinical diagnosis of CKD who were already being treated with maximally tolerated RAS blocker therapy. Patients with heart failure with reduced ejection fraction were excluded. Patients received finerenone 10 mg daily if they had an eGFR of 25-59 mL/min/1.73 m2 and 20 mg daily for an eGFR greater or equal to 60 mL/min/1.73 m2 or placebo. Patients had a serum potassium of 4.8 mmol/L or less upon study entry. Either finerenone or placebo were held if potassium concentration exceeded 5.5 mmol/L. Finerenone or placebo were restarted when potassium levels fell to 5.0 mmol/L or less. The average dose of finerenone was 15.1 mg daily. The primary composite outcome was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline over at least 4 weeks, or death from renal causes. The main secondary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The median follow-up time was 2.6 years and the primary outcome event occurred in 504 (17.8%) patients in the finerenone group and 600 (21.1%) in the placebo group (HR: 0.82; 95% CI: 0.73-0.93; P=0.001)6. This benefit was mostly due to a reduction in the sustained decrease of at least 40% in eGFR from baseline (HR: 0.81, 95% CI: 0.72-0.92). There was not a statistically significant difference in the incidence of kidney failure or death from renal causes. However a total of 4.6% of patients were on a SGLT2 inhibitor, which have been shown to have renal benefits as well. The secondary outcome occurred in 367 (13.0%) patients in the finerenone group and 420 (14.8%) in the placebo group (HR: 0.86; 95% CI: 0.75-0.99; P=0.03)6. Finerenone was associated with a 31% greater reduction in the UACR from baseline to month four compared to placebo (ratio of least-squares mean change from baseline: 0.69; 95% CI: 0.66-0.71)6. A total of 252 (8.9%) of finerenone patients compared to 326 (11.5%) of placebo patients had a secondary composite kidney outcome event which included kidney failure, a sustained decrease of 57% or greater in the eGFR from baseline, or death from renal causes (HR: 0.76; 95% CI: 0.65-0.90)6. The incidence of hyperkalemia-related adverse events was more frequent in the finerenone group compared to placebo (18.3% and 9.0% respectively)6. The incidence of hyperkalemia-related discontinuation was higher in the finerenone group compared to placebo (2.3% and 0.9% respectively), but no fatal hyperkalemia adverse events were reported6. This study showed a statistically significant benefit in kidney outcomes and cardiovascular benefit with finerenone with the main adverse event being hyperkalemia.

    The FIGARO-DKD trial evaluated the effectiveness of finerenone in reducing major cardiovascular event and death from cardiovascular cause in type 2 diabetics with CKD. The study included patients who were at least 18 years old or older with type 2 diabetes and CKD stage 2 to 4 with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria who were receiving a RAS inhibitor. Patients with symptomatic chronic heart failure with reduced ejection fraction and patients highly represented in the FIDELIO-DKD trial (UACR of 300-5000 mcg/mg and eGFR of 25 to less than 60 mL/min/1.73 m2) were excluded. Patients received finerenone 10 mg once daily if eGFR was 25 to less than 60 mL/min/1.73 m2 and 20 mg once daily if eGFR was at least 60 mL/min/1.73 m2 or placebo. Patients had a serum potassium of 4.8 mmol/L or less upon study entry and finerenone or placebo were held if potassium concentration exceeded 5.5 mmol/L. Finerenone or placebo were restarted when potassium levels fell to 5.0 mmol/L or less. The average dose of finerenone received was 17.5 mg daily. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The main secondary outcome was a composite of the first occurrence of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR for a period of at least 4 weeks, or death from renal causes. The median follow up time was 3.4 years and the primary outcome event occurred in 458 (12.4%) in the finerenone group compared to 519 (14.2%) in the placebo group (HR: 0.87; 95% CI: 0.76-0.98; P=0.03)7. The number needed to treat to prevent one primary outcome event was 47 based on a between group difference of 2.1% after 3.5 years7. More specifically, there was a lower incidence of hospitalization for heart failure in the finerenone group compared to placebo (HR: 0.71; 95% CI: 0.56-0.90)7. However 8.4% of patients were also on SGLT2 inhibitors, which have also been shown to have cardiovascular and heart failure benefits. The secondary composite outcome occurred in 350 (9.5%) in the finerenone group compared to 395 (10.8%) in the placebo group (HR: 0.87; 95% CI: 0.76-1.01)7. The reduction in the UACR from baseline to month 4 was 32% greater in the finerenone group compared to the placebo group (ratio of the least-squares mean change from baseline: 0.68; 95% CI: 0.65-0.70)7. The incidence of hyperkalemia was higher in the finerenone group compared to placebo (10.8% and 5.3%), but no adverse events resulted in death7. Hyperkalemia led to discontinuation in 1.2% in the finerenone group compared to 0.4% of placebo patients7. The incidence the composite outcome of kidney failure occurred in 108 (2.9%) patients in the finerenone group compared to 139 (3.8%) in the placebo group (HR: 0.77; 95% CI: 0.60-0.99)7. This study showed a statistically significant benefit in cardiovascular events mostly due to a reduction in heart failure hospitalizations, but the benefit in kidney outcomes was not statistically significant. 

    Table 3 FIDELIO-DKD vs FIGARO-DKD Trials6,7

    Esaxerenone Trial on the Progression Diabetic Kidney Disease

    The ESAX-DN investigated the effects of esaxerenone on microalbuminuria defined as a UACR 45 to <300 mg/g creatinine in type 2 diabetes patients receiving RAS inhibitors. The primary outcome was UACR remission defined as a <30 mg/g creatinine and a  30% reduction from baseline on two consecutive occasions. The study included 455 type 2 diabetes patients with microalbuminuria who received esaxerenone 1.25 mg and titrated to 2.5 mg daily or placebo. After 52 weeks, the esaxerenone showed a significantly increased incidence of UACR remission (22%) compared to the placebo group (4%) with an absolute difference of 18% (95% CI: 12%-25%; P<0.001)8. The change in UACR from baseline was a 58% decrease in the esaxerenone group compared to 8% in the placebo group8. Furthermore there was a significant improvement in time to first remission and time to first UACR 300 mg/g creatinine. Hyperkalemia was observed in 9% in the esaxerenone group compared to 2% in the placebo group, but the events were asymptomatic8. Hyperkalemia was resolved after dosage reduction or treatment discontinuation. Esaxerenone in addition to a RAS inhibitor in patients with type 2 diabetes and microalbuminuria increased the incidence albuminuria returning to normal and reduced the progression of albuminuria to higher levels. However, esaxerenone has only been approved in Japan for the treatment of hypertension since January 2019.

    Other Agents with Cardiorenal Benefits

    Newer antihyperglycemic agents, which include SGLT2 inhibitors and GLP-1 receptor agonists have also been shown to have cardiorenal benefits. The SGLT-2 inhibitors that have shown cardiovascular benfit include empagliflozin and canagliflozin9. In addition, dapagliflozin and empagliflozin have shown a benefit in heart failure as well9. The SGLT-2 inhibitors that have shown renal benefits as the primary outcome include dapagliflozin and canagliflozin9. The GLP-1 receptor agonists that have shown cardiovascular benefit include albiglutide, dulaglutide, liraglutide and semaglutide (injection)9. The cardiovascular and renal benefits of these SGLT-2 inhibitors and GLP-1 receptor agonists have become the preferred agents used in type 2 diabetics.

    Table 4 Agents with Cardiorenal Benefits in Type 2 Diabetics

    Application to Practice

    The FIDELIO-DKD study showed renal benefits and the FIGARO-DKD study showed cardiovascular benefits with finerenone in type 2 diabetics with CKD in addition to guideline recommended RAS blockers, cardiovascular medications, and well-controlled hemoglobin A1c levels and blood pressure levels. In addition, both trials covered a wide spectrum of CKD stage 2 to stage 4 with moderately elevated albuminuria or stage 1 to stage 4 CKD with severely elevated albuminuria. The FIDELIO-DKD trial showed a statistically significant decrease from baseline of at least 40% in the eGFR, but the FIGARO-DKD trial showed a decrease that was not statistically significant difference as a secondary outcome. The FIGARO-DKD did show a significant cardiovascular benefit, but it was mostly due to a reduction in heart failure hospitalizations. There is a need for more data to determine whether combination therapy with finerenone will result in greater cardiorenal protection in patients with DKD. In addition, the ESAX-DN trial also showed that esaxerenone is beneficial in returning albuminuria to normal and reducing the progression of albuminuria in type 2 diabetes patients with microalbuminuria. However esaxerenone is not available in the United States. One of the major concerns with use of MRAs is the increase serum potassium, but finerenone has been showed to have a lower incidence of hyperkalemia compared to spironolactone making it a better option for patients with DKD. Dosing for finerenone is adjusted based on serum potassium levels which requires frequent potassium monitoring especially during initaition. Currently finerenone is only available under the brand name Kerendia with an estimated cash price of $680 for a 30 day supply. There are savings programs available for patients who qualify, but cost is still a major concern for this medication. Overall, finerenone is another agent that provides cardiorenal benefits for patients with DKD.

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    1. Al Dhaybi O, Bakris GL. Non-steroidal mineralocorticoid antagonists: Prospects for renoprotection in diabetic kidney disease. Diabetes Obes Metab. 2020;22(Suppl.1):69-76. doi:10.1111/dom.13983
    2. Kawanami D, Takashi Y, Muta Y, et al. Mineralocorticoid receptor antagonists in diabetic kidney disease. Front Pharmacol. 2021;12. doi:10.3389/fphar.2021.754239
    3. AHFS DI. Lexicomp. UpToDate, Inc,; 2021. Updated periodically. Accessed December 2021. http://online.lexi.com
    4. Bakris GL, Agarwal R, Chan JC, et al. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA. 2015;314(9):884–894. doi:10.1001/jama.2015.10081
    5. Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J. 2016;37(27):2105-2114. doi:10.1093/eurheartj/ehw132
    6. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229. doi:10.1056/nejmoa2025845
    7. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. August 2021. doi:10.1056/nejmoa2110956
    8. Ito S, Kashihara N, Shikata K, et al. Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN): Phase 3 Randomized Controlled Clinical Trial. Clin J Am Soc Nephrol. 2020;15(12):1715-1727. doi:10.2215/CJN.06870520
    9. Rangaswami J, Bhalla V, de Boer IH, Staruschenko A, Sharp JA, Singh RR, Lo KB, Tuttle K, Vaduganathan M, Ventura H, McCullough PA; on behalf of the American Heart Association Council on the Kidney in Cardiovascular Disease; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Lifestyle and Cardiometabolic Health. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association. Circulation. 2020;142:e265–e286. doi:10.1161/CIR.0000000000000920
  • 06 Apr 2022 11:03 AM | Anonymous

    By: Jordan Welch, Pharm.D. Candidate 2022

    Mentor: Sara Lingow, Pharm.D., BCACP

    What is a preceptor? Pharmacy preceptors are mentors and educators to pharmacy students and residents. They facilitate approximately 30% of the Doctor of Pharmacy curriculum for student pharmacists via practice-based learning.1 The Accreditation Council for Pharmacy Education (ACPE) states that preceptor development is mandatory, but currently does not outline a specific set of requirements for the “optimal” preceptor.2 The council encourages pharmacy schools to recruit preceptors who excel in the areas of collaboration and professionalism, as well as strategic plan development.These qualities are vital when teaching students how to behave and interact with an interprofessional team, while also sharpening the student’s focus to achieve both personal and professional deadlines. In order to ensure a successful experiential education program, preceptor development, education, and engagement should not only be emphasized, but prioritized. 3

    There are many challenges that experiential education offices face while implementing effective preceptor development.3 Content preparation and development poses a great obstacle to overcome with regard to the time it takes to create and deliver a program. Geographic location can become an issue if the content is being delivered in-person. The cost for continuing education (CE) accreditation can also serve as a drawback to preceptor development, as well as locating pharmacists that are interested in becoming a preceptor.3Additionally, it may be challenging for preceptors to dedicate time for additional development while also working full-time at their practice sites. This article aims to identify and provide potential solutions to the challenges of preceptor development through implementation of strategic, evidence-based programs.

    A 2015 qualitative analysis discovered that pharmacy schools continue to face challenges creating and implementing developmental programs for preceptors.4 Preceptor development varies amongst pharmacy schools, with many taking an individualized approach to address the topic. Preferences for learning and teaching styles when designing and implementing a preceptor development program can vary by generations.3 Therefore, it may be optimal to offer more than one learning approach, such as online modules and in-person training sessions. It is also important to consider preceptor background, certification(s), and experience when designing a program.5 By taking these factors into account, the method of preceptor development should be approached as multifaceted.

    A 2021 survey from the American Society of Health-System Pharmacists (ASHP) was conducted to identify the needs of a preceptor based on his or her background and previous experience.5 Of the 272 respondents, a majority of the preceptors reported the highest need for skill development in precepting, leadership, and communication. For precepting skills needed, preceptors requested specific skill development in setting expectations, assessing performance, developing rotation activities, and managing generational differences. For teaching skills needed, effective didactic education strategies and patient counseling were most requested. For communication skills needed, promoting critical thinking was the most requested, followed by resolving conflicts, communicating feedback, and presentation skills. For leadership skills needed, implementing quality improvement projects, general leadership skills, and time management were similarly requested.Results were independent of years spent precepting and did not favor one skill over another.5

    The survey found on-demand web-based programs for education delivery to be the preferred method amongst the preceptors. A high percentage of the survey respondents also appreciated a “tip of the week” email. Finally, the survey reported that 81% of preceptors prefer to use a survey as a tool to identify areas of self-improvement, followed by the strength’s finder. The learning styles inventory for preceptors and students’ assessment tool, student self-evaluation templates, and grading rubrics were also helpful instruments to utilize when identifying areas for improvement.5

    The Canadian Experiential Education Project for Pharmacy published articles in a three-part series to determine best practice recommendations for the Canadian colleges of pharmacy experiential education program.6,7,8 The project aimed to streamline a national preceptor development program (PDP) that could be adopted by pharmacy schools in Canada, which has not been achieved elsewhere. Twelve recommendations were constructed to guide successful development and implementation of a PDP.6 The national PDP focused on the primary principles: preceptor performance and competency indicators, preceptor engagement strategies, and quality improvement/assurance measures to ensure ongoing feedback.8

    The project proposes developing a web-based platform that allows rotation-specific training alongside continuous professional development for the preceptor.8 It is hypothesized that preceptors can interact with the online modules, once constructed, based on the twelve core recommendations.6,8 The electronic delivery platform will allow flexibility, sharing of resources and social networking between institutions and preceptors, and virtual collection of data that would provide insight for continuous adaptation. The final installation of the series was published in 2021, however, the website has yet to set a launch date.8

    Preceptor development is a complex topic that requires a multi-level approach. Though a national program may be helpful, the limitations such as increased workload, insufficient time, and accessibility may support college- or site-specific programs. These could be spearheaded by experiential education offices and/or compensating the cost of pre-made preceptor development modules by national pharmacy organizations. Development strategies would ideally be no-cost to preceptors, and CE credit could be offered as an incentive to complete the additional training. Many pharmacy schools across the nation offer free CE to their preceptors.10-12 The American Pharmacist Association (APhA) and ASHP also offer continuing education credit for a fee. Pharmacy schools have the opportunity to develop modules or offer CE certified modules as an incentive to become a preceptor for their students.13-14 Based on feedback form the ASHP survey, a web-based, asynchronous program would allow for virtual delivery at a time that is most convenient for the preceptor.5

    Approaching preceptor development from multiple angles by offering courses that encompass many skills is instrumental to both the program and preceptor success. Above all, it is important to assess the preceptor needs of each institution. Developing and adapting the training modules to fit the preferences of the preceptors is crucial for a successful experiential education program.9 Investment in educating the preceptors will not only be beneficial for the precepting pharmacist, but also ensure achievement of the ultimate goal – properly training students, the future of pharmacy.

    Preceptor Development Opportunities for Missouri Pharmacists:

    MSHP Preceptor Development Series: http://www.moshp.org/Professional-Development

    UHSP Preceptor Development: https://www.uhsp.edu/experiential/preceptors/development.html


    1. Vos SS, Trewet CB. A comprehensive approach to preceptor development. Am J Pharm Educ. 2012;76(3):47.
    2. Accreditation Standards and Guidelines for the Professional Program in Pharmacy Leading to the Doctor of Pharmacy Degree. Chicago, IL: Accreditation Council for Pharmacy Education;  http://www.acpe-accredit.org/standards/default.asp. Accessed February 12, 2022.
    3. Howard ML, Yuet WC, Isaacs AN. A Review of Development Initiatives for Pharmacy Student and Resident Preceptors. Am J Pharm Educ. 2020;84(10):ajpe7991.
    4. Danielson J, Craddick K, Eccles D, Kwasnik A, O'Sullivan TA. A qualitative analysis of common concerns about challenges facing pharmacy experiential education programs. Am J Pharm Educ. 2015;79(1):06.
    5. Enderby CY, Davis S, Sincak CA, Shaw B. Health-system pharmacist preceptor development and educational needs for accessible resources. Curr Pharm Teach Learn. 2021;13(9):1110-1120.
    6. Mulherin K, Walter S, Cox CD. National preceptor development program (PDP): Influential evidence and theory. The first of a 3-part series. Curr Pharm Teach Learn. 2018;10(3):255-266.
    7. Walter S, Mulherin K, Cox CD. A Preceptor competency framework for pharmacists. Part 2 of a 3-part series. Curr Pharm Teach Learn. 2018;10(3):402-410.
    8. Cox CD, Mulherin K, Walter S. National preceptor development program (PDP) prototype. The third of a 3-part series. Curr Pharm Teach Learn. 2018;10(3):298-306.
    9. Williams CR, Wolcott MD, Minshew LM, Bentley A, Bell L. A Qualitative Preceptor Development Needs Assessment to Inform Program Design and Effectiveness. Am J Pharm Educ. 2021;85(10):8450.
    10. Preceptors' corner. Purdue University College of Pharmacy Office of Continuing Education. https://ce.pharmacy.purdue.edu/preceptors-corner. Published 2022. Accessed February 18, 2022. 
    11. Online preceptor development modules. https://www.pharmacy.umaryland.edu/about/offices/elp/online-preceptor-development modules/. Published 2022. Accessed February 18, 2022. 
    12. Preceptors. https://www.uhsp.edu/experiential/preceptors/index.html. Accessed February 22, 2022. 
    13. Preceptor toolkit. ASHP. https://www.ashp.org/pharmacy-practice/resource-centers/preceptor-toolkit?loginreturnUrl=SSOCheckOnly. Published 2022. Accessed February 18, 2022. 
    14. APhA advanced preceptor training. American Pharmacists Association. https://www.pharmacist.com/Education/eLearning/Advanced-Training/Advanced-Preceptor. Published 2021. Accessed February 18, 2022. 
  • 06 Apr 2022 10:51 AM | Anonymous

    The MSHP R&E Foundation continues to offer our new Resident Ground Rounds series and our Preceptor Development Series. 

    Information for the Resident Ground Rounds Series can be found here:


    This series is expected to run routinely (approximately every other week) for the next several months.  We are excited to bring this offering forward to provide a vehicle for residents within the state to continue to hone their presentations skills as well as share new information with other pharmacy practitioners (pharmacists, technicians, and students) throughout the state.  These sessions are available for CE through the Missouri State Board of Pharmacy.

    The latest session of our Preceptor Development Series took place on March 3rd titled Enhancing Layered Learning Experiences for Preceptors and Learners.  This event was well attended and sparked excellent discussion amongst the panel and participants.

    Spring Meeting poster and award submissions have been received and are being reviewed.  All submitted posters were accepted for presentation.  Award winners will be announced in the coming weeks.

    Regarding the Spring Meeting if you, your organization, or other colleagues want to assist in the R&E Foundation fundraising efforts, we will once again be hosting a virtual auction and will be accepting donations of gift baskets from groups across the state.  Of course, if you cannot sponsor a basket, we encourage you to bid on the baskets throughout the meeting later in the year!

    Please check out the recently updated R&E Website at https://www.moshp.org/foundation which includes the R&E Board, updated award winners, and award archives!

    Have a great spring and see you virtually during the spring meeting.

    Respectfully submitted,

    Tony Huke, Pharm.D., BCPS

    MSHP R&E Executive Director

  • 06 Apr 2022 10:26 AM | Anonymous

    By: Annie Kliewer, PharmD, BCPS

    Legislative advocacy can be an intimidating endeavor. It requires that you know what bills have been introduced to the legislature and if they are important for your profession. Then, it is important to know what those pieces of legislation say and what this means for your profession. The bills up for discussion during the 2022 Missouri Legislative Session affect all of us. They affect our profession as pharmacists and the level of care that can be provided to our patients. The following are the pharmacy/healthcare related bills of MSHP, MHA and MPA’s advocacy focus for this 2022 Legislative session:

    HB 2305
    Creates provisions relating to insurance coverage of pharmacy services
    Sponsored by: Representative Dale Wright, represents portions of St. Francois, Ste. Genevieve, and Perry counties

    • Amends chapter 376 by adding three sections pertaining to insurance coverage of pharmacy services
    • Summary: A health carrier, PBM or any of their agents or affiliates shall not impose any penalty on participating providers, covered persons, or any pharmacy, including hospital pharmacies, for dispensing medically necessary clinician-administered drugs regardless of if the participating provider obtains the drugs from a source that is in network
    • What this means: Previously patients had 2 options when it came to medications administered by their provider in an office or clinic if they wanted it to be covered by insurance.
    1. Patients would have to work with their provider to ensure that the medication was obtained through one of the entity’s covered by their insurance
    2. The patient would have to go pick up a medication from a covered entity and take it to the providers’ office for the provider to then administer it.
    This bill would eliminate that barrier, ensuring that a health carrier, PBM or one of their agents cannot penalize or provide less reimbursement to a provider, patient or pharmacy based on whether the clinician-administered medication came from one of the carrier’s covered entities.

    SB 921 and HB 1677
    Enacts provisions relating to payments for prescription drugsSponsored by: Senator Bill White, represents Jasper, Dade and Newton counties and Representative Dale Wright, represents portions of St. Francois, Ste. Genevieve, and Perry counties

    • Repeals sections 338.015, 376.387, and 376.388, and to enact in their place five new sections relating to payments for prescription drugs
    • Summary:
    1. Pharmacy benefits managers (PBM) utilized by the Missouri consolidated health care plan shall file reports with the plan for the immediately preceding year contain information regarding:
      • The aggregate dollar amount of all rebates the PBM collected from pharmaceutical manufacturers that manufactured outpatient prescription drugs
      • The aggregate dollar amount of all rebates, excluding any portion of the rebates received by the plan, concerning drug formularies that the PBM collected from pharmaceutical manufacturers that manufactured outpatient prescription drugs.

      That were covered by the plan during that calendar year and were attributed to the utilization of such drugs during said calendar year.

    2. The plan shall establish a form for the PBM to report the information required under the above-mentioned section 
    3. No documents, materials or other information submitted to the plan under the aforementioned section shall be subject to disclosure under chapter 610, except ones that are required under subsection 4 of this section.
    4. Starting July 1, 2024, and annually thereafter, the plan shall submit a report to the standing committees of the general assembly having jurisdiction of health insurance matters containing the information stated above in section 1, subsection a from the preceding year. In addition, the plan shall prepare a report for the same time period, describing rebate practices of the plan and its PBM.
    5. The plan may impose a penalty of no more than $7,500 on its PBM for each violation of the sections to follow. 
      • What this means: PBMs will be required to provide information regarding their MAC prices for medications, rebates obtained from manufacturers and business practices in relation to individual pharmacies. A PBM cannot pay a pharmacy less than the cost to purchase a drug or reimburse less for pharmacist services than they would for a PBM affiliate providing the same service. If violations of this bill are found then the PBMs will be held responsible by paying a violation fee.
      • See the bills in their entirety here: https://www.senate.mo.gov/22info/pdf-bill/intro/SB921.pdf and https://house.mo.gov/billtracking/bills221/hlrbillspdf/4311H.02C.pdf

    SB 1126 and HB2452
    Modifies provisions relating to the administration of medications by pharmacists
    Sponsored by: Senator Holly Thompson Rehder, represents Bollinger, Cape Girardeau, Madison, Perry, Scott, and Wayne counties and Representative Bennie Cook, represents Texas, Phelps, Pulaski and Howell Counties.

    • Repeals sections 338.010 and 338.165, and enacts in lieu thereof three new sections relating to the administration of medications by pharmacists
    • Summary: 
      • This bill repeals language defining the practice of pharmacy as including the administration of specific vaccines for specific patients by written physician protocol and adds language defining the practice of pharmacy as including the ordering and administering of US FDA-approved or authorized vaccines to persons at least 7 years of age or the CDC-approved age, whichever is older.
      • This act permits a pharmacist with a certificate of medication therapeutic plan authority to provider medication therapy services pursuant to a statewide order issued by the Department of Health and Senior Services. Medication therapy services may be provided by a pharmacist for patients of a hospital pursuant to a statewide standing order issued by the Department or pursuant to a physician protocol.
    • What this means: Pharmacists authority to order and administer vaccinations will not be limited to certain kinds of vaccines and will be pursuant to rules promulgated by the Board of Pharmacy and Board of Registration for the Healing Arts or rules promulgated under a state of emergency instead of requiring a written physician protocol for specific vaccinations.
    • See the bills in their entirety here: https://www.senate.mo.gov/22info/pdf-bill/intro/SB1126.pdf and https://house.mo.gov/billtracking/bills221/hlrbillspdf/5157H.02C.pdf
  • 19 Jan 2022 12:59 PM | Anonymous

    New Treatment Options for Multidrug-Resistant Pseudomonas aeruginosa
    By: Will Miller, PharmD, MBA; PGY2 Infectious Diseases Pharmacy Resident

    Mentor: Tamara Krekel, PharmD, BCPS, BCIDP; Infectious Diseases Clinical Pharmacy Specialist

    Program Number:  2021-12-05
    Approved Dates:   February 1, 2022-August 1, 2022
    Approved Contact Hours:  One Hour(s) (1) CE(s) per session


    1. Recall the most common resistance mechanisms of Pseudomonas aeruginosa.
    2. Identify the place in therapy for new agents used in the treatment of multidrug-resistant Pseudomonas aeruginosa.
    3. Discuss treatment recommendations for multidrug-resistant Pseudomonas aeruginosa in the “Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa)”.


    Pseudomonas aeruginosa is an aerobic Gram-negative bacillus that is found commonly in the environment and is capable of causing severe infections, particularly in hospitalized patients. As P. aeruginosa thrives in moist environments, it is often associated with pneumonia, catheter-related infections, and surgical site infections. It is capable of extensive colonization and represents a significant challenge in healthcare due to its intrinsic and acquired resistance to many common antibiotics. As a result, the Centers for Disease Control and Prevention (CDC) has described carbapenem-resistant P. aeruginosa as a serious threat, with 32,600 estimated cases and 2,700 estimated deaths in hospitalized patients in 2017. Despite not getting the highest level of classification as an urgent threat, the designation as a serious threat indicates that increasing incidence, decreased antimicrobial efficacy, and significant clinical and economic impact are anticipated, thus greater attention and action are needed.

    P. aeruginosa is intrinsically resistant to many β-lactams and cephalosporins. Antimicrobials that are usually active against P. aeruginosa, and may be considered as first-line agents, include aztreonam, cefepime, ceftazidime, ciprofloxacin, imipenem/cilastatin, levofloxacin, meropenem, and piperacillin/tazobactam. Local antibiograms should be consulted to determine the preferred agent(s) at each institution.


    Multidrug-resistant (MDR) P. aeruginosa is defined as nonsusceptibility to at least three classes of antibiotics (penicillins, cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems) to which susceptibility is generally expected.3 However, some MDR P. aeruginosa isolates are resistant to all of these antibiotics (known as difficult-to-treat resistance “DTR” P. aeruginosa). P. aeruginosa can acquire resistance through a combination of mechanisms including AmpC β-lactamases, carbapenemases, porin loss, and efflux pumps.

    AmpC β-lactamases are ubiquitously produced by P. aeruginosa and are responsible for the majority of its antibiotic resistance. These β-lactamases do not typically confer resistance to antipseudomonal penicillins, cephalosporins, or carbapenems; this is accomplished with the addition of a carbapenemase, porin loss mutation, and/or efflux pumps.4 Carbapenemases can include Klebsiella pneumoniae carbapenemases (KPCs), metallo-β-lactamases (MBLs: NDM, IMP, VIM), and OXA-48. These confer resistance to all β-lactams but may be overcome with the addition of a β-lactamase inhibitor such as avibactam (exception: MBLs). Porin loss mutations, specifically OprD, confer resistance to carbapenems by preventing them from entering the periplasmic space of P. aeruginosa. As this is largely specific for carbapenems, antipseudomonal cephalosporins may be unaffected by this mutation.5 Perhaps the most unpredictable resistance mechanisms of P. aeruginosa are efflux pumps. There are a variety of efflux pumps that have unique substrates and cause certain antibiotics to be exported from the cell. Through a combination of one or more of these resistance mechanisms, P. aeruginosa can develop resistance to many or all of the traditionally used antibiotics.

    New Treatment Options for MDR Pseudomonas aeruginosa

    Prior to 2014, the only available treatment options for DTR P. aeruginosa were polymyxin B/colistin and aminoglycoside-based regimens. As these agents have severe toxicities, there was a need for new antibiotics to combat DTR P. aeruginosa that have fewer toxicities. Since 2014, multiple new agents have been developed to meet this need. These include ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol. Of note, meropenem/vaborbactam has no added activity against P. aeruginosa as compared to meropenem alone and should not be utilized against isolates that are resistant to meropenem.


    Ceftolozane/tazobactam is a combination advanced-generation cephalosporin/β-lactamase inhibitor that is known for its potent activity against P. aeruginosa. Ceftolozane/tazobactam is stable in the presence of most extended-spectrum β-lactamases (ESBLs), AmpC cephalosporinases, OprD porin loss mutations, and efflux pumps. It is currently FDA-approved for complicated intra-abdominal infections (cIAI) in combination with metronidazole, complicated urinary tract infections (cUTI) including pyelonephritis, and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).7

    Ceftolozane/tazobactam is typically dosed at 1.5 g IV every 8 hours (exception: 3 g IV every 8 hours for treatment of HABP/VABP) and is renally adjusted for patients with CrCl < 50 mL/min.8 Ceftolozane has a half-life of 2-3 hours and is primarily eliminated in the urine as unchanged drug.9 It is generally well-tolerated but may be associated with constipation, headache, and pyrexia.

    A retrospective cohort study comparing 200 patients with resistant P. aeruginosa highlighted the potential benefit of ceftolozane/tazobactam over traditional polymyxin or aminoglycoside-based therapy.10 Of the patients included in this analysis, 69% were in the intensive care unit, 63% were mechanically ventilated, and 42% were in severe sepsis or septic shock at enrollment. 65% of patients were treated for HABP/VABP, 14% for cUTI, and 7% of patients for a bloodstream infection. The authors conducted a multivariate logistic regression looking at the impact of ceftolozane/tazobactam on clinical cure (defined as the resolution of the signs and symptoms of infection with the initial study regimen without the need for therapy modification due to clinical failure or toxicity), acute kidney injury (AKI), and in-hospital mortality. They found that ceftolozane/tazobactam was independently associated with clinical cure [adjusted odds ratio (aOR) 2.63; 95% confidence interval (CI) 1.31–5.30] and was protective against AKI (aOR 0.08; 95% CI 0.03–0.22), with no difference in in-hospital mortality. This was associated with a number needed to treat of five for clinical cure with ceftolozane/tazobactam and a number needed to harm of four for AKI with a polymyxin or aminoglycoside-based regimen, indicating substantial benefits of ceftolozane/tazobactam.


    Ceftazidime/avibactam is a combination third-generation cephalosporin/β-lactamase inhibitor that is active against many carbapenemases (exception: MBLs) and is not stable to porin loss mutations or efflux pumps. It is currently FDA-approved for cIAI in combination with metronidazole, cUTI including pyelonephritis, and HABP/VABP.11

    Ceftazidime/avibactam is typically dosed at 2.5 g IV every 8 hours and is renally adjusted for patients with CrCl < 50 mL/min. It has a half-life of 3-4 hours and is primarily excreted in the urine as unchanged drug. Adverse reactions associated with ceftazidime/avibactam include CNS effects (e.g., seizures, coma, anxiety) and constipation.12

    Clinical trial data for ceftazidime/avibactam in the treatment of MDR P. aeruginosa became available in a 2018 pooled data subgroup analysis of the phase III clinical trial data.13 Of the 95 patients that were included, 56 had received ceftazidime/avibactam and 39 had received a carbapenem comparator. The majority of patients were being treated for a cUTI, with fewer patients being treated for HABP/VABP or cIAI. In this analysis, microbiological response was assessed (defined as absence of causative organism or presumed eradication as determined by clinical cure without repeat cultures) and found a 57.1% microbiological response rate with ceftazidime/avibactam and a 53.8% microbiological response rate with carbapenems. Clinical efficacy was assessed as well but was not specifically reported for the cohort of patients with MDR P. aeruginosa infections. Therefore, the authors concluded that ceftazidime/avibactam demonstrated similar clinical and microbiological efficacy to carbapenems against MDR P. aeruginosa.


    Imipenem/cilastatin/relebactam is a combination carbapenem/β-lactamase inhibitor that has activity against some carbapenemases (KPCs) and also often retains activity in the presence of efflux pumps. However, it not active against MBLs or in the presence of porin loss mutations. It is currently FDA-approved for cIAI in patients who have limited or no alternative treatment options, cUTI including pyelonephritis in patients who have limited or no treatment options, and HABP/VABP.14

    Imipenem/cilastatin/relebactam is typically dosed at 1.25 g IV every 6 hours and is renally adjusted for patients with CrCl < 90 mL/min. It has a half-life of 1 hour and is excreted in the urine as mostly unchanged drug. Adverse reactions associated with imipenem/cilastatin/relebactam include nausea, diarrhea, headache, and CNS reactions including seizures.15

    To assess the utility of imipenem/cilastatin/relebactam in treating MDR bacterial infections, investigators conducted the RESTORE-IMI 1 trial, a multicenter, randomized, double-blind trial that compared imipenem/cilastatin/relebactam to colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections.16 Thirty-one hospitalized patients with HABP/VABP, cIAI, or cUTI were assigned 2:1 to imipenem/cilastatin/relebactam versus colistin plus imipenem. 77% of patients had P. aeruginosa as their qualifying pathogen. The primary endpoint of this study was favorable overall response (HABP/VABP, 28-day all-cause mortality; cIAI, day 28 clinical response; cUTI, composite clinical and microbiologic response at the end-of-therapy visit) and secondary endpoints included clinical response, 28-day all-cause mortality, and treatment-emergent toxicity. For the primary endpoint, 71% of patients who received imipenem/cilastatin/relebactam achieved a favorable overall response, compared to 70% of patients who received a combination of colistin and imipenem (90% CI -27.5%-21.4%), indicating no difference between groups. However, imipenem/cilastatin/relebactam was associated with a significantly higher favorable clinical response [71% v. 40% (90% CI 1.3%-51.5%)], numerically lower 28-day all-cause mortality [10% v. 30% (90% CI -46.4%-6.7%)], and significantly less treatment-emergent nephrotoxicity (10% v. 56%, p=0.002). As a result, the authors concluded that imipenem/cilastatin/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections.


    Cefiderocol is a novel siderophore cephalosporin with activity against MDR P. aeruginosa, including most isolates with carbapenemases (including KPCs, MBLs, and OXA-48), porin loss mutations, and efflux pumps. Cefiderocol has a unique mechanism in that it binds to free iron and is actively transported into the periplasmic space of Gram-negative bacteria through iron transport channels. Once gaining entry into the cell, it acts like other β-lactams to inhibit bacterial cell wall synthesis.17

    Cefiderocol is FDA-approved for the treatment of cUTI, including pyelonephritis, and HABP/VABP. It is typically dosed at 2 g IV every 8 hours and is renally adjusted for patients with CrCl < 60 mL/min. Of note, cefiderocol is also dose-escalated to 2 g IV every 6 hours for patients with CrCl > 120 mL/min. It has a half-life of 2-3 hours and is primarily excreted in the urine as unchanged drug.18 Listed adverse reactions and warnings include neurotoxicity and increased risk of mortality as compared to best available therapy in critically ill patients with carbapenem-resistant Gram-negative bacterial infections.

    The CREDIBLE-CR study, a randomized, open-label, phase III study, compared cefiderocol to best available therapy for the treatment of serious carbapenem-resistant Gram-negative infections.19 Of the 118 patients who were included in the analysis, 22 of them had P. aeruginosa as the causative pathogen, 12 of whom were assigned to the cefiderocol arm and 10 of whom were assigned to the best available therapy arm. Best-available therapy was left to the discretion of the provider and most often included combination therapy (71%) and/or colistin-based treatment (66%). Of patients with P. aeruginosa infection, 18% of patients receiving cefiderocol and 18% receiving best-available therapy met the outcome of all-cause mortality at 28 days following the end of therapy.

    While the CREDIBLE-CR study included a subgroup of patients with carbapenem-resistant P. aeruginosa infection, the study as a whole included patients with carbapenem-resistant Acinetobacter spp (n=59), Klebsiella pneumoniae (n=43), P. aeruginosa (n=22), Escherichia coli (n=4), or Stenotrophomonas maltophilia (n=3). 59% of patients were treated for nosocomial pneumonia, 31% for bacteremia or sepsis, and 24% for cUTI. The primary endpoint differed by indication (nosocomial pneumonia or bacteremia/sepsis, clinical cure at day 7; cUTI, microbiological eradication at test of cure visit). Overall, 66% of patients receiving cefiderocol achieved clinical cure versus 58% of patients receiving best available therapy. Comparative efficacy was seen within the nosocomial pneumonia population (50% cefiderocol v. 53% best available therapy) and bacteremia/sepsis population (43% in each group), with higher rates of clinical cure with cefiderocol in the cUTI group (53% v. 20%). As such, the study concluded that cefiderocol had similar clinical and microbiological efficacy to best available therapy in infections caused by carbapenem-resistant Gram-negative bacteria.

    The CREDIBLE-CR trial also reported other results that may have important clinical implications. First, cefiderocol was associated with substantially higher cure rates as compared to best available therapy in isolates producing MBLs (75% v. 29%), suggesting that cefiderocol may be a good treatment option for organisms known to harbor this resistance mechanism. Second, more patients in the cefiderocol arm died by the end of the study (34% v. 18%), which led to the mortality warning on the package insert of cefiderocol. However, it is important to note that this difference was mostly attributed to patients with Acinetobacter as the causative pathogen (50% v. 18%). With all other included organisms, including P. aeruginosa, there was no difference in mortality.

    Treatment Recommendations

    As part of an effort to identify the place in therapy of each of these new agents and to improve the outcomes of patients with MDR Gram-negative infections, Infectious Diseases Society of America (IDSA) recently published a living guidance document titled ““Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa)”, that includes recommendations for treating DTR P. aeruginosa. These recommendations account for the source of infection and assume that in vitro activity of the antibiotics has been demonstrated.3

    Treatment of MDR and DTR P. aeruginosa infections should be guided by susceptibility testing and first-line treatment options should be utilized as appropriate. In isolates that are non-susceptible to all first-line treatment options, utilization of ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, or cefiderocol is appropriate. However, susceptibility of these agents must also be confirmed.

    When susceptibility testing indicates the activity of multiple agents against DTR P. aeruginosa, there are several areas to consider when selecting an agent, some of which include antibiotic stewardship, duration of therapy, and presence of a mixed infection. From a stewardship perspective, ceftolozane/tazobactam may be an ideal option as it has increased activity against P. aeruginosa and does not have activity against most other MDR organisms, allowing agents that have this extra activity to be spared for that purpose. Duration of therapy considerations may influence agent selection as it relates to patient tolerability, affordability, and ability to utilize outpatient parenteral antibiotic therapy. Lastly, in patients with mixed infections, agents with broader coverage such as ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol may allow the consolidation of therapy and decreased antibiotic use.


    The treatment of P. aeruginosa is increasingly difficult due to the emergence of MDR and DTR isolates. However, newly developed agents including ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol provide new treatment options that may be more effective and better tolerated than previous agents. Therefore, it is imperative that pharmacists have a solid understanding of these agents in order to employ them in appropriate clinical scenarios.

    CE Quiz


    1. Centers for Disease Control and Prevention (U.S.). Antibiotic Resistance Threats in the United States, 2019. Centers for Disease Control and Prevention (U.S.); 2019.
    2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 31st ed. CLSI supplement M100. Clinical and Laboratory Standards Institute; 2021.
    3. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin Infect Dis. 2021;72(7):e169-e183.
    4. Mo Y, Lorenzo M, Farghaly S, Kaur K, Housman ST. What’s new in the treatment of multidrug-resistant gram-negative infections? Diagn Microbiol Infect Dis. 2019;93(2):171-181.
    5. Li H, Luo YF, Williams BJ, Blackwell TS, Xie CM. Structure and function of OprD protein in Pseudomonas aeruginosa: from antibiotic resistance to novel therapies. Int J Med Microbiol. 2012;302(2):63-68.
    6. Young K, Painter RE, Raghoobar SL, et al. In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa. BMC Microbiol. 2019;19(1):150.
    7. Merck.com. Zerbaxa package insert. Accessed November 15, 2021. https://www.merck.com/product/usa/pi_circulars/z/zerbaxa/zerbaxa_pi.pdf
    8. Xiao AJ, Miller BW, Huntington JA, Nicolau DP. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol. 2016;56(1):56-66.
    9. Lizza BD, Betthauser KD, Ritchie DJ, Micek ST, Kollef MH. New perspectives on antimicrobial agents: Ceftolozane-tazobactam. Antimicrob Agents Chemother. 2021;65(7):e0231820.
    10. Pogue JM, Kaye KS, Veve MP, et al. Ceftolozane/tazobactam vs polymyxin or aminoglycoside-based regimens for the treatment of drug-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2020;71(2):304-310.
    11. Allergan.com. Avycaz package insert. Accessed November 15, 2021. https://media.allergan.com/actavis/actavis/media/allergan-pdf-documents/product-prescribing/Avycaz_Final_PI_CBE-0_10_2019.pdf
    12. van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations. Clin Infect Dis. 2016;63(2):234-241.
    13. Stone GG, Newell P, Gasink LB, et al. Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: pooled data from the ceftazidime/avibactam Phase III clinical trial programme. J Antimicrob Chemother. 2018;73(9):2519-2523.
    14. Merck.com. Recarbrio package insert. Accessed November 15, 2021. https://www.merck.com/product/usa/pi_circulars/z/zerbaxa/zerbaxa_pi.pdf
    15. Mansour H, Ouweini AEL, Chahine EB, Karaoui LR. Imipenem/cilastatin/relebactam: A new carbapenem β-lactamase inhibitor combination. Am J Health Syst Pharm. 2021;78(8):674-683. doi:10.1093/ajhp/zxab012
    16. Motsch J, Murta de Oliveira C, Stus V, et al. RESTORE-IMI 1: A multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis. 2020;70(9):1799-1808.
    17. Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs. 2019;79(3):271-289.
    18. Shionogi.com. Accessed November 19, 2021. https://www.shionogi.com/content/dam/shionogi/si/products/pdf/fetroja.pdf
    19. Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021;21(2):226-240.
    20. Tsuji BT, Pogue JM, Zavascki AP, et al. International consensus guidelines for the optimal use of the polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP): Endorsed by the American college of clinical pharmacy (ACCP), European society of clinical microbiology and infectious diseases (ESCMID), infectious D. Pharmacotherapy. 2019;39(1):10-39.
    Disclaimer: T.K. reports being on the speakers’ bureau for Merck (manufacturers of ceftolozane/tazobactam and imipenem/cilastatin/relebactam) and AbbVie (manufacturers of ceftazidime/avibactam) and has received consulting fees from Shionogi (manufacturers of cefiderocol).
  • 19 Jan 2022 5:34 AM | Anonymous

    By: Naphtali Eke, PharmD

    Mentor: Justinne Guyton, PharmD, BCACP, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis/St. Louis County Department of Public Health


    According to the National Diabetes Statistics Report, published by the Centers for Disease Control and Prevention, approximately 34.2 million people (10.5% of the population in the U.S.) have diabetes, with 7.3 million of those people who continue to go undiagnosed.1 Blood glucose monitoring (BGM) allows patients to measure their glucose from a blood drop, commonly through a fingerstick. However, continuous glucose monitoring (CGM) allows patients to measure their glucose in the interstitial fluid, in a continuous manner providing results every 5 minutes. Interstitial glucose levels correlate well with blood glucose levels, although there may be a delay if the glucose levels change quickly.2 Capillary blood glucose measurement via the fingerstick method in comparison to interstitial fluid measurements via CGMs has shown to provide more accuracy during periods of rapidly changing glucose levels such as hypoglycemia or right after a meal or dose of bolus insulin.3 Despite this, use of CGMs provide a wide variety of benefits, such as no fingerstick, alarms during periods of trending hyper or hypoglycemia, 24-hour monitoring, increased quality of life, and the ability to share results with primary care providers and family. However, they do come with a few well known disadvantages such as increased costs, reimbursement from Medicare mainly for insulin-dependent type-1 diabetics, and the inconvenience of having to constantly wear a device for benefit.4 The role of CGMs has been well established in type 1 diabetes, and more recent data from a meta-analysis in patients with type 2 diabetes also found that the use of CGMs compared to BGM resulted in improvement in hemoglobin A1c, improved ability to detect hypoglycemic events and nocturnal hypoglycemia, decreased time spent in hyperglycemia, and improved patient satisfaction.5 The purpose of this review is to compare and contrast the different features of the most common CGM systems on the U.S. market today: Dexcom G6, Freestyle Libre 2, and Medtronic’s Guardian Sensor.

    Dexcom G66

    The G6 is Dexcom’s latest generation CGM system, the Dexcom G6 is one of the most popular and commonly used devices in the U.S. It consists of a sensor, transmitter, and a display device, which can either be a receiver, compatible smartphone or watch. Compatible with these devices through their “Dexcom G6” and “Dexcom CLARITY” apps, it automatically sends real-time glucose readings every 5 minutes and is considered a real-time CGM (rtCGM). A new sensor is applied to the skin every 10 days. Another feature is that it is factory calibrated, which means the patient does not have to calibrate the device, or obtain a confirmatory blood glucose reading to make clinical decisions, although the option to calibrate is still available if the patient were to need it. The system can be used alone, or in conjunction with the Tandem t:slim X2 or the Tubeless Omnipod insulin pump. It is FDA-approved for ages 2 and up, which is the lowest approved age out of the three. The Dexcom G6 is covered by Medicare for patients with type 1 or 2 diabetes on intensive insulin therapy through approved Durable Medical Equipment (DME) suppliers. Of note, Missouri Medicaid does cover this device for patients with type 1 diabetes based on certain approval criteria. 

    Freestyle Libre 27

    The Freestyle Libre 2 system is one of the latest systems from Abbott, and it consists of a sensor and a reader. It works by holding the reader over the sensor each time a reading is desired, and is considered an intermittent scanned CGM (is-CGM), with readings as frequently as every 1 minute. Patients should scan at least every 8 hours for a full dataset. A new sensor is applied every 14 days and is a much simpler process in comparison to other systems. Just like the Dexcom G6, calibration is not required and the readings can be seen with a phone app rather than the reader. Also similar to Dexcom G6, the Freestyle Libre is covered by Medicare for patients with type 1 or 2 diabetes on intensive insulin therapy through DME suppliers. A great benefit to using this sensor is that despite whether a patient has insurance or not, the cost is priced 70% lower than the list price of other CGM systems. The FDA has approved its use in patients ages 4 and up.

    Medtronic Guardian 38

    A lesser-known option, Guardian 3, from Medtronic is similar to the Dexcom G6 in that it is a rtCGM that will transmit glucose readings to either a compatible smartphone or integrated insulin pump. It is composed of just the sensor and a rechargeable transmitter, using a smartphone as a reader. A disadvantage of this sensor is that it must be calibrated twice daily via BGM to maintain accuracy, an unfavorable characteristic for patients who are trying to avoid doing so in the first place. Its sensor use has the least durability, lasting 7 days before needing to be changed. Medicare does not provide coverage for Medtronic CGM supplies, so patients can either enroll in their CGM Medicare Discount Access Program, use their secondary insurance, or pay the out-of-pocket cost. The FDA has approved its use in patients age 14-75 years.


    There are many ways to compare these systems. The Medtronic seems to be the least favored due to its need for daily calibration, and lack of Medicare coverage. It also has the shortest sensor lifespan. Changing a sensor may not be bothersome to some patients, but can be an inconvenience to others. The Freestyle Libre 2 has the longest sensor lifespan, the shortest sensor warm-up time, and is the lowest cost option for uninsured patients. The sensor warm-up time is the time it takes for a newly inserted sensor to acclimatize to the body before a patient is able to obtain accurate readings. A couple of disadvantages include no alerts when the glucose levels are trending to abnormal ranges (only notifies when it is already out of range), and no integration with an insulin pump. The patient would have to scan the sensor at least every 8 hours with either the reader or smartphone to obtain the current levels. This can be an inconvenience for patients who would prefer to be more discrete. Lastly, the Dexcom G6 has the benefit of real-time monitoring on an Apple Watch, unique from the others. Another consideration between meters is the potential for drug interactions (e.g. uric acid, galactose, xylose, acetaminophen, L-DOPA, and ascorbic acid) that can affect readings and vary by monitor.2 Patient’s should be instructed to check the device manual when receiving a CGM.


    With the known challenges of the fingerstick method, it is anticipated that the desire for CGMs will continue to be on the rise. It is important for pharmacists to be knowledgeable about the variations in these devices to provide information to patients and providers.  This brief review of the most commonly used CGM systems highlighted some of the key considerations patients and providers may inquire about when selecting a CGM. Overall, when it comes to which sensor is the best, it may simply come to patient or provider preference, insulin pump compatibility, and cost. With new models of these sensors in development, such as the Guardian 4 and the Dexcom G7, additional and improved features may affect the patients’ decision-making process.


    1. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. [cited 2021 Dec 27]. Available from: https://www.cdc.gov/diabetes/data/statistics-report/index.html
    2. American Diabetes Association Professional Practice Committee. 7. Diabetes Technology: Standards of Medical Care in Diabetes – 2022. Diabetes Care. 2022 Jan 1;45(Supplement 1): S97-112.
    3. Cengiz E, Tamborlane WV. A tale of two compartments: interstitial versus blood glucose monitoring. Diabetes Technol Ther. 2009 Jun;11 Suppl 1(Suppl 1):S11-6.
    4. Hermanides J, Phillip M, DeVries JH. Current application of continuous glucose monitoring in the treatment of diabetes: pros and cons. Diabetes Care. 2011 May;34 Suppl 2(Suppl 2):S197-201.
    5. Janapala RN, Jayaraj JS, Fathima N, Kashif T, Usman N, Dasari A, Jahan N, Sachmechi I. Continuous Glucose Monitoring Versus Self-monitoring of Blood Glucose in Type 2 Diabetes Mellitus: A Systematic Review with Meta-analysis. Cureus. 2019 Sep 12;11(9):e5634.
    6. Dexcom. Descom G6 continuous glucose monitoring system. [cited 2021 Dec 27]. Available from: www.dexcom.com.
    7. Abbott. Freestyle Libre CGMs. [cited 2021 Dec 27]. Available from: www.freestyle.abbott/us-en/myfreestyle.html.
    8. Medtronic. Guardian 3 Sensor. [cited 2021 Dec 27]. Available from www.medtronic.com
    9. Diabetesnet. Comparison of current continuous glucose monitors (CGMs). [cited 2021 Dec 27]. Available from: https://www.diabetesnet.com/diabetes-technology/meters-monitors/compare-current-monitors/.
  • 19 Jan 2022 5:28 AM | Anonymous

    By Meleah Collins, PharmD. Candidate 2022, Xavier University College of Pharmacy

    Mentor: Christine Kelso, PharmD, BCPS, AE-C, Barnes-Jewish Hospital, St. Louis

    Sodium-glucose-co-transporter-2 (SGLT-2) inhibitors are oral agents that were originally approved to treat type-2 diabetes mellitus (T2DM), working by inhibiting renal glucose absorption. Their integration into clinical practice has continued to rise and approval has been expanded to patients without T2DM due to cardiovascular and renal benefits associated with some of these agents, as well as advantages of weight reduction, low hypoglycemia risk, and decreases in blood pressure. Despite its relative rarity in phase 3 clinical trials, 20 cases of diabetic ketoacidosis (DKA) associated with SGLT-2 inhibitors have been reported in both type 1 and type 2 diabetes, subsequently resulting in the U.S. Food and Drug Administration (FDA) publishing a formal warning regarding this potential complication in May of 20151.

    Euglycemic Diabetic Ketoacidosis

    Euglycemic DKA (EDKA) is characterized by euglycemia (BG <250 mg/dL) in the presence of severe metabolic acidosis and ketonemia.2 DKA is one of the more severe and life threatening complications of diabetes mellitus, and in the setting of euglycemia, delayed diagnosis may lead to poorer outcomes.3


    While EDKA can have many causes, the overall mechanism stems from a state of starvation that is usually a carbohydrate deficit. This results in a decrease in serum insulin and an increase in counter-regulatory hormones.4 As the insulin to glucagon ratio increases, lipolysis and free fatty acids also increase, resulting in ketoacidosis.

    SGLT-2 inhibitors enhance excretion and block reabsorption of filtered glucose from the proximal convoluted tubule.5 The loss of urinary glucose can create carbohydrate starvation while this class of agents simultaneously stimulates the direct release of glucagon from the pancreas.5 Additionally, SGLT-2 inhibitors suppress the kidney’s ability to remove beta-hydroxybutyrate and acetoacetate.2 Once an anion gap is present, it triggers respiratory compensation, accompanied by dyspnea, nausea, vomiting, and anorexia, further worsening DKA.

    Risk Factors

    Any condition that involves or mimics being in a fasted state such as anorexia, alcohol use disorder, or being on a ketogenic diet, can put one at risk for EDKA.6 Other triggers include pancreatitis, surgery, infection, cirrhosis, pregnancy, and use of an insulin pump. In addition, there may be evidence that patients with type 1 diabetes mellitus (T1DM) are prone to EDKA following bariatric surgery, with an incidence of over 20%.7

    Among patients on SGLT-2 inhibitors, those with low body mass index and decreased glycogen stores are at increased risk; even more so if suffering major illness or trauma, reduced insulin doses, and the conditions previously stated. A common trigger of EDKA seen in practice is when patients who are on SGLT-2 inhibitors and insulin miss doses or decrease their doses of insulin either by too much or too rapidly when they have decreased intake whether because of a gastrointestinal issue such as nausea/vomiting, or otherwise.

    Clinical Presentation

    Euglycemic DKA presents similarly to hyperglycemic DKA. Patients may present with general malaise, fatigue, lethargy, nausea, vomiting, loss of appetite, abdominal pain, or shortness of breath. Patients may also present with Kussmaul respiration (deep and rapid breathing) which is indicative of respiratory compensation for metabolic acidosis.2 They may have a fruity odor to their breath due to the loss of acetone. In more severe cases, patients may experience hypovolemic shock, respiratory failure, coma, or even death due to extensive dehydration and metabolic changes.2 Unlike with DKA, symptoms less likely to be present in EDKA are polyuria, polydipsia, or severe changes in mental status since patients with EDKA have glucose levels within the normal range. As a result, it can be difficult to detect from a clinical perspective, as well as for patients who are monitoring their glucoses and symptoms at home.

    Early Evaluation, Recognition, and Diagnosis

    When detected and treated promptly, most patients who experience EDKA will recover. Delays in diagnosis and treatment can lead to persistent symptoms, longer hospitalizations, and poorer outcomes.

    Patients presenting with malaise and the accompanying symptoms of EDKA while on SGLT-2 inhibitors should immediately undergo screening of serum pH and ketone testing via blood or urine.3,8 Successful and timely diagnosis is dependent on early screening with serum or urine ketones, even when serum glucose is normal, whenever EDKA is suspected. The initial laboratory evaluation of EDKA includes a basic metabolic panel, calcium, magnesium, serum ketones, beta-hydroxybutyrate, arterial or venous blood gas analysis, lactic acid, chest radiograph, and electrocardiogram.2 If infection is a suspected cause or factor, complete blood count and blood cultures may also be pertinent to obtain. In patients who appear to have acidosis, all other possible causes must be ruled out, such as sepsis or ketoacidosis due to alcohol consumption. Serum levels of beta-hydroxybutyrate greater than 3 mmol/L, blood glucose less than 250 mg/dL, metabolic acidosis, and a total decreased serum bicarbonate are indicative of EDKA. Serum ketones must also be elevated to make the diagnosis of EDKA.2

    Patient Education

    It is important to educate patients taking SGLT-2 inhibitors about the signs and symptoms, as well as the severity of DKA if left unaddressed. Additionally, it is important to stress the importance of adequate calorie intake, proper blood glucose monitoring, and communication with primary care providers, especially if on insulin so that providers can make adjustments to the regimen as appropriate. Insulin dosing should correlate with patients’ intake in order to avoid exacerbation of a potential carbohydrate deficit. Patients should contact their primary care provider if they have any significant changes to their enteral intake, especially carbohydrates, or if they experience nausea or vomiting. Ketogenic diets, as well as any other diet consisting of low-carbohydrate intake should be avoided if taking an SGLT-2 inhibitor, especially if the patient is insulin dependent.


    Patients should hold SGLT-2 inhibitors in the setting of surgery (at least 3 days prior, and up to 5 days prior if performing bariatric surgery).9 Postoperatively, volume status, caloric intake, and glucose levels should be monitored, and the SGLT-2 inhibitor should be discontinued if T2DM is in remission.9 In patients who will continue therapy post-procedure, ensure all risk factors for EDKA have resolved prior to reinitiating. Although the SGLT-2 inhibitors have been shown to have extra benefits on cardiovascular and kidney health, they are not recommended to be used in the management of patients with T1DM because of the high risk of DKA.10-12

    Pharmacists’ Role

    Pharmacists play a pivotal role in both the education and prevention of EDKA. Pharmacists can assist in patient education surrounding self-monitoring and communication, particularly in the outpatient setting. Both inpatient and outpatient, providers and other healthcare professionals can look to pharmacists for appropriate interventions and education on drug interactions or agents that may contribute to EDKA.

    Overall, working together as a healthcare team to properly weigh the risks and benefits of SGLT-2 inhibitor use, encourage proactive patient self-monitoring, and implement early surveillance and recognition of potential EDKA can ensure positive patient outcomes.


    1. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38(9):1638-1642.
    2. Plewa MC, Bryant M, King-Thiele R. Euglycemic Diabetic Ketoacidosis. 2021 Jun 4. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 32119457.
    3. Rawla P, Vellipuram AR, Bandaru SS, et al. Euglycemic diabetic ketoacidosis: A diagnostic and therapeutic dilemma. Endocrinology, Diabetes &amp; Metabolism Case Reports. 2017;2017.
    4. Modi A, Agrawal A, Morgan F. Euglycemic diabetic ketoacidosis: A Review. Current Diabetes Reviews. 2017;13(3):315-321.
    5. Pfützner A, Klonoff D, Heinemann L, Ejskjaer N, Pickup J. Euglycemic ketosis in patients with type 2 diabetes on SGLT2-inhibitor therapy—an emerging problem and solutions offered by diabetes technology. Endocrine. 2017;56(1):212-216.
    6. Sinha N, Venkatram S, Diaz-Fuentes G. Starvation ketoacidosis: A cause of severe anion gap metabolic acidosis in pregnancy. Case Reports in Critical Care. 2014;2014:1-4.
    7. Dowsett J, Humphreys R, Krones R. Normal blood glucose and high blood ketones in a critically unwell patient with T1DM post-bariatric surgery: A case of euglycemic diabetic ketoacidosis. Obesity Surgery. 2018;29(1):347-349.
    8. Dhatariya K. Blood ketones: Measurement, interpretation, limitations, and utility in the management of diabetic ketoacidosis. The Review of Diabetic Studies. 2016;13(4):217-225.
    9. Bobart SA, Gleason B, Martinez N, Norris K, Williams SF. Euglycemic ketoacidosis caused by sodium–glucose cotransporter 2 inhibitors: A case report. Annals of Internal Medicine. 2016;165(7):530.
    10. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with Empagliflozin in heart failure. New England Journal of Medicine. 2020;383(15):1413-1424.
    11. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. New England Journal of Medicine. 2019;381(21):1995-2008.
    12. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine. 2020;383(15):1436-1446.
    13. Candelario N, Wykretowicz J. The DKA that wasn't: A case of euglycemic diabetic ketoacidosis due to empagliflozin. Oxford Medical Case Reports. 2016;2016(7):144-146.
  • 19 Jan 2022 5:16 AM | Anonymous

    Author: Hyoeun Ashley Kang, PharmD Candidate 2022, UMKC School of Pharmacy
    Mentor: Annie Ungerman, PharmD, BCPS; Clinical Lead Pharmacist, Rheumatology Truman Medical Centers


    Romosozumab subcutaneous injection was approved by the U.S. Food and Drug Administration (FDA) in April 2019 for osteoporosis in postmenopausal women who are at high risk of fracture.Osteoporosis is a common disease state in women and affects more than 10 million individuals in the United States.1 Among multiple risk factors for developing osteoporosis, glucocorticoid (GC)-induced osteoporosis is the most common cause of secondary osteoporosis. Long-term use of GC therapy reduces bone formation and can trigger significant bone loss. In rheumatology clinics, GC medications are frequently prescribed for the treatment of rheumatoid arthritis (RA).2 Lee et al. showed that the incidence of osteoporosis is 1.9 times higher in patients with RA than without.3 Romosozumab is not mentioned in the American College of Rheumatology (ACR) Glucocorticoid-induced Osteoporosis guideline as it was last updated in 2017.

    Risk of Glucocorticoid-induced Osteoporosis

    Both the dose and duration of GC therapy are associated with the risk of fractures. Risk of fracture is significantly increased with relatively low daily doses of prednisolone (as low as 2.5 mg) for three to six months of therapy. According to the 2017 ACR Guideline for the Prevention and Treatment of GC-induced osteoporosis, fracture risk generated with FRAX score increased by 15% for major osteoporotic fracture and 20% for hip fracture risk in individuals who received daily doses >7.5 mg daily.5 Without appropriate treatment, bones become brittle and are more likely to fracture in the future. After a bone fracture, patients are more than 5 times as likely to fracture again within a year.6 Therefore, it is crucial to prevent and slow down bone loss to reduce the risk of fracture. 

    Mechanism of Action

    Romosozumab is an agent that has a different mechanism of action to stimulate bone formation than other osteoporosis treatments. Romosozumab is a monoclonal antibody that inhibits the action of sclerostin protein, which is a regulatory factor to block bone formation.Romosozumab is the first agent with a dual effect that increases bone formation (osteoblastic activity) and decreases bone resorption (osteoclastic activity).1,7

    Dosage and Administration

    The recommended dose of romosozumab is 210 mg by subcutaneous injection every four weeks for a total of 12 months. A healthcare professional should administer it as two separate injections of a 105 mg/1.7 mL syringe on the same day. The recommended injection sites of administration are abdomen, thigh, or upper arm. Additionally, patients should be on daily calcium and vitamin D supplements while taking romosozumab. If a dose is missed it is recommended to administer as soon as possible and reschedule subsequent doses from the date of the last dose.Use after 12 months is not advised as the effect of bone formation wanes after 12 doses.1,7


    There are two completed head-to-head trials available that evaluate the efficacy and safety of romosozumab in the treatment of postmenopausal women with osteoporosis. Romosozumab was compared to the most commonly used antiresorptive agent Fosamax®(Alendronate) and formulation-stimulating agent Forteo®(Teriparatide). 


    The most common side effects of romosozumab are arthralgia (8% to 13%), hypersensitivity reaction (7%), and headache (5% to 7%).10 Romosozumab has a black boxed warning that it can increase the risk of stroke, myocardial infarction (MI), and cardiovascular death. Thus, romosozumab should not be used in patients who previously have had an MI or stroke within the past year.7,10 The data for the Major Adverse Cardiac Events (MACE) from the ARCH trial (2017) are analyzed in Table 3.  


    Romosozumabis the first monoclonal antibody agent designed to target sclerostin protein. The ARCH trial and STRUCTURE trial demonstrated the efficacy and safety of romosozumab versus active comparator agents. This novel pathway of romosozumab provides an important treatment option for osteoporosis in postmenopausal women who are at high risk of fracture.




    1. FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-osteoporosis-postmenopausal-women-high-risk-fracture. Accessed October 10, 2021.
    2. What People With Rheumatoid Arthritis Need To Know About Osteoporosis. National Institutes of Health Osteoporosis and Related Bone Diseases National Resource Center. https://www.bones.nih.gov/sites/bones/files/pdfs/rheum_arthritis_and_osteo_11-18_0.pdf. Published November 2018. Accessed October 10, 2021.
    3. Lee SG, Park YE, Park SH, et al. Increased frequency of osteoporosis and BMD below the expected range for age among South Korean women with rheumatoid arthritis. Int J Rheum Dis 2012;15:289–96.
    4. Raterman HG, Bultink IEM, Lems WF. Current treatments and new developments in the management of glucocorticoid-induced osteoporosis. Drugs 2019; 79(10):1065–1087. 
    5. Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 2017;69(8):1521-1537.
    6. Van Geel TA, Van Helden S, Geusens PP, Winkens B, Dinant GJ. Clinical subsequent fractures cluster in time after first fractures. Ann Rheum Dis. 2009;68(1):99-102.
    7. Evenity [prescribing information]. Thousand Oaks, California: Amgen Inc; Revised April 2020. Accessed October 11, 2021.
    8. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med. 2017;377(15):1417-1427.
    9. Langdahl BL, Libanati C, Crittenden DB, et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet. 2017;390(10102):1585-1594.
    10. Romosozumab. Lexicomp. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6798426?cesid=0QxZflMLLDc&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Devenity%26t%3Dname%26va%3Devenity#. Updated September 30, 2021. Accessed October 15, 2021.

  • 19 Jan 2022 5:02 AM | Anonymous

    De-Sema-nating the Best Semaglutide Formulation for Your Patient

    By Kelly Williams, PharmD Candidate Class of 2023, UMKC School of Pharmacy and Jordan Rowe, PharmD, BCACP, BC-ADM, UMKC School of Pharmacy

    Semaglutide, a glucagon-like peptide (GLP-1) receptor agonist, works by mimicking the effects of human GLP-1 to induce insulin secretion and augment the metabolism of blood sugar. Current American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) guidelines recommend GLP-1 agonists as a possible second-line therapy following first-line metformin for most patients, and the recent ADA 2022 update recommends that GLP-1 agonists may be appropriate initial therapy for those with certain risk or disease factors.1, 2 Semaglutide has been used on label for the last four years in the treatment of type 2 diabetes (T2DM) and off-label for weight management through its favorable glycemic profile, A1c-lowering, weight-reducing effects. Further data has shown additional benefits in secondary atherosclerotic cardiovascular disease (ASCVD) prevention. With the U.S. Food and Drug Administration’s (FDA) approval of Novo Nordisk’s third semaglutide formulation, Wegovy™, for weight management in early 2021, a clear, concise clinical decision support tool would be beneficial for providers who may be scratching their heads at the different forms of semaglutide and their appropriate uses. This article aims to describe the similarities and differences between three formulations of semaglutide (Ozempic®, Rybelsus®, and Wegovy™) and provide an overview given patient-specific factors.

     The first formulation of semaglutide approved was Ozempic®. On December 5th, 2017, Novo Nordisk approved Ozempic®, a once weekly 0.5 mg or 1 mg injection, as adjunctive therapy with diet and exercise for the treatment of T2DM in patients with or without cardiovascular complications.3  The results of the SUSTAIN trials skyrocketed Ozempic® to the public eye by demonstrating several eye-catching attributes, including significant weight loss, A1c lowering, and secondary ASCVD risk reduction.3 Ozempic® was studied as a once weekly injection, yielding another advantage over several other currently available once or multiple daily GLP-1 injections. Although the associated weight reduction is a particularly attractive feature of Ozempic® given the benefits of achieving a healthy weight in those with T2DM, the formulation is not FDA-approved for obesity or weight management. Consequently, Ozempic® would not be ideal in patients only seeking weight management or patients who do not feel comfortable with injection therapy. Analogous to all currently available semaglutide formulations, Ozempic® is not available as a generic and thus carries a significant price tag. Although patient assistance programs and coupons for Ozempic® are available, cost may direct prescribers away from semaglutide formulations and towards more cost-effective alternatives as Ozempic® average wholesale price (AWP) costs over $1000 for a one-month supply.4

    Next came Rybelsus®, a once-daily oral alternative to Ozempic®. On September 20th, 2019, less than two years after the release of Ozempic®, Novo Nordisk announced Rybelsus® was FDA-approved as 7 mg or 14 mg tablets for the treatment of T2DM.5 A pioneer in its class, Rybelsus® was the first oral GLP-1 agonist, providing an option to patients unable or unwilling to use injections. The PIONEER trials showed that Rybelsus® had similar favorable A1c lowering and weight lowering effects to Ozempic®, although it failed to demonstrate superiority in secondary ASCVD risk reduction.6 Although current literature has not fully elucidated why Rybelsus® did not show a similar secondary ASCVD benefit profile like Ozempic®, some theories about the mechanism by which GLP-1 agonists reduce risk as well as the discrepancy between agents have been described. Proposed theories include differing kinetic concentration profiles between the oral and subcutaneous formulations are the root of the difference, or perhaps that there is no difference, and the duration of the PIONEER trials was simply not long enough to identify cardiovascular benefits.6 Comparable to Ozempic®, Rybelsus® is not advantageous for those only seeking weight reduction or weight management as the only FDA-indication for Rybelsus® is for the treatment of T2DM. Cost should also be considered with Rybelsus®, as similar to Ozempic®, the drug also has an AWP cost of over $1000 per month.4 It is noteworthy that both Ozempic® and Rybelsus® would likely have a lower price tag for insured patients compared to Wegovy™ as most insurance companies have relatively robust coverage for agents treating T2DM, while many plans have limited to no coverage for medications with indications for weight management alone.

    Lastly, on June 4th, 2021, Novo Nordisk announced Wegovy™ as a new semaglutide product to be FDA-approved for the exclusive indication of chronic weight management (in addition to diet and exercise) as a once-weekly 2.4 mg injection.7 Candidates for Wegovy should have a BMI of ≥30 kg/m2 or have one weight-related comorbidity (i.e. high blood pressure, high cholesterol, type 2 diabetes) with a BMI of ≥27 kg/m2.8  The STEP trials demonstrated that Wegovy™ showed significant weight loss and improved physical function.8  These trials did not show A1c-lowering effects in the general population, which is likely due to the trials excluding patients living with T2DM in all but the STEP 2 trial. In this instance, cost concerns are most dramatically at the forefront of clinical decision-making, as many insurance companies have limited to no coverage in medications indicated for weight management. Thus, Wegovy™ may incur the largest out-of-pocket expense by the patient of all semaglutide formulations with a price tag starting over $1600 per month AWP, regardless of strength.4

    Given the similarity of Wegovy™ to its semaglutide predecessor, Ozempic®, the injectable dosage form of 2.4 mg once weekly begs the question whether two separate formulations are even necessary, as all semaglutide formulations are exclusively manufactured by Novo Nordisk. The SUSTAIN FORTE trial compared weekly Ozempic® 1 mg to Ozempic® 2 mg (not currently commercially available) for the purposes of assessing A1c lowering in patients with T2DM.9 The trial showed statistical superiority of the 2 mg dosage over 1 mg of Ozempic® in A1c reduction, although the absolute difference of 0.3% between the two dosages may or may not be considered clinically significant.9 The most substantial difference in study arms was in mean bodyweight change, mirroring results in the STEP trials.8, 9  This suggests that while the weight loss potential with semaglutide increases with escalating doses, the glycemic management benefits seem to plateau. It will be intriguing to see if the cardiovascular risk reduction will also be mirrored between the two injectable formulations, but the results of the SELECT trial, investigating secondary ASCVD risk reduction in patients using Wegovy™ for weight management, are not anticipated for several years.10

    While differentiating between the three formulations of semaglutide may seem intimidating initially, this article hopes to help clarify key clinical pearls for their utilization in practice. The following decision support figure shown below may be beneficial in helping to determine which semaglutide formulation may be appropriate for your patient. 


    1. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 executive summary. Endocrine Practice. 2020;26(1):107-139.
    2. American Diabetes Association. Introduction: standards of medical care in diabetes—2022. Diabetes Care. 2021;45(Supplement_1)
    3. A quick guide to the SUSTAIN trials | diabetes.medicinematters.com. Accessed December 5, 2021. https://diabetes.medicinematters.com/semaglutide/type-2-diabetes/a-quick-guide-to-the-sustain-trials/12206922
    4. RED BOOK search - MICROMEDEX. Accessed January 11, 2022. https://www-micromedexsolutions-com.proxy.library.umkc.edu/micromedex2/librarian/CS/9C6AFE/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/94FAE0/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/redbook.FindRedBook?navitem=topRedBook&isToolPage=true
    5. FDA approves Rybelsus® (semaglutide), the first GLP-1 analog treatment available in a pill for adults with type 2 diabetes. Accessed December 5, 2021. https://www.prnewswire.com/news-releases/fda-approves-rybelsus-semaglutide-the-first-glp-1-analog-treatment-available-in-a-pill-for-adults-with-type-2-diabetes-300922438.html
    6. A quick guide to the PIONEER trials | diabetes.medicinematters.com. Accessed December 5, 2021. https://diabetes.medicinematters.com/semaglutide/cardiovascular-outcomes/a-quick-guide-to-the-pioneer-trials/16877792
    7. WegovyTM (semaglutide 2.4 mg), the first and only once-weekly GLP-1 therapy for weight management, approved in the US. Accessed December 5, 2021. https://www.globenewswire.com/news-release/2021/06/04/2242293/0/en/Wegovy-semaglutide-2-4-mg-the-first-and-only-once-weekly-GLP-1-therapy-for-weight-management-approved-in-the-US.html
    8. A quick guide to the STEP trials | diabetes.medicinematters.com. Accessed December 5, 2021. https://diabetes.medicinematters.com/semaglutide/obesity/quick-guide-step-trials/18854832
    9. Frías JP, Auerbach P, Bajaj HS, et al. Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. The Lancet Diabetes and Endocrinology. 2021;9(9). doi:10.1016/S2213-8587(21)00174-1
    10. Ryan DH, Lingvay I, Colhoun HM, et al. Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design. American Heart Journal. 2020;229:61-69. doi:10.1016/J.AHJ.2020.07.008 https://www.clinicaltrials.gov/ct2/show/NCT03574597.
  • 19 Jan 2022 4:18 AM | Anonymous

    Reviewing Best Practices in the Treatment of Acute Agitation

    Author: Tyler Frieda, PharmD, PGY-1 Pharmacy Resident, Mercy Hospital Springfield

    Mentors: Hannah Norris, PharmD, BCPS; Amanda Troup, PharmD, BCPS, PGY-1 Pharmacy Residency Program Director

    Program Number:  2021-12-06
    Approved Dates:   February 1, 2022-August 1, 2022
    Approved Contact Hours:  One Hour(s) (1) CE(s) per session


    • Explain the importance of appropriate management of acute agitation
    • List conditions that contribute to acute agitation
    • Explain the importance and role of de-escalation as primary agitation intervention
    • Identify the role of pharmacological treatment in acute agitation
    • Identify preferred pharmacological treatments of acute agitation based on associated conditions and treatment population


    Acute agitation is a symptom that can result from a variety of several different medical and psychiatric conditions. Agitation, especially if severe, can result in harm to the patient themselves, those trying to provide care, or both if not appropriately managed.1 Several studies consistently show high rates of violence experienced by healthcare workers even in areas other than the emergency department. In a survey study by Li et al of 196 emergency medicine residents, 91% of residents reported experiencing some form of abuse, ranging from verbal abuse to physical attacks.2 Similarly, a prospective study of 272 emergency medicine residents and attending physicians by Behnam et al found 78% of study respondents reported at least one act of violence in the last year,3 and a study of 101 emergency medicine physicians by Al-Sahwali et al reported 86% experiencing violence in the workplace with 7% experiencing physical assaults likely to have caused serious harm.4 These trends extend beyond the emergency room with 73% of psychiatry residents reported having been threatened with 36% having been physically assaulted based on a study by Schartz and Park,5 and a study of 364 workers at public infectious disease clinics by Schulte et al reported 38% experiencing a violent incident.6 Workplace violence is not only experienced by physicians as Kansagra et al study of 65 emergency departments found that nurses were least likely to report feeling safe among the healthcare workers interviewed.7 While these statistics are not strictly due to cases of agitation, they emphasize the prevalence of violence among healthcare workers, and highlight the importance of taking actions to prevent or minimize situations that place workers in harm. Appropriately managing agitation is one such action in which pharmacists can play an important role.


    As mentioned previously, agitation has several potential causes, and the pathophysiology, while not completely understood, is multifactorial in nature.1,8 While psychiatric illnesses are often associated with agitation, they are by no means the only conditions associated with agitation. Table 1 lists conditions attributed to agitation. Differentiating the likely cause of a patient’s agitation is key in determining the treatment of agitation. Knowing the underlying condition will not only guide pharmacological therapy but non-pharmacological approaches as well. However, a thorough medical assessment may not be viable in an acutely agitated patient due to difficulties in acquiring clinical data in patients that may be uncooperative. A retrospective analysis of emergency psychological evaluations by Olshaker et al found that patient history as opposed to other clinical data studied (physical examination, vital signs, and laboratory testing) had the highest sensitivity (94%) for identifying underlying medical problems.9 This makes patient history the most important piece of data to collect when trying to assess an agitated patient. If an underlying medical condition that may be attributed to agitation is identified, treatment should focus on resolving the underlying condition.1 Many of the medical conditions that contribute to agitation (noted in Table 1) are reversible such as metabolic abnormalities or infections. Reversing the contributing medical condition is likely to resolve the agitation as well. However, the time needed to resolve these conditions varies, and patients may require immediate action through one of the pathways discussed in this article.

    Non-Pharmacological Treatment

    As a pharmacist, it is important to understand the role these non-pharmacological treatment measures have in the treatment of acute agitation. The American Association for Emergency Psychiatry Project BETA expert consensus guidelines on the best practices in the treatment of agitation outline these approaches.1,10,11 Historically, non-pharmacological approaches have included restraint and seclusion.11 While these approaches are appropriate in select cases after other treatments have failed, de-escalation is regarded as the key approach to calming patients while maintaining the safety of coworkers.1,10,11 Utilization of de-escalation strategies have been found to enhance a positive clinician-patient relationship, decrease the likelihood of restraints, seclusion, and hospital admissions, and decrease length of stay.10 Meanwhile, the use of restraints is associated with increased lengths of stay, increased likelihood of psychiatric hospitalization, increased likelihood to cause severe distress to patients harming the clinician-patient relationship, and more likely to result in harm to both patients and healthcare workers.11 De-escalation contains key domains outlined by the Project BETA guidelines that were developed by a workgroup of emergency psychiatry practitioners experienced in behavioral emergencies. The key domains include: respect personal space, be concise and clear, listen to the patient, avoid further provocation, identify wants and needs, explain expectations and limits, establish verbal contact, agree or agree to disagree, offer choices and optimism, and debrief the patient and staff.10 The Project BETA workgroup consisted of emergency psychiatry practitioners experienced in behavioral emergencies who established these domains based on their collective experience and available evidence.10 For those interested in learning more about de-escalation, the website partnersincalm.com offers materials and updates for the treatment agitation including de-escalation.12

    Pharmacological Treatment

    When to Use Medications and Best Practices

    Medication therapy may be used in moderate to severe forms of agitation after de-escalation has failed.1,8 The goal of medication administration in agitation is to calm the patient without over sedation.1,8 In patients who partially respond to de-escalation, oral medications may still be offered but parenteral medication should be reserved only for patients posing an immediate threat to themselves or others.8 Even if de-escalation failed to sufficiently calm the patient, it may encourage the patient to be more cooperative to medication if it is offered as a choice to the patient.8,10 Oral medications should be offered over parenteral medications in patients that are cooperative as the use of oral medications has been shown to be just as effective as parenteral medications in acute agitation.8,13,14 Two prospective studies comparing oral and parenteral administration found no difference in the level of agitation at all the time points measured.13,14 Administration of parenteral medications without consent harm the clinician-patient relationship as it can be viewed as punishment rather than treatment by the patient and can potentially cause distress to the patient.8 Parenteral medications without patient consent should only be used if the patient displays a clear risk of harm to themselves or others due to their agitation.8 In most patients, one dose of medication is effective in calming the patient. In the event that a single dose is insufficient, subsequent doses should be administered after enough time has been given for the prior dose to take effect. This length of time varies by the agent and route of administration used as shown in Table 3. Along with this, these medications have a maximum recommended 24-hour dose. Exceeding these increases the risk for adverse effects, particularly oversedation.

    Special Populations


    Data for treatment of acute agitation in pediatric populations is poor with mostly retrospective studies. Diphenhydramine is commonly for its well-established safety profile and familiarity despite having poor data in pediatric agitation. It also has the potential to cause a paradoxical reaction by worsening agitation. Lorazepam has more evidence but also caries the same risk for paradoxical reaction. Risperidone, olanzapine, chlorpromazine and ziprasidone have some evidence in pediatric populations as well. In general, diphenhydramine (PO/IM), lorazepam (PO/IM), risperidone (PO) or olanzapine (PO) can be used for moderate agitation. Avoid diphenhydramine and lorazepam if the child has a history of paradoxical reactions or diagnosis of autism or developmental disability. For severe agitation, chlorpromazine (PO/IM), olanzapine (IM) and ziprasidone (IM) can be added to the available agents, but diphenhydramine is not recommended in severe agitation due to its poor efficacy data compared to other agents. Dosing can be found in Table 3.


    These patients should be treated depending on the cause in a similar manner to adult patients with a few key differences. Doses should be decreased as these patients tend to have slower metabolisms and increased risk for adverse effects. Benzodiazepines should be avoided in most cases unless they are specifically indicated (alcohol withdrawal). Similarly, anticholinergics should be avoided especially in delirium. Patients with Parkinson’s disease or Lewy Body dementia, antipsychotics should be avoided with the exception of low dose quetiapine. Benzodiazepines may be used in these patients at reduced doses if indicated.


    Benzodiazepines are associated with cleft lip/palate in the first trimester, and low birth weight/muscle tone and premature births when used in the third trimester. However, these are from studies with long term use. Effects of single doses is not yet fully understood. Antipsychotics used in agitation are not associated with any teratogenic effects but long-term use may cause neonatal withdrawal. Short term use or single doses of antipsychotics can be used safely in acutely agitation pregnant patients


    Follow PADIS guidelines to treat ICU specific causes of agitation (pain, delirium, etc.). For acute agitation, one-time doses of antipsychotics can be used. However, in cases of delirium, routine use of antipsychotics does not improve delirium symptoms or duration and may lead to unnecessary prescriptions for antipsychotics at discharge. Dexmedetomidine can be used in mechanically ventilated patients weaning off ventilation.


    Adhering to appropriate treatment for acute agitation is an area that in which pharmacists can make an impact. As displayed by the statistics discussed earlier, violence in healthcare work is widespread and appropriately managing agitation can potentially help.1-7 As such, de-escalation should always be performed first prior to medication or restraints/seclusion.10 Unless the patient is severely agitated, an attempt to offer oral medication should be made. If the patient is severely agitated and posing a risk to themselves or others, then parenteral medications can be administered. Restraint and seclusion should be used only as a last resort and for the shortest duration possible11 The medication used should be directed towards the suspected contributing condition and population being treated while keeping safety parameters in mind such as maximum dosing and dosing intervals.1,8 These recommendations are based on the Project BETA guidelines, and these guidelines should be used as a reference when treating acute agitation.1

    CE Quiz


    1. Roppolo LP, Morris DW, Khan F, et al. Improving the management of acutely agitated patients in the emergency department through implementation of Project BETA (Best Practices in the Evaluation and Treatment of Agitation). J Am Coll Emerg Physicians Open. 2020;1(5):898-907. Published 2020 Jul 3. doi:10.1002/emp2.1213812138
    2. Li SF, Grant K, Bhoj T, Lent G, Garrick JF, Greenwald P, Haber M, Singh M, Prodany K, Sanchez L, Dickman E, Spencer J, Perera T, Cowan E. Resident experience of abuse and harassment in emergency medicine: ten years later. J Emerg Med. 2010 Feb;38(2):248-52. doi: 10.1016/j.jemermed.2008.05.005. Epub 2008 Nov 20. PMID: 19022605.
    3. Behnam M, Tillotson RD, Davis SM, Hobbs GR. Violence in the emergency department: a national survey of emergency medicine residents and attending physicians. J Emerg Med. 2011 May;40(5):565-79. doi: 10.1016/j.jemermed.2009.11.007. Epub 2010 Feb 4. PMID: 20133103.
    4. Al-Sahlawi KS, Zahid MA, Shahid AA, Hatim M, Al-Bader M. Violence against doctors: 1. A study of violence against doctors in accident and emergency departments. Eur J Emerg Med. 1999 Dec;6(4):301-4. doi: 10.1097/00063110-199912000-00005. PMID: 10646917.
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