Author: Bert McClary

In early April I saw a news segment titled “When Women Rule the World,” featuring Tina Brown discussing her 10^th annual “Women in the World” conference.  Just a week before I had seen four women on the stage, and no men, taking the MSHP oath of office, administered to them by a fifth woman.  It was the first time that had occurred.

We have had women active in MSHP since the beginning.  Today they outnumber the men and are a driving force in the organization, but it wasn’t always that way.  Even though there was no effort to exclude women from leadership or recognition, there was still an occasional unintended chauvinistic characteristic that came through. 

Eleven of 54 registrants for the organizational meeting in 1970 were women, five of them members of religious orders, and one, Sister Jane McMenamy, had served on the original organizing committee from 1969.  Among women in hospital pharmacy during the early years, more were nuns because hospitals operated by religious orders funded pharmacy education for their staff.  Both the Metropolitan St. Louis Hospital Pharmacists Association and the Greater Kansas City Society of Hospital were formed by nuns.  A notable Missourian who participated in the preparation of the landmark 1964 Mirror to Hospital Pharmacy was Sister Mary Berenice, Director of Pharmacy at St. Mary’s Hospital, St. Louis.

While gender was not called out as a specific issue in the early years, the first female elected MSHP officer was Secretary (of course) in 1973, and female membership was usually 10 to 20 percent.  There was also an MSHP BOP Advisory Committee memo that went out announcing a new BOP Executive Secretary, the managing staff employee of the Board (male, of course), “as well as a woman on the Board” (a Board member appointed by the Governor).  The memo did not include the name of either person, but the fact of a female appointee was notable.  Women as BOP appointees are frequent now.  The BOP has had five Executive Secretaries during the last 50 years, and the last two have been females.

We have had many women serve in important positions of leadership as elected officers, members of the board of directors, and committee chair positions through the years, but it was 16 years before we elected our first woman MSHP president, Bonnie Grabowski, in 1986.  There have been 15 female presidents in 50 years; however we have done better recently, as 11 of our presidents in the last 20 years have been women, including five of the last seven. 

WOW (Women of the World)!

Authors: Caitlynn Tabaka, PharmD and

Livia Allen, PharmD, BCCCP

Learning Objectives

1. Analyze the mechanism of action and pharmacokinetic properties of vasopressors to determine which vasopressor to use in specific scenarios.
2. Identify the differences in dosing and preparation requirements for push-dose vasopressors.
3. Evaluate current literature pertaining to the use of push-dose vasopressors outside of the operating room.
4. Evaluate the safety concerns of utilizing push-dose vasopressors outside of the operating room.

Introduction

Vasopressors are excitatory and inhibitory agents utilized to increase a patient’s blood pressure through actions on the heart and/or vascular smooth muscle.¹ They are traditionally administered through a central line as a continuous infusion for the management of fluid refractory systemic hypotension. Systemic hypotension is a medical emergency that can lead to end-organ ischemia if not managed properly.² It is classified by a systolic blood pressure less than 90 mmHg, a diastolic blood pressure less than 60 mmHg or a mean arterial pressure less than 65 mmHg. The most common causes of hypotension include hypovolemic, cardiogenic, and distributive shock. Effective fluid resuscitation is crucial for stabilization of tissue hypoperfusion. The 2016 Surviving Sepsis Guidelines recommend that vasopressors be administered only once hypotension is found to be persistent despite adequate fluid challenges.³ 

Vasopressor agents are typically administered as continuous infusions. However, bolus doses of vasopressors have been used to optimize a patient’s hemodynamic status when rapid intervention is required. This method of intermittently administering bolus vasopressor doses can be referred to as push-dose vasopressors, neo-sticks, or phenyl-sticks.^4,5 Utilizing push-dose vasopressors to treat hypotension and maintain adequate perfusion is a common evidence-based practice by anesthesiologists in the operating room (OR). Studies that used push-dose epinephrine, phenylephrine, and ephedrine in the OR for hemodynamic management, secondary to sedation and spinal anesthesia, had positive outcomes. Push-dose vasopressors were shown to be as efficacious and safe as continuous infusion vasopressors and patients who received them required less vasopressors overall.^6-9 Due to the success in the OR, the use of push-dose vasopressors has transitioned to the emergency department (ED) and intensive care unit (ICU) in recent years as a practical strategy to urgently manage hemodynamically unstable patients.

Hypotension in the ED and ICU settings are often multifactorial. Depending on the severity and duration, hypotension has been associated with acute organ failure, need for ICU stay, and in-hospital mortality. Potential etiologies include septic shock, post intubation hypotension, traumatic brain injury, transient hypotension related to procedural sedation, or while crystalloid or blood product volume resuscitation is in progress.^4,5 In these cases, push-dose vasopressors may be given rapidly through a peripheral line to serve as a temporary bridging measure. Push-dose vasopressors can provide adequate perfusion to vital organs until a central line is placed and a continuous vasopressor infusion is initiated.^4,10

Vasopressors

The most commonly used vasopressors for bolus dosing are epinephrine and phenylephrine.^4,5 Phenylephrine is preferred over epinephrine in patients who present with tachycardia or tachyarrhythmias.Similarly, push-dose norepinephrine has recently gained attention in the anesthesia literature due to its lower tendency to cause tachycardia. Norepinephrine also has the quickest onset and shortest duration of action. It can be utilized in a setting where quick on and offset of a vasopressor is desirable. Evidence supporting the use of push-dose norepinephrine outside the OR is lacking.^11-14 Ephedrine is popular among the anesthesiologists due to its extended duration of action, however, using a product with an extended duration in the ED or ICU could lead to overcorrection of hypotension and bradycardia.^4,16

Literature

The available literature consists of efficacy and safety evaluations of push-dose vasopressors for the management of hypotension. The evidence is currently limited to case series and retrospective studies conducted in the ED and ICU settings. Results from prospective, randomized controlled trials are not yet available. The two main push-dose vasopressors analyzed were epinephrine and phenylephrine with only one study evaluating the use of ephedrine and none evaluating norepinephrine. ^{10, 17-20} Push-dose vasopressors were used for a variety of indications including sepsis, respiratory distress/failure, cardiac arrest, trauma-induced hypotension, and post-intubation or procedural sedation induced hypotension.^{10, 17-20}

 There was a wide range of doses and dosing frequencies between the studies. Only one study had a protocol in place with standard dosing regimens of push-dose vasopressors.²⁰ Most of the patients included in the studies were transitioned to continuous infusion vasopressors. The three patient cases described by Gottlieb et al. required continuous norepinephrine to maintain hemodynamic control after receiving push-dose epinephrine.¹⁹ Schwartz et al. evaluated the need for continuous support within 30 minutes following push-dose vasopressors.¹⁸ They found that patients who were appropriately fluid challenged required less vasopressor boluses and had a lower rate of continuous vasopressor infusions compared to those inadequately fluid challenged. Only two other studies assessed patients that received adequate fluid resuscitation prior to the initiation of push-dose vasopressors.^19,20 The most common adverse effects noted in the literature include bradycardia, hypertension, and tachycardia. Rotando et al. reported that 11% of the included patients had a dose related medication error.²⁰ Overall, the studies concluded that further assessments of appropriateness, efficacy, and safety need to be conducted for the use of push-dose vasopressors outside of the OR.^10,17-20

Push-Dose Vasopressor Preparation

Push-dose vasopressor concentrations are not available commercially and must be prepared at bedside prior to administration. The preparation generally involves diluting commercially available products with normal saline (NS) to achieve appropriate concentrations. It is recommended that organizations preparing and utilizing these products develop a standardized process for naming, dosing, ordering, preparing and administering push-dose vasopressors.⁴

Safety Concerns

Vasopressors are strong vasoconstrictors that can lead to tissue hypoperfusion and injury if extravasation occurs. The risk of extravasation is greater when administered peripherally versus centrally. Studies have shown the vast majority of vasopressor-induced tissue damage occurs in peripheral lines that are distal to the antecubital or popliteal fossa and when infused for greater than four hours.²¹ Peripheral administration of vasopressors should be monitored frequently and reserved for emergency situations as a temporizing measure until central venous access can be obtained. If dosed correctly, push-dose vasopressors can be a great way to prevent peripheral extravasation due to the administration of small intermittent doses at diluted concentrations. Additional adverse effects that can occur when push-dose vasopressors are dosed incorrectly include local skin and soft-tissue injury (necrosis), end-organ tissue ischemia, acute hypertension, cardiac ischemic events, and left ventricular dysfunction.²²

Ensuring patient safety in the ED setting can be challenging due to treatment of unfamiliar patients, crowding, high stress situation, reliance on verbal orders, and dispensing and administering medications without verification by a pharmacist.⁴ The risk of error increases when utilizing push-dose vasopressors because of required dose calculations, drug dilutions, and incremental push-dose administrations. Errors in preparation, drug selection, and administration have been frequently reported. Acquisto et al.describes patients receiving high doses of push-dose epinephrine and phenylephrine due to dosing errors.²³ In one case, a post-surgical hypovolemic shock patient developed hypotension during transport. Once in the ICU, the physician ordered “phenylephrine 50” and the patient was given 50 mg instead of the intended 50 mcg push dose. Another case occurred when a post-surgical patient developed atrial fibrillation and was treated with diltiazem IV boluses. The patient developed asymptomatic hypotension and a phenylephrine push-dose was ordered. In this case, the entire 1000 mcg phenylephrine pre-mixed syringe was administered instead of the intended 100 mcg. In both cases, fluid resuscitation had not been implemented prior to the initiation of push-dose vasopressors.

Another common push-dose vasopressor error includes physicians asking for epinephrine mixed to the 100 mcg/mL phenylephrine concentration instead of the 5-20 mcg/mL epinephrine concentration. Epinephrine is available in various doses and concentrations to be delivered by multiple routes depending on the indication. Four cases related to dosing errors of push-dose epinephrine resulted in cardiogenic shock, ST-elevation myocardial infarction, and ventricular tachycardia.²² Contribution to these errors were multifactorial and included inadequate physician knowledge about appropriate dose and route of epinephrine, complicated dose calculations involving decimals and ratios, and lack of adequate communication between physicians and nurses. The Institute for Safe Medication Practices (ISMP) has Safe Practice Guidelines for Adult IV Push Medications that states a lack of administrative policies/protocols/guidelines for IV injections is a risk factor for error.²⁴ ISMP recommends guidelines for parenteral medications through IV push administration route should be simplified, standardized, and communicate safe practices associated with the IV medication.

Conclusion

Successful practice migration from the operating room to the ED and ICU has been a continuous process for ages. The use of succinylcholine and other neuromuscular blockers for rapid sequence intubation was reserved for the OR until rigorous clinical research evaluating the utilization of neuromuscular blockers for procedures in the ED demonstrated superior outcomes.^25,26 Propofol for procedural sedation has a similar history. It was only being utilized in the OR until clinical trials demonstrated that it was safe and effective for procedural sedation in the ED and ICU settings.^27,28 Both of these practices that were initially met with resistance are now mainstay practices in the ED and ICU.

The resistance against the migration of push-dose vasopressors to the ED and ICU stems from the limited literature available evaluating efficacy and safety. The studies available are retrospective and have several notable limitations including significant variations in dosing and timing of administration, reduced utilization of crystalloid fluids, and small patient sample sizes. Overall there is a lack of clear systematic practice patterns concerning the use of vasopressors which lead to adverse effects and medical errors. Currently, there are no guidelines discussing the management of an unintentional push-dose vasopressor overdose. Tachycardia, hypertension, and reflexive bradycardia are the most likely adverse effects of these agents when utilizing bolus dosing. Due to the short half-lives of these agents the adverse effects should not last longer than 30 minutes. However, in extreme overdoses more severe adverse events may occur including arrhythmias, limb ischemia, hypertension leading cerebrovascular events, metabolic acidemia, and lactic acidosis.^1,4

Institutions that implement push-dose vasopressors should have clear protocols and procedures indicating appropriate patients, medications, doses, preparation, and administration for push-dose vasopressors. If used at all, push-dose vasopressors should only be utilized as a temporary bridging measure until a continuous vasopressor infusion can be initiated. Push-dose vasopressors should only be used in those patients who have received adequate fluid resuscitation.^18,19 Further studies need to be conducted to evaluate the safety and efficacy of utilizing push-dose vasopressors outside of the OR.

References

1. Overgaard C, Dzˇavík V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation. 2008; 118:1047-1056.
2. Kellum J, Pinsky M. Use of Vasopressor Agents in Critically Ill Patients. Curr Opin Crit Care. 2002 June;8(3):236-41.
3. Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377.
4. Holden D, Ramich J, Timm E, et al. Safety Considerations and Guideline-Based Safe Use Recommendations for “Bolus-Dose” Vasopressors in the Emergency Department. Ann Emerg Med. 2018;71(1): 83-92.
5. Tilton L, Eginger K, Gastonia N. Utility of Push-Dose Vasopressors for Temporary Treatment of Hypotension in the Emergency Department. J Emerg Nurs. 2016;42(3):279-81.
6. Siddik-Sayyid S, Taha S, Kanazi G, et al. A randomized controlled trial of variable rate phenylephrine infusion with rescue phenylephrine boluses versus rescue boluses alone on physician interventions during spinal anesthesia for elective cesarean delivery. Anesth Analg. 2014; 118:611-618.
7. Doherty A, Ohashi Y, Downey K, et al. Phenylephrine infusion versus bolus regimens during cesarean delivery under spinal anesthesia: a double-blind randomized clinical trial to assess hemodynamic changes. Anesth Analg. 2012; 115:1343-1350.
8. Mohta M, Harisinghani P, Sethi AK, et al. Effect of different phenylephrine bolus doses for treatment of hypotension during spinal anesthesia in patients undergoing elective caesarean section. Anaesth Intensive Care. 2015; 43:74-80.
9. Heesen M, Stewart A, Fernando R. Vasopressors for the treatment of maternal hypotension following spinal anaesthesia for elective caesarean section: past, present and future. Anesthesia. 2015;70: 252-257.
10. Swenson K, Rankin S, Daconti L, et al. Safety of bolus-dose phenylephrine for hypotensive emergency department patients. Am J Emerg Med. 2018 Oct;36(10):1802-1806.
11. Wang X, Mao M, Liu S, et al. A Comparative Study of Bolus Norepinephrine, Phenylephrine, and Ephedrine for the Treatment of Maternal Hypotension in Parturients with Preeclampsia During Cesarean Delivery Under Spinal Anesthesia. Med Sci Monit. 2019; 25:1093-1101.
12. Wang X, Shen X, Liu S, et al. The Efficacy and Safety of Norepinephrine and Its Feasibility as a Replacement for Phenylephrine to Manage Maternal Hypotension during Elective Cesarean Delivery under Spinal Anesthesia. Biomed Res Int. 2018; 2018:1869189.
13. Hassani V, Movaseghi G, Safaeeyan R, et al. Comparison of Ephedrine vs. Norepinephrine in Treating Anesthesia-Induced Hypotension in Hypertensive Patients: Randomized Double-Blinded Study. Anesth Pain Med. 2018;8(4):e79626.
14. Levy B, Clere-Jehl R, Legras A, et al. Epinephrine Versus Norepinephrine for Cardiogenic Shock After Acute Myocardial Infarction. J Am Coll Cardiol 2018;72(2):173-182.
15. Vazculep (phenylephrine hydrochloride) label - FDA package insert. Chesterfield MO: Eclat Pharmaceuticals; June 2014.
16. Bangash M, Kong M, Pearse R. Use of inotropes and vasopressor agents in critically ill patients. Br J Pharmacol. 2012 Apr; 165(7);2015-33.
17. Panchal A, Satyanarayan A, Bahadir J, et al. Efficacy of Bolus-dose Phenylephrine for Peri-intubation Hypotension. J Emerg Med. 2015;49(4):488-94.
18. Schwartz M, Ferreira J, Aaronson P. The impact of push-dose phenylephrine use on subsequent preload expansion in the ED setting. American Journal of Emergency Medicine. 2016; 34:2419-2422.
19. Gottlieb M. Bolus dose of epinephrine for refractory post-arrest hypotension. CJEM. 2018; 20(S2):S9-13.
20. Rotando A, Picard L, Delibert S, et al. Push dose pressors: Experience in critically ill patients outside of the operating room. Am J Emerg Med. 2019;37(3):494-498.
21. Loubani O, Green R. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015; 30:653.e9-e17. 
22. Anwar M, Irvin C, Frank J, et al. Confusion about epinephrine dosing leading to iatrogenic overdose: a life-threatening problem with a potential solution. Ann Emerg Med. 2010; 55:341-4.
23. Acquisto N, Bodkin R. Medication Errors with Push Dose Pressors in the ED and ICU. Am J Emerg Med. 2018 Mar;36(3):520-521.
24. Institute for Safe Medication Practices. ISMP safe medication practice guidelines for adult IV push medications. Available at: http://www.ismp.org/Tools/guidelines/ivsummitpush/ivpushmedguidelines.pdf. Accessed, September 20^th, 2019.
25. Roberts D, Clinton J, Ruiz E. Neuromuscular Blockade for Critical Patients in the Emergency Department. Ann Emerg Med. 1986; 15:152-156.
26. Tayal V, Riggs R, Marx J, et al. Rapid-sequence intubation at an emergency medicine residency: success rate and adverse events during a two-year period. Acad Emerg Med. 1999; 6:31-37.
27. Burton J, Miner J, Shipley E, et al. Propofol for emergency department procedural sedation and analgesia: a tale of three centers. Acad Emerg Med. 2006; 13:24-30.
28. Godwin S, Burton J, Gerardo C, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2014; 63:247-258.

Submit for CE

Author: Sarah Cox, PharmD, MS

Impact of Drug Shortages:

The number of drugs impacted by shortages nearly tripled over a five-year period (2007-2012).¹

Today, drug shortages continue to pose a threat to health-systems and patients. A survey conducted in collaboration with ASHP and sent to 1300 directors of pharmacy nationwide, indicated that 99% of health-systems had experienced at least one shortage in the past 6 months and about a third or respondents stated having shortages with over 30 different drugs. Costs were estimated to be near $216 million from labor resources allocated to preventing or preparing for shortages.² Another survey of directors of pharmacy estimated that drug shortages account for one to five percent of medication errors.³

Resources for Your Health-System to Manage Drug Shortages:

While drug shortages are not new and health-systems already have put processes in place in attempt to prevent and address shortages, there are many resources available to aide in this process.

1. ASHP Drug Shortages List: Includes a master list of current drug shortages and the date the shortage was updated. This list is very user friendly and allows browsing or searching for a specific drug. Clicking on the drug of choice will bring up a new web page with details about the products impacted (including NDC), reason for the shortage, available products, and estimated resupply dates
2. ASHP Guidelines on Managing Drug Product Shortages: This resource provides strategies health-systems can take to preventing, planning for, and responding to drug shortages.
3. ASHP Drug Shortages Roundtable Report: This document describes some background on drug shortages including common causes and potential remedies.
4. ASHP Additional Resources: Webpage includes additional links to best practices, guidelines, tools, and publications on drug shortages including links to the FDA Drug Shortage site and CDC Vaccine Shortage site.

Legislative Efforts:

The FDA Safety and Innovation Act (FDASIA) was enacted in 2012 and included a requirement that drug manufacturers notify the Food and Drug Administration (FDA) “of any change in production that is reasonably likely to lead to reduction in supply.” While this legislation did lead to a reduction in the number of drug shortages, additional legislation may help reduce shortages even further.

The Mitigating Emergency Drug Shortages Act was introduced by Senator Susan Collins (R-ME) and Senator Tina Smith (D-MN) on October 29, 2019. ASHP played a role in developing the objectives for this piece of legislation including:

• “Requiring manufacturers to disclose the root causes and expected duration shortages
• Extending reporting requirements to include contract manufacturers and active pharmaceutical ingredients
• Requiring manufacturers to develop contingency plans to ensure an ongoing supply
• Developing recommendations to incentivize manufacturers to enter the market for drugs in shortage; and
• Examining the national security risks of shortages.”⁴

Take Action:

To advocate for this legislation, go to ASHP’s online advocacy center, contact your representative, and ask them to co-sponsor S. 2723.

References:

1. Public Health Threat Continues Despite Efforts to Help Ensure Product Availability. United States Government Accountability Office, Washington DC. 2014;pp14-194.
2. Kaakeh R, Sweet BV, Reilly C, et al. Impact of Drug Shortages on National Survey Reveals High Level of Fristration, Low Level of Safety. Am J Health Syst Pharm. 2011;68(19):1811-1819.
3. Caulder CR, Mehta B, Bookstaver PB, et al. Impact of Drug Shortages on Health-System Pharmacies in the Southeaster United States. Hosp Pharm. 2015;50(4):279-286.
4. Issue Update: ASHP Influencing the National Conversation on Drug Shortages. https://ashsp.ac360.aristotleactioncenter.com/#/alertId/03de88de-d2d9-4f57-bf2d-b37fe4bc57b5/ October 24, 2019. 
   

Author: Jackie Harris, Pharm.D, BCPS, Executive Director, MSHP Research and Education Foundation

MSHP R&E Foundation is currently accepting submissions and nominees for several awards. 

MSHP R&E Best Practice Award

The Best Practice Award program recognizes innovation and outstanding performance in a pharmacy directed initiative. The theme for the 2020 award focuses on Innovative Stewardship Roles.  Submission deadline is December 30^th, 2019.

A poster of the program will be highlighted during the Spring Meeting Poster Session. The award recipient will be honored at a Reception during the Spring Meeting and have the opportunity to provide a brief podium presentation detailing the implementation and impact of the project to the attendees.

Applicants will be judged on their descriptions of programs and practices currently employed in their health system based on the following criteria:

·    Inventiveness of the program

·    Significance of the program to the health system

·    Demonstration of benefit to patient care as supported by program evaluation data

·    Significance of the program to pharmacy practice

·    Quality of submitted program report

·    Relevance to other institutions

Applicants must be active MSHP members practicing in a health-system setting such as a large or small hospital, home health, ambulatory clinic or other health care system. More than one successful program from a health system may be submitted for consideration.

Award recipient will receive half off their meeting registration, a plaque and a $250 honorarium.

Submission Instructions: A program summary not to exceed 400 words must be submitted with the application and include the following information.

·    Background – description of need for program

·    Goals and specific aims of the program

·    Program description/methods – description of development process, role(s) of the pharmacist, timeline

·    Results - when results are not yet available, include a description of how impact of the program will be measured

·    Conclusion – established and/or expected clinical impact of the program

·    Submissions may also include any pictures, graphs, figures or data tables that support the summary. Each of these must be clearly labeled and described. Such information will not count against the 400 word limit.

• Email your submission to mshp@qabs.com with Best Practice Award Submission in the subject line.

MSHP R&E Best Residency Project Award

The Best Residency Project Award recognizes innovation and outstanding performance in a pharmacy residency project.   A poster of the program will be highlighted during the Spring Meeting Poster Session. The award recipient will be honored at a Reception during the Spring Meeting and have the opportunity to provide a brief podium presentation detailing the implementation and impact of the project to the attendees. Submission deadline is December 30^th, 2019.

Applicants will be judged based on the following criteria:

·    Inventiveness of the project

·    Significance of the project to the health system

·    Demonstration of benefit to patient care as supported by project evaluation data

·    Significance of the project to pharmacy practice

·    Quality of submitted project report

·    Relevance to other institutions

Applicants must be active MSHP members completing a residency in a health-system setting such as a large or small hospital, home health, ambulatory clinic or other health care system.

Award recipient will receive half off their meeting registration, a plaque and a $250 honorarium.

Submission Instructions: A program summary not to exceed 400 words must be submitted with the application and include the following information.

·    Background – description of need for project

·    Goals and specific aims of the project

·    Results - when results are not yet available, include a description of how impact of the project will be measured

·    Conclusion – established and/or expected clinical impact of the project

Email your submission to mshp@qabs.com with Best Residency Project Award Submission in the subject line.

Garrison Award

The Garrison award was established in 1985, named after Thomas Garrison for his long standing support of MSHP (past-president 1974-1976), ASHP (past-president 1984) and numerous professional and academic contributions to Pharmacy. The Garrison Award is presented each year to a deserving candidate who has been nominated in recognition of sustained contributions in multiple areas:

·    Outstanding accomplishment in practice in health-system pharmacy;

·    Outstanding poster or spoken presentation at a state or national meeting;

·    Publication in a nationally recognized pharmacy or medical journal;

·    Demonstrated activity with pharmacy students from St. Louis or the UMKC Schools of Pharmacy;

·    Development of an innovative service in a health-system pharmacy in either education, administration, clinical service, or distribution;

·    Contributions to the profession through service to ASHP, MSHP and/or local affiliates.

Each letter of nomination must include:

·    Name, work address, and telephone number of nominee;

·    Name, work address, and telephone number of nominator;

·    Sufficient explanation and documentation of the nominee’s accomplishment(s) to allow a proper decision by the selection committee;

·    and Curriculum Vitae of the Nominee.

·    To be considered for the Garrison Award, the nominee must be a current active member of the Missouri Society of Health-System Pharmacists. The winner will be selected by the Board of Directors of the MSHP Research and Education Foundation.  Email your nomination to mshp@qabs.com with Garrison Award Submission in the subject line.

Submission Deadline for Garrison Award is January 31, 2020.

Authors: Shu-wen Tran, B.S., UMKC PharmD Candidate 2020 and Diana Tamer, B.S., Pharm.D., BCOP

How is it possible that patients with certain metastatic cancers are still treated with traditional chemotherapy when targeted precision medicine is available for them as first line agents? While sequencing the whole genome led to having technologies today to sequence each patient’s tumor DNA, and finding targeted therapies for tumorigenesis driving mutations; these therapies are costly and not affordable to most patients—even those with insurance coverage. Is there any way to drive down the cost of oncolytic agents? Let’s explore some avenues.

Targeted therapy, otherwise known as precision medicine, are medications designed to specifically target driving mutation(s) that is/are causing the cancer type. Targeted therapy differs from traditional therapy in that they act on a specific pathway or gene mutation related to the cancer type instead of acting systemically, affecting all normal and abnormal cells. Over the past 10 years, the FDA has approved more than 80 targeted oncolytic therapies, with more than half of them approved for oral administration.¹ It is important to understand that traditional chemotherapies remain the standard of care in early stages of cancer, while targeted drug therapies are options for patients with metastatic disease—if they harbor a particular mutation.  That is also partly because as new drugs are studied in clinical trials for cancer patients, they start testing them in patients that have no other options and are at more advanced stages of their disease. That being said, as these drugs gain approval, clinical trials in earlier stages of the disease are underway; which will lead to maybe more use of these agents at all stages of cancer.

Disparities in insurance plan coverage for cancer treatment is one of the most challenging aspects patients are facing. Patients are faced with a financial burden when their plan coverage diverges (medical versus pharmacy benefit), and their oral cancer drug therapy treatment is submitted through their pharmacy benefit, instead of their medical benefit. Often times a set-back in cancer treatment occurs because they are unable to afford therapy. So why is this happening?

“Medical benefits often require patients to pay a flat copayment (perhaps $20 to $50 per visit) for care in an outpatient setting, which can include administration of intravenous medications. Pharmacy benefits, by contrast, often have a tiered copayment structure and other provisions that increase cost sharing for more expensive medications. Pharmacy benefits may include coinsurance (in which patients are responsible for a percentage of the medication cost), high overall deductibles, and caps on annual drug benefits.”² Most insurance plans place oral cancer agents into a “specialty tier” or “fourth tier,” which may require a cost-sharing responsibility for the patient of anywhere from 25 to 33 percent of the cost of the drug, leading to copays which can range from$150-$7,000 per month. And these medications are taken chronically, typically on a daily basis, until disease progression, unacceptable toxicity, or death. And a common question that patient ask in clinic is: “What would I do when I can no longer afford this treatment?”

In 2013, the Cancer Drug Parity Act³ was first introduced to Congress. The purpose of this bill is to help ensure that patients will not pay more for oral chemotherapy agents under their pharmacy benefit than they would for an intravenous chemotherapy agent under their medical benefit. One might wonder, don’t we have something like this in effect? Well, yes—in 43 states. Since 2007, many states have passed their own oral parity law, but it only applies to state health plans, leaving out patients under self-funded and fully insured health plans. If Congress approves this bill, the new federal legislation will require all health plans, including the remaining seven states to adopt this cancer drug parity act. Currently, seven states have yet to adopt this cancer drug parity act: Alabama, Idaho, Michigan, Montana, North Carolina, South Carolina, and Tennessee⁴.

In a retrospective claims analysis published by Dr. Dusetzina and colleagues⁵, authors found that oral chemotherapy parity laws showed only “modest” financial benefit for patients. Their analysis encompassed 63,780 patients from three nationwide insurers (Aetna, Humana, and UnitedHealthcare), comparing effects before and after oral chemotherapy parity laws. Patients that were studied lived in one of 16 states that had implemented oral chemotherapy parity laws from July 2008 to July 2012, and who were receiving chemotherapy treatment. Results showed an increase in patient out-of-pocket (OOP) spend of more than $100 per month in plans subject to parity versus a slight decline in plans not subject to parity (8.4% to 11.1% vs. 12.0% to 11.7%, p=0.004). Monthly patient OOP spend on oral chemotherapy agents showed a decline in plans subject to parity in the 25^th-, 50^th-, and 75^th percentile ($19.44, $32.13, $10.83, p<0.001), but saw an increase at the 90^th- and 95^th percentile ($37.19, $143.25, p<0.001). Dr. Dusetzina and colleagues conclude that “these laws alone may be insufficient to ensure that patients are protected from high out-of-pocket costs.”

So what should we do? As more and more precision, targeted therapies are being pumped into the market, cancer patients should not have to pay any less for their oral cancer drug treatment under their pharmacy benefit than they would under their medical benefit. It is currently unclear exactly how many patients will benefit from this bill. This federal act is a start to help patients gain access to precision medicine. The underlying issue may be the price of the agents themselves. But that’s another article for another time.

References:

1. Abramson, R. “Overview of Targeted Therapies for Cancer”. My Cancer Genome 2018. Available from: https://www.mycancergenome.org/content/molecular-medicine/overview-of-targeted-therapies-for-cancer/ (Updated May 25).
2. Wang B, Joffe S, Kesselheim AS et al. Chemotherapy parity laws: a remedy for high drug costs?. JAMA Internal Medicine 2014. 174(11):1721-1722. Available from: https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/1907003
3. Cancer Drug Parity Act of 2019, H.R. 1730, 116^th Cong. (2019). Available from: https://www.congress.gov/bill/116th-congress/house-bill/1730/text
4. “Oral anti-cancer therapy access legislative landscape-2018”. Patients Equal Access Coalition, 2018. Available from: http://peac.myeloma.org/oral-chemo-access-map/
5. Dusetzina SB, Huskamp HA, Winn AN et al. Out-of-pocket and healthcare spending changes for patients using orally administered anti-cancer therapy after adoption of state parity laws. JAMA Oncology 2018. 4(6):e173598. Available from: https://jamanetwork.com/journals/jamaoncology/article-abstract/2661763

Authors: Marissa Chow, Pharm.D. Candidate Class of 2021 and
Emily Shor, Pharm. D.

Patients with malignancies have a 20% to 30% increased risk for venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE), due to their hypercoagulable state.^1-3 Additionally, a VTE at the time of or within one year of cancer diagnosis is correlated with more advanced stages of cancer and increased risk of death.⁴ The 2019 NCCN and 2016 CHEST guidelines recommend that patients with a cancer associated VTE be anticoagulated for at least three months or indefinitely while cancer is active, patient is undergoing treatment, or risk factors remain present.^2-3,5 However, the NCCN guidelines do not provide recommendations regarding routine VTE prophylaxis in ambulatory cancer patients unless they have certain risk factors, such as certain cancer types and/or chemotherapy agents. ² Managing cancer-associated thrombosis (CAT) must balance both a patient’s increased risk of recurrent VTE patients alongside risks of bleeding. 

The CLOT trial established low-molecular-weight heparin (LMWH) as first line therapy for chronic anticoagulation therapy in patients with metastatic disease with acute VTE.⁶ Despite frequent self-injections, which can affect patient adherence, LMWHs have a faster onset and reaches steady state more quickly than vitamin K antagonists.⁷ Moreover,  dalteparin significantly decreased risk of recurrent VTE compared to oral anticoagulants.⁶ While warfarin offers an oral alternative, it can be difficult to maintain a therapeutic INR due to frequent follow-up, drug-drug interactions with chemotherapy agents, malnutrition, and possible liver dysfunction.   

Since their development, utilization of direct oral anticoagulants (DOACs) has greatly increased as their efficacy and safety were established in the setting of VTE treatment within the general population in various landmark trials. DOACs do not require frequent lab monitoring and have few drug-food interactions. However, until recently, the role of DOACs in CAT has been unclear due to limited evidence from subgroup analyses of cancer patients in each DOAC’s landmark trials. Although DOACs offer more convenient administration, further investigation of the role of DOACs as effective and safe agents in the prophylaxis and treatment of VTE in cancer patients is needed. This article will review the recently published literature regarding the use of DOACs in cancer patients. 

VTE Treatment in Cancer Patients 

The studies assessing the efficacy and safety of DOACs for VTE treatment in the general population had limited enrollment of cancer patients, ranging from 3% to 9%.^8-11 Subgroup analyses of these patients show promising results, but the enrolled cancer patients likely had a lower risk profile. Randomized trials have recently assessed the role of apixaban, rivaroxaban, and edoxaban in CAT treatment as compared to the efficacy and safety of utilizing therapeutic dosing of a LMWH, dalteparin.

Apixaban: ADAM VTE¹² 

The ADAM VTE Trial, a multicenter, open-label trial, randomized patients with cancer-associated acute VTE to receive dalteparin or apixaban (10 mg twice daily for seven days followed by 5 mg twice daily). The most frequent types of cancer were colorectal, lung, pancreas, and breast cancers, and 65.5% of patients had metastatic disease. In the apixaban group (n=145), no major bleeding events occurred within six months compared to three major bleeding events (2.1%) in the dalteparin group (n=142) (p=0.9956). Recurrent VTE occurred in five patients (3.4%) in the apixaban group and 20 patients (14.1%) in the dalteparin group (HR [hazard ratio]: 1.36; 95% CI [confidence interval]: 0.79-2.35). Monthly quality of life surveys regarding concern for excess bruising, stress, irritation, burden of delivery, and overall satisfaction (p<0.05) also favored apixaban. Thus, data from this trial supports oral apixaban therapy as it was associated with low rates of bleeding and significantly lower VTE recurrence rates.  However, full results of this study have not been published yet.

Rivaroxaban: SELECT-D¹³ 

The SELECT-D Trial was a multicenter, open-label pilot study that assessed the safety and efficacy of rivaroxaban for treatment of active VTE in patients with cancer.  Patients with an active VTE were randomized to receive dalteparin or rivaroxaban (15 mg BID for three weeks, followed by 20 mg daily for a total of six months). The most prevalent primary tumors included colorectal cancer and lung cancer. The primary efficacy endpoint (VTE recurrence at 6 months) occurred in 18 (8.9%) of 203 dalteparin patients and eight (3.9%) of 203 rivaroxaban patients, resulting in a cumulate VTE recurrence rate at six months of 11% for patients receiving dalteparin and 4% for those receiving rivaroxaban (HR: 0.43; 95% CI: 0.19-0.99). The primary safety endpoint of major bleeding occurred in six patients (3.0%) receiving dalteparin and 11 patients (5.4%) receiving rivaroxaban, resulting in a cumulative major bleeding rate of 4% for the dalteparin group and 6% for rivaroxaban group (HR: 1.83; 95% CI: 0.68-4.96). Major bleeding events most commonly occurred within the gastrointestinal tract, and there were no identified CNS bleeds. Clinically relevant non-major bleeding (CRNMB) during the six-month period occurred in 4% of dalteparin patients and 13% of rivaroxaban patients (HR: 3.76; 95% CI: 1.63-8.69), indicating that although rivaroxaban and dalteparin have similar rates of major bleeding, patients receiving rivaroxaban experienced higher rates of CRNMB. Most CRNMB occurred within gastrointestinal or urologic systems. Overall, patients with esophageal/gastroesophageal cancer experienced more bleeding compared to other cancer types, which may be related to the site of action of rivaroxaban. Ultimately, this trial suggests that rivaroxaban may be a viable alternate VTE treatment option to LMWH in cancer patients. However, results of this trial cannot be translated to longer treatment due to the short follow up period.

Edoxaban: Hokusai VTE Cancer ¹⁴

The Hokusai VTE Cancer trial was an open-label, noninferiority trial that assessed the role of edoxaban for CAT treatment. Adult patients with active cancer and VTE were randomized and stratified to receive either dalteparin or edoxaban 60 mg daily after receiving a LMWH for five days. The edoxaban dose was adjusted based on renal function (CrCl 30-50 mL/min), body weight (< 60 kg), or use of concomitant potent P-glycoprotein inhibitors. Colorectal, lung, genitourinary, and breast cancer were the most common cancer types included. Patients were treated for six to 12 months as determined by the treating physician. The primary outcome (composite of recurrent VTE or major bleeding after 12 months) occurred in 67 of 522 edoxaban patients (12.8%) and 71 of 524 dalteparin patients (13.5%) (HR: 0.97; 95% CI: 0.70-1.36; p=0.006 for noninferiority; p=0.87 superiority). Separately, recurrent VTE occurred in 41 patients (7.9%) in the edoxaban group and 59 patients (11.3%) in the dalteparin group (HR: 0.71; 95% CI: 0.48-1.06; p = 0.09) while major bleeding occurred in 36 (6.9%) and 21 (4.0%) in the edoxaban and dalteparin group, respectively (HR: 1.77; 95% CI: 1.03-3.04; P = 0.04). Most major bleeding events in the edoxaban arm occurred as gastrointestinal bleeding in the setting of gastrointestinal cancer. Ultimately, edoxaban was found to be noninferior to dalteparin in regard to the primary composite outcome, but it is important to consider the patient’s risk for bleeding, particularly based on cancer type. However, the study was underpowered to determine a difference in major bleeding based on cancer site in order to determine if solely patients with gastrointestinal cancer had an increased risk of bleeding compared to other cancer types. Additionally, similar to the ADAM VTE and SELECT-D studies, the ideal duration of anticoagulation treatment remains unclear as patients received anticoagulation for up to 12 months.

Conclusions

Based on the available literature, rivaroxaban, edoxaban, and apixaban appear to be well-tolerated and efficacious in the treatment of CAT. However, a patient-specific approach that takes into consideration a patient’s type of cancer, renal function, hepatic function, and adherence should be utilized. A recent consensus statement from the International Society of Thrombosis and Haemostasis Scientific and Standardization Committee recommends DOACs as first-line options in cancer patients if they have a low bleeding risk, and there are no drug-drug interactions.¹⁵ Remaining patients should continue to receive LMWH, especially if they have a high risk of bleeding. In particular, DOACs appear to consistently be associated with increased bleeding risk in patients with gastrointestinal or genitourinary cancers, so DOACs should be avoided in these populations. In accordance, the NCCN guidelines caution the use of DOACs in patients with cancer and urinary or GI tract lesions, pathology, or instrumentation as noted in the SELECT-D and Hokusai VTE Cancer studies.^3,13-14 At this time, it is difficult to make direct comparisons between DOACs in regard to their efficacy and safety due to the trial designs only comparing each DOAC to LMWH, but, most notably, rivaroxaban and edoxaban were found to have a statistically significant increased risk of CRNMB and major bleeding, respectively. Thus, patient specific factors, such as renal function, hepatic function, cancer type, and bleeding risk, should be considered when selection anticoagulation therapy.

VTE Prophylaxis in Ambulatory Cancer Patients 

A cancer patient’s risk of CAT is strongly associated with the type of cancer. Currently, thromboprophylaxis in ambulatory cancer patients is not routinely recommended but has been considered in high risk patients, such as those with a high Khorana Risk Score (> 3 points indicates high risk). The Khorana score assess the patient’s cancer diagnosis, body mass index, and CBC. DOACs offer a convenient alternative for VTE prophylaxis to LMWH.¹⁶ Recently, apixaban and rivaroxaban have been assessed in trials to be utilized in this setting.

Apixaban: AVERT Trial¹⁷

The AVERT Trial was a placebo-controlled, double-blind trial that assessed the role of apixaban compared to placebo for thromboprophylaxis in intermediate-to-high risk (Khorana score >2) ambulatory patients with cancer and initiating chemotherapy. Patients were randomized to initiate apixaban 2.5 mg twice daily or placebo within 24 hours of chemotherapy initiation for a treatment period of 180 days. The most common types of primary cancer included gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%) cancers.  The primary efficacy outcome (first episode of objectively documented major VTE (proximal DVT or PE) within 180 days) occurred in 12 of 288 patients (4.2%) in the apixaban group and 28 of 275 patients (10.2%) in the placebo group (HR: 0.41; 95% CI: 0.26-0.65; p<0.001), indicating a significantly lower risk of VTE in patients treated with apixaban, which was primarily driven by a lower rate of PE in the apixaban group. However, a statistically significant increase in major bleeding episodes was found in the apixaban group. Major bleeding events occurred in 10 of 288 patients (3.5%) in the apixaban group and five of 275 patients (1.8%) in the placebo group (HR: 2.0; 95% CI: 1.01-3.95; p=0.046). The major bleeding events were primarily associated with gastrointestinal bleeding, hematuria, and gynecologic bleeding with apixaban, and major bleeding most commonly occurred in patients with cancer of gastrointestinal or gynecologic nature. Overall, this trial displayed that there was no difference in survival between the apixaban and placebo groups; however, most of the patients in the trial had advanced stages of cancer.  The study consisted of limited types of cancers, so it is difficult to make conclusions regarding apixaban’s safety and efficacy in other cancer types; however, most commonly, included patients had cancers that significantly increased their risk for thrombosis events. Additionally, this study had a limited population with reduced renal function, a population at an increased risk of bleeding.   

Rivaroxaban: CASSINI Trial¹⁸

The CASSINI Trial was a double-blind, multi-centered, placebo-controlled trial. This study randomized patients with a solid tumor or lymphoma initiating a new cancer regimen and a Khorana score of at least two to receive rivaroxaban 10 mg or placebo daily for up to 180 days. Patients were screened every eight weeks for the development of the efficacy and safety endpoints. The most common types of primary cancer included pancreatic cancer (32.6%) and gastric/gastroesophageal junctional cancer (20.9%). Of patients with a solid tumor, 54.5% had metastatic disease. Of note, more patients with a history of VTE were randomly assigned to the rivaroxaban group compared to the placebo group (2.6% v. 0.5%). Additionally, 43.7% of patients in the rivaroxaban group and 50.2% of patients in the placebo group discontinued therapy prematurely. The mean intervention period (time period from the first dose of either drug through the last dose plus two days) was 4.3 months. The primary efficacy endpoint (development of DVT or PE) occurred in 11 (2.6%) of 420 rivaroxaban patients compared to 27 (6.4%) of 421 placebo patients during the intervention period (HR: 0.40; 95% CI: 0.20-0.80). However, during the period up to day 180, the primary efficacy composite endpoint occurred in 25 (6.0%) of the rivaroxaban patients compared to 37 (8.8%) of the 421 placebo patients (HR: 0.66; 95% CI: 0.40-1.09). The primary safety endpoint (major bleeding) occurred in 8 (2.0%) of the 405 rivaroxaban patients and 4 (1.0%) patients in the placebo arm (HR: 1.96; 95% CI: 0.59-6.49; p=0.26). Ultimately, in this population, low-dose rivaroxaban did not result in a statistically significant reduction in VTE at 180 days when compared to placebo, but, in the pre-specified intervention period, there was a 3.6% absolute reduction in thromboembolism with rivaroxaban, which may be hypothesis generating as this time period could be subject to bias. These findings are consistent with results of previous trials assessing rivaroxaban for thromboprophylaxis in cancer patients, such as the PROTECHT and SAVE-ONCO trials. However, the CASSINI trial included a higher-risk population. Additionally, an overall discontinuation rate of approximately 47% may be a limitation due to the inability to fully depict the bleeding and VTE occurrence. Overall, the role of rivaroxaban as thromboprophylaxis in this patient population remains promising.             

Conclusions  

Apixaban and rivaroxaban have both been shown to be noninferior to current standard therapy placebo. Current recommendation for anticoagulation therapy for ambulating cancer patients suggest that no further anticoagulation is needed. However, these studies show that DOACs may be used as primary prophylaxis in high-risk patients. Most notably, both studies showed an increased risk of bleeding, which must be considered and evaluated for each patient. Further research is needed in order to determine optimal anticoagulation in ambulating cancer patients with less advanced stages of cancer.  Additionally, the optimal timing and duration of thromboprophylaxis as well as the impact of thromboprophylaxis on cancer prognosis remain unclear.  

References 

1. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. Available at http://doi.org/10.1182/blood-2013-04-460121.  
   
2. Kearon C., Akl EA., Ornelas J, et al. Antithrombotic theraoy for VTE disease: CHEST guidelines and expert panel report. Chest. 2016; 149 (2): 315-352. DOI: 10.1016/j.chest.2015.11.026.  
   
3. Streiff MB, Holmstrom B, Angelini D, et al. NCCN clinical practice guidelines in oncology: cancer-associated venous thromboembolic disease: Version 1.2019. htpps://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Published February 28, 2019. Accessed September 4, 2019.  
   
4. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000; 343: 1846-1850.  
   
5. Kuderer NM, Francis CW, Culakova E, et al. Venous thromboembolism and all-cause mortality in cancer patients receiving chemotherapy. J Clin Oncol. Published 12 Dec 2016. DOI: 10.1200/jco.2008/26/15_suppl/9521.  
   
6. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003; 349: 146-153. DOI: 10.1056/NEJMoa025313.  
   
7. Khorana AA, Yannicelli D, McCrae KR, et al. Evaluation of US prescription patterns: Are treatment guidelines for cancer-associated venous thromboembolism being followed? Throm Res. DOI: 10.1016/j.thromres.2016.07.013.  
   
8. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009; 361:2342–2352.
   
9. Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013; 369:1406–1415,
   
10. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism, N Engl J Med. 2013: 369;799–808
    
11. EINSTEIN–PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism, N Engl J Med. 2013:366; 1287–1297,
    
12. McBane II RD, Wysokinski WE, Le-Rademacher J, et al. Apixaban, dalteparin, in cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018; 132(1): 421.  
    
13. Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018; 36(20): 2017-2023.  
    
14. Raskob GE, Van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018; 378(7): 615-624.  
    
15. Khorana AA, Noble S, Lee AYY, et al. Role of direct oral anticoagulants in the treatment of cancer associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018; 16(8): 1891-1894.
    
16. Choudury A, Balakrishnam A, Thai C, et al. Validation of the Khorana score in a large cohort of cancer patients with venous thromboembolism. Blood. 2016; 128(22):879.
    
17. Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019; 380:711-719.  
    
18. Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019; 380: 720-738.

Authors: Nicholas Pauley, PharmD Candidate 2020 and
Mallory Crain, PharmD

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults.¹ The average age at diagnosis is 69 years with a 5-year survival rate of 28.3%.² A key determinant for increased survival is the patient’s ability to undergo intense induction chemotherapeutic regimens. However, intensive therapies are not always an option since some patients are unable to tolerate these treatments due to age and comorbidities. Fortunately, targeted therapies have expanded treatment options for these patients.

Targeting specific genetic mutations in AML has become a large area of research in recent years.  Specifically, isocitrate dehydrogenase (IDH) 1 or 2 mutations are present in approximately 20% (IDH1: 7-14%, IDH2: 8-19%) of newly diagnosed patients with AML.³ Until recently, there were no specific therapies for patients with these mutations.  Two IDH inhibitors, enasidenib and ivosidenib, were FDA approved in August 2017 and July 2018, respectively. Both agents increase myeloid differentiation through inhibition of the IDH enzymes.^4,5

Enasidenib is currently FDA approved at a dose of 100 mg by mouth once daily for the treatment of relapsed/refractory AML in patients with an IDH2 mutation.⁴ Although enasidenib is only FDA approved for relapsed/refractory patients, the NCCN guidelines also recommend enasidenib as an option for older patients who are unfit for intensive therapy.⁶ No significant drug interactions requiring dose adjustments have been identified.⁴

A phase 1, dose escalation and expansion study evaluated AML patients with an IDH2 mutation who were treated with enasidenib.  A total of 109 patients in the study had relapsed/refractory AML.  The median age was 67 years, and most patients received at least two prior therapies.  The overall response rate (ORR) was 38.5% with a complete remission (CR) of 20.2%.  The median overall survival (OS) was 9.3 months.  Of note, the median time to first response was 1.9 months.⁷ This study also evaluated 29 newly diagnosed patients who were deemed unfit for standard regimens. The ORR was 30.8% with a CR of 18%.  The estimated median OS was 11.3 months.⁸

Ivosidenib is FDA approved at a dose of 500 mg for patients with an IDH1 mutation who have relapsed/refractory AML or are > 75 years with newly diagnosed AML (or those who cannot tolerate intensive induction chemotherapy). Dose adjustments for ivosidenib are recommended if it is given with strong CYP3A4 inhibitors since ivosidenib is a major CYP3A4 substrate. Induction of CYP3A4 has also been reported.⁵

A phase 1, dose escalation and expansion study evaluated AML patients with an IDH1 mutation who were treated with ivosidenib.  A total of 179 patients had relapsed/refractory AML with a median age of 68 years. The ORR was 41.6% with a CR of 21.6%.  The median OS in the primary efficacy group was 8.8 months.  Similar to enasidenib, the median time to response was 1.9 months.  This study also included 34 patients with untreated AML (median age: 76.5 years).  The ORR was 58.8% with a CR of 26.5%. Survival data was not published for these patients.⁹

In regard to safety, both agents have a similar adverse effect profile.  The most common adverse events observed in clinical trials were diarrhea, nausea, leukocytosis, febrile neutropenia, and anemia.  In addition, 38% of patients treated with enasidenib had indirect hyperbilirubinemia, and 24.6% of patients who received ivosidenib had a prolonged QTc interval.  Both agents caused differentiation syndrome in approximately 5% of patients, which is a serious complication that can become life-threatening. Therefore, it is imperative that clinicians are able to identify and treat differentiation syndrome when it occurs.^7,10,13

Differentiation syndrome results from rapid proliferation and differentiation of myeloid cells leading to cytokine imbalance and inflammation throughout the body.  It can present as a fever, cough, dyspnea, hypoxia, pleural effusions, pulmonary infiltrates, or organ dysfunction of unknown cause.  The median onset was 29 days (range 5 to 59) for ivosidenib and 48 days (range 10 to 340) for enasidenib in the phase 1 trials.^7,9 Patients who experience differentiation syndrome should be initiated on dexamethasone 10 mg IV every 12 hours for a minimum of 3 days or until symptoms resolve.  If patients also develop leukocytosis, initiation of hydroxyurea may be considered.  Ivosidenib and enasidenib should only be discontinued if severe symptoms persist for more than 48 hours after the start of dexamethasone.^4,5

Within recent years, several new agents, including targeted therapy, have emerged as treatment options for AML.  In a disease state with previously limited options, having additional lines of therapy potentially allows for increased survival compared to historical treatment options. While intensive induction therapy is still the standard of care for those who can tolerate it, it is not an option for every patient. IDH inhibitors provide another treatment option for relapsed/refractory AML patients as well as those who cannot tolerate intensive induction therapy. In addition, an oral medication taken at home may be more convenient or desirable for some patients. When comparing these agents to traditional chemotherapy, one important factor to consider is the longer expected time to response.  The median time to response with IDH inhibitors is 1.9 months compared to an expected response within 30 days with traditional chemotherapy. Although long-term efficacy data is not yet available, the IDH inhibitor phase 1 trials show similar results compared to other standard treatment options given in the relapsed/refractory and newly diagnosed settings.^6-9,11 Overall, both of these agents have proven efficacy in AML patients with an IDH mutation, and it is likely that use of IDH inhibitors for the treatment of AML will only continue to grow.

References

1. Sant M, Allemani C, Teareanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of HAEMECARE project. Blood. 2010;116(19):3724-34.
2. SEER Cancer Stat Facts: Acute Myeloid Leukemia. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/amyl.html. Accessed August 20, 2019.
   
3. Medeiros BC, Fathi AT, DiNardo CD, et al. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;(31):272-281. 
   
4. IDHIFA [package insert]. Summit, NJ: Celgene Corporation; (2017).
5. TIBSOVO [package insert]. Cambridge, MA: Agios Pharmaceuticals; 2018.
6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: acute myeloid leukemia. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Published May 5, 2019. Accessed June 26, 2019.
7. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
   
8. Pollyea DA, Tallman MS, deBotton S, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019.
   
9. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib (AG-120) induced durable remissions and transfusion independence in patients with IDH1-mutant untreated AML: results from a phase 1 dose escalation and expansion study. Blood. 2018;(132):561.
   
10. Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014;123(18):2777-2782.
    
11. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398.
    
12. Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012;97(12):1916-24.
    
13. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015; 373: 1136–1152.
    
14. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016;127(1):53-61.

Authors: Avatar Patel, PharmD Candidate 2020; Marissa Olson, PharmD, BCOP and Kristan Augustin, PharmD, BCOP

Cytomegalovirus (CMV) is the largest β-herpesvirus transmitted by direct contact with infectious body fluids and is prevalent in over half of adults by the age of 40 years.¹ CMV infection and disease are often characterized together, although they are not synonymous. CMV infection refers to the detection of viral antigens in tested bodily fluid or tissue, while CMV disease refers to symptomatic end-organ disease.² While most individuals do not have signs or symptoms associated with CMV infection, primary infection leads to life-long latency. Reactivation of CMV infection occurs in 50-60% of patients after hematopoietic stem cell transplantation (HSCT) due to decreased CD4⁺ and CD8⁺ lymphocytes and represents the most common infection in HSCT.² CMV reactivation is associated with increased morbidity and mortality post-HSCT. Common complications include pneumonia, colitis, and hepatitis. Risks for CMV reactivation include recipient and donor CMV seropositivity, transplant modality, and recipient’s age. Infection risk in HSCT patients can be broken down into three phases which include early phase (day 0 to day 30), intermediate phase (day 31 to day 100), and late phase (day 101 and after) post-transplant. Although CMV reactivation in HSCT patients can occur at any time, most reactivation is seen during the intermediate phase. Without prophylaxis, 80% of CMV-seropositive patients undergoing HSCT will have CMV reactivation.⁴

Prevention of CMV complications in HSCT patients can be approached by primary prophylaxis or preemptive therapy. Primary prophylaxis includes treating high risk patients, defined as recipients who are CMV-seropositive, during the first 100 days after transplant. Preemptive therapy is defined as the initiation of therapy after the detection of CMV viremia. Current National Comprehensive Cancer Network (NCCN) guidelines for preemptive therapy recommend valganciclovir or ganciclovir as first-line agents for the treatment of CMV viremia. Foscarnet or cidofovir are recommended as second-line agents for resistant CMV or for patients unable to tolerate first line therapy.⁵ The major limitations of preemptive therapy include weekly clinical follow-up and lack of protection against early CMV reactivation, which can lead to complications. While primary prophylaxis reduces early CMV reactivation, it does not prevent late onset reactivation, and use of antiviral therapies may be associated with significant adverse events such as myelosuppression and nephrotoxicity.⁶

Letermovir (Prevymis^TM) was approved by the Food and Drug Administration (FDA) in November 2017 for CMV prophylaxis in HSCT CMV-seropositive recipients. Letermovir is the first non-nucleoside 3,4 dihydroquinazoline, reversible viral terminase inhibitor. It acts on the late stages of viral replication by inhibiting viral terminase at UL56 subunit which prevents viral DNA cleavage and results in inhibition of viral replication.⁶ Letermovir differs from other antiviral agents with CMV activity, such as ganciclovir, valganciclovir and foscarnet, in that it does not target UL54. Rather, it has a unique binding domain on UL56, which prevents cross-resistance with other agents.⁵ It is available as both an immediate-release tablet and intravenous formulation. It is initiated at 480 mg once daily beginning between day 0 and day 28 posttransplant and continued through day 100. Letermovir is eliminated via hepatic uptake OATP1B1/3 with a half-life of 12 hours.

In addition, letermovir is also a substrate of P-glycoprotein and a moderate inhibitor of CYP3A and CYP2C8 which can lead to drug-drug interactions. Trials have shown letermovir reduces the AUC of voriconazole by 50% and increases the AUC and T_max of atorvastatin.² Dosage should be decreased to 240 mg once daily in patients receiving concomitant therapy with cyclosporine as cyclosporine-mediated OTAP1B1/3 inhibition has been shown to double the AUC of letermovir.⁷ There are no dose adjustments recommended for creatinine clearance > 10 ml/min and mild or moderate hepatic impairment (Child Pugh class A or B). Letermovir is also not recommended in patients with severe hepatic impairment (Child Pugh class C) due to increased exposure.

NCCN guidelines updated in early 2019 added letermovir as a first-line agent for CMV prophylaxis in CMV-seropositive allogeneic HSCT recipients based on the results of a phase III study. The trial randomized 545 subjects in a 2:1 ratio to receive letermovir or placebo daily through week 14. The primary end point was the proportion of subjects with clinically significant CMV infection, defined as > 300 copies/ml via PCR testing, through week 24. Patients were stratified based on CMV disease risk and were eligible if they were CMV-seropositive and had an undetectable level of CMV DNA within 5 days of randomization. A decrease in clinically significant CMV infection at week 24 was observed in the letermovir group compared to the placebo group (37.5% vs. 60.6%, p < 0.001). In addition, all-cause mortality was lower at week 24 for patients receiving letermovir (10.2% vs. 15.9%, p < 0.03). Patients being treated for graft versus host disease (GvHD) or those with T-cell depleted grafts were found to have the greatest benefit from letermovir prophylaxis. However, the trial did show a rise in CMV infection when letermovir was discontinued after 100 days which may suggest the reduced benefit of letermovir prophylaxis when discontinued. There were no statistical significant differences in adverse effects between the two treatment groups.⁷

Letermovir has proven efficacy when used as CMV prophylaxis in HSCT CMV-seropositive recipients. It offers clinicians a therapeutic option without the significant toxicities seen with other antiviral treatments. Although the phase III trial showed a significant decline in rates of CMV infection and all-cause mortality at 24 weeks, there are still unanswered questions. Upon discontinuation of letermovir, high risk patients were more likely to have CMV reactivation. In addition, while this trial only evaluated letermovir for prevention of CMV in HSCT patients, future trials may assess the potential option to use letermovir as a treatment option due to the minimal adverse effect profile.

References

1. Centers for Disease Control and Prevention. Cytomegalovirus (CMV) and Congenital CMV Infection. www.cdc.gov/cmv/overview (accessed 2019 June 6).

2. Ljungman P, Boeckh M, Hirsch HH et al. Definitions of Cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2016;1(1):87-91.

3. Deleenheer B, Spriet I, Maertens J. Pharmacokinetic drug evaluation of letermovir prophylaxis for cytomegalovirus in hematopoietic stem cell transplantation. Expert Opinion on Drug Metabolism & Toxicology. 2018;14(12):1197-1207.

4. Styczynski J. Who is the patient at risk of CMV recurrence: A review of the current scientific evidence with a focus on hematopoietic cell transplantation. Infect Dis Ther. 2018;7:1-16.

5. National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections (updated 2019). www.nccn.org/professionals/physician_gls/pdf/infections.pdf (accessed 2019 Jul 18).

6. Razonable RR. Role of letermovir for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation. Curr Opin Infect Dis. 2018;31:286-291.

7. Foolad F, Aitken SL, Chemaly RF. Letermovir for the prevention of cytomegalovirus infection in adult cytomegalovirus-seropositive hematopoietic stem cell transplant recipients. Expert Review of Clinical Pharmacology. 2018;11(10):931-941.

8. Marty FM, Ljungman P, Chemaly RF et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433-2444. 

Authors: Betsy Abraham, PharmD: PGY-1 Pharmacy Resident, NorthShore University HealthSystem
Katie Lentz, PharmD, BCOP: Oncology Clinical Pharmacy Specialist, Barnes-Jewish Hospital

Nausea and vomiting are common in patients who are on chemotherapy. A recent analysis of 991 patients receiving chemotherapy showed an incidence of anticipatory nausea of 8 to 14%, with rates increasing with each subsequent cycle.¹  Patients beginning a cancer treatment consistently list chemotherapy-induced nausea and vomiting (CINV) as one of their greatest fears.² Patient factors which increase the risk of nausea and vomiting include: female gender, age less than 50 years, dehydration, history of motion sickness, prior history of nausea and vomiting with chemotherapeutic agents, receiving chemotherapy outpatient, dose and emetogenicity of chemotherapy, no history of alcohol consumption and radiation (whole body or upper abdomen). Inadequately controlled emesis decreases the quality of life for patients, increases the use of healthcare resources, and can impair a patient from completing chemotherapy.^3-4 However, new insights into the pathophysiology of CINV and a better understanding of the risk for these effects have helped clinicians better treat and prevent CINV. 

There are three subtypes of CINV which include: acute, delayed and anticipatory (see Table 1 for list of available agents). Acute CINV occurs within 24 hours after chemotherapy. Patients who are at greater risk for anticipatory CINV include those who have any of the patient factors which increase the risk of nausea and vomiting. The neurotransmitter responsible for anticipatory CINV is serotonin (5HT3). Therefore, treatment of CINV is with 5HT3 receptor antagonists (5HT3-RA) such as ondansetron (Zofran®). On the other hand, delayed CINV occurs 1 to 7 days after chemotherapy. The chemotherapeutic classes/agents which increase the risk for delayed CINV are ones of high emetic risk (> 90% of patients experience CINV without appropriate prophylaxis) which include, but are not limited to: anthracyclines, platinum analogs, cyclophosphamide (Cytoxan®), and ifosfamide (Ifex®).⁵ The neurotransmitter believed to primarily be responsible for delayed CINV is Substance P. However, delayed CINV is treated with a combination of antiemetics which include Neurokinin-1 receptor antagonists (NK1-RA) such as aprepitant (Emend®) and fosaprepitant intravenous (Emend®), corticosteroids, and the 5HT3-RA palonosetron (Aloxi®) (see Table 2 for list of combinations).^6-7 Finally, anticipatory CINV happens prior to receiving a chemotherapeutic agent and is seen in patients with a history of CINV with prior use of chemotherapeutic agents. Treatment of anticipatory CINV is with benzodiazepines, specifically lorazepam (Ativan®).

Despite receiving antiemetic prophylaxis for acute and/or delayed CINV, some patients may experience breakthrough nausea and vomiting. Various antiemetics may be used during this time, including 5HT3-RAs, dopamine receptor antagonists, and cannabinoids. 5HT3-RAs such as ondansetron, palonosetron, granisetron (Kytril®) and dolasetron (Anzemet®) are usually well-tolerated by most patients and have constipation and migraine-like headaches as its side effects. Dopamine receptor antagonists such as prochlorperazine (Compazine®), promethazine (Phenergan®), and metoclopramide (Reglan®) are commonly prescribed; however, these agents carry unpleasant side effects such as extrapyramidal symptoms such as acute dystonia as well as sedation.^6-7 Patients who develop acute dystonic reactions are treated with anticholinergics: benztropine (Cogentin®) and diphenhydramine (Benadryl®). Furthermore, cannabinoids, like dronabinol (Marinol®) and nabilone (Cesamet®) can be used second line for breakthrough CINV. These are synthetic analogs of delta-9-tetrahydrocannabinol, a naturally occurring component of Cannabis sativa. Cannabinoids carry side effects such as increased appetite, sedation, dysphoria, or euphoria. Therefore, these agents are prescribed only when patients have CINV with the preferred agents.^6-8

Additionally, one agent that has recently come to prominence for CINV is the second-generation anti-psychotic olanzapine (Zyprexa®) typically used for the treatment of bipolar I disorder and schizophrenia. A randomized, double-blind phase 3 trial compared olanzapine with placebo in combination with dexamethasone (Decadron®), aprepitant or fosaprepitant, and a 5HT3-RA. The study revealed that the anti-emetic combination with olanzapine, as compared with placebo, had a lower proportion of patients with no CINV in the first 24 hours (74% vs. 45%, p = 0.002), the period from 25 to

120 hours after chemotherapy (42% vs. 25%, p = 0.002), and the overall 120-hour period (37% vs. 22%, P=0.002).⁹ Moreover, complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (p < 0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001).⁹ Dosed at 5-10 mg by mouth daily, olanzapine has become a novel agent used in combination with dexamethasone and palonosetron in patients with moderate to high emetogenic potential.

The goal for each patient is to prevent CINV and to start antiemetics prior to chemotherapy. The risk of nausea and vomiting can persist for up to 3 days after receiving the last dose of high emetic potential agents and for up to 2 days with moderate emetic potential agents.  CINV is a fear of patients who are starting chemotherapy or already receiving chemotherapy. Over the past two decades, more effective and better tolerated pharmacologic agents have been developed to prevent CINV. Currently, 5HT3-RAs, NK1-RAs, and corticosteroids are the most effective therapeutic agents to help prevent and control CINV. Despite the use of these therapeutic agents, uncontrolled vomiting and inadequately controlled nausea remain a problem in patients. Nevertheless, complete remission from CINV should be a goal for each patient with the hopes that patients can receive chemotherapy without having the fear of CINV.

References

1. Aapro M. CINV: still troubling patients after all these years. Supportive Care in Cancer. 2018;26(1):55-59.
2. de Boer-Dennert M, de Wit R, Scmitz PI, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer 1997;76:1055-1061.
3. Bloechl-Daum B, Deuson RR, Mavros P, et al. Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol 2006;24:4472-4478.
4. Farrell C, Brearley SG, Pilling M, et al. The impact of chemotherapy-related nausea on patients' nutritional status, psychological distress and quality of life. Support Care Cancer 2013;21(1): 59-66.
5. National Comprehensive Cancer Network/ Anti-Emesis Guidelines. Version 2.2017. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf
   
6. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2492.
7. Navari R, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;374:1356-1367.
8. Hesketh PJ, Kris GM, Basch E, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2017;35:3240-3261.
9. Navari R, Qin R, Ruddy JK, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;375(2):137-142.

Authors: Justice Oehlert, PharmD Candidate 2020 and
Kathryn Lincoln, PharmD, BCPS, BCIDP, Clinical Pharmacist – Infectious Diseases, Olathe Medical Center

Learning Objectives:

1. Describe the magnitude of the problem of multi-drug resistant gram negative bacteria
2. Identify the bacteria that pose the most risk in the United States and globally
3. Describe mechanisms of resistance for selected bacteria against antibiotic agents
4. Evaluate the use of novel antibiotic agents against multi-drug resistant bacteria

Background

The discovery of antibiotics in the 20th century ushered in a golden age of medicine. Before the discovery of penicillin in 1928 and its subsequent wide-spread use, bacterial infections were much more deadly. The introduction of antimicrobial therapies markedly increased the average life expectancy and drastically reduced the mortality rate of communicable diseases. Over the next several decades many new classes of antibiotics were discovered and marketed. As we entered the 21st century, the discovery of new antibiotic classes plateaued, and newly approved agents had been limited to classes that were already established. Bacterial resistance to antibiotics has steadily followed the introduction of new agents. As soon as an agent is used in clinical practice, populations of bacteria that are exposed begin selecting individuals that harbor genetic mechanisms of resistance. Furthermore, resistance mechanisms often render the pathogen resistant to multiple, if not all, agents in a given class of antibiotics. Due to the costly development process and low rate of return on investment, pharmaceutical companies have had little incentive to perform research and development on new antimicrobial agents. Thus, we are currently seeing higher rates of resistance to our commonly employed antibiotics. Agents that had typically been reserved due to toxicity or low resistance, such as colistin, tigecycline or carbapenems, are being forcibly employed. As a result, resistance to these agents is increasing at an alarming rate. Pairing this resistance with a lack of viable antibiotic treatment options leads to a global crisis. The 2014 study commissioned by the UK government used predictive modeling to demonstrate that, in a worst case scenario, by 2050, the death rate from resistant bacteria could be as high as 10 million individuals per year, surpassing the current death rate of cancer.¹

Pathogenic bacteria in humans are acquiring resistance at an alarming rate, often to many different available antibiotics. Multi-drug resistant (MDR) bacteria are non-susceptible to at least one agent in three or more antimicrobial classes, extensively-drug resistant (XDR) are non-susceptible to at least one agent in all but two or fewer classes, and pandrug-resistant bacteria are non-susceptible to all available agents.² Some of the most concerning organisms to consider are gram negative bacilli (GNB), which are responsible for 45-70% of ventilator-associated pneumonia cases (VAP), 20-30% of catheter-related bloodstream infections, and commonly cause sepsis related to urinary tract infections (UTI) or surgical site infections.³ Gram-negative bacteria are often intrinsically more resistant to common antibiotics due to their additional lipopolysaccharide membrane, which serves as a permeability barrier to many drugs.² Additionally, gram-negative bacteria can acquire resistance through mutations as well as horizontally transfer resistance genes through transformation, transduction, and conjugation both within and between species. Bacteria introduced into humans via consumption of livestock is potentially able to transfer resistance, having been demonstrated with extended spectrum beta-lactamase (ESBL) and the colistin resistance gene mcr-1 in GNR.²

The most relevant MDR gram-negative pathogens in humans are members of Enterobacteriaceae, such as Escherichia coli, Citrobacter spp., Enterobacter spp., Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter spp. In the latest antibiotic resistance report released by the CDC in 2013, carbapenem-resistant Enterobacteriaceae (CRE) account for approximately 9,000 infections and 600 deaths per year.¹⁰

Several studies have been performed to evaluate resistance rates of GNB in institutional settings. The INICC, SENTRY, ANSRPRG, and EARS-NET analyzed data in a multitude of countries and in both ICU and non-ICU settings. Results demonstrated Enterobacteriaceae resistance to fluoroquinolones from 0-70%, 3rd generation cephalosporins 0-72%, and carbapenems 0-59%, depending on the study. Pseudomonas aeruginosa was 0-53% resistant to fluoroquinolones, 0-51% resistant to aminoglycosides, 0-55% resistant to piperacillin/tazobactam, 0-44% resistant to ceftazidime, and 3-60% resistant to carbapenems. The resistance variability between study sites reiterates the importance of generating local antibiograms to help guide empiric therapy for bacterial infections.

Resistance Mechanisms

For Enterobacteriaceae, the primary mechanism of resistance to beta-lactams is the production of beta-lactamases, which are enzymes that hydrolyze the beta-lactam ring of these agents and render them unable to bind to penicillin-binding protein (PBP). Additionally, AmpC, an inducible beta-lactamase, can confer further resistance to 2nd and 3rd generation cephalosporins in Enterobacter spp., Citrobacter freundii, Serratia marcescens, Morganella morganii, and others. Exposure to penicillins and 1st-3rd generation cephalosporins can cause the AmpC gene to become de-repressed and resistance can evolve quickly. Additionally, plasmid-borne beta-lactamases of the ESBL variety confer resistance to all cephalosporins. Finally, strains which carry plasmid-borne carbapenemases that inactivate carbapenems have rapidly spread.³

While all Enterobacteriaceae are naturally susceptible to fluoroquinolones, chromosomal mutations in DNA gyrase and topoisomerase IV genes modify the binding affinity and raise the MIC for specific agents. Additionally, mutations may lead to decreased permeability into the cytoplasm or increased drug efflux. Plasmid-borne mechanisms of resistance have also been observed, and are frequently associated with ESBL producing strains.³

Pseudomonas aeruginosa, like the Enterobacteriaceae, also carry an inducible AmpC cephalosporinase that confer resistance to 3rd generation cephalosporins. Wild-type strains are intrinsically resistant to amoxicillin, amoxicillin/clavulanate, 1st and 2nd generation cephalosporins, cefotaxime, ceftriaxone, and ertapenem. They are susceptible to piperacillin, ceftazidime, cefepime, imipenem, meropenem, and doripenem. Mutations in efflux transporters rendering them overexpressed confers resistance to aztreonam, cefepime, and meropenem. Fluoroquinolone resistance results from mutations in topoisomerase-encoding genes and/or hyperactive efflux systems. Finally, colistin resistance has been well documented in regards to selection of mutants. More recently, transferable resistance has been described in Pseudomonas harboring mcr-5, a variant of the gene discussed previously.^3,11

The newest advancement in the bacterial arms race is the emergence of resistance to colistin. Certain species are intrinsically resistant, such as Proteus spp., Providencia spp., Serratia spp., and Morganella spp. Naturally, MDR strains of these organisms are concerning due to the lack of susceptibility to colistin, which is currently the last resort agent for CRE. Until recently, transferable resistance to colistin had not been observed. The plasmid-borne mcr-1 gene confers resistance to colistin and was described in farm animals in several countries, including the U.S. In China, the mcr-1 gene has been found in humans, livestock, and food products.^2,3

Novel Agents

Ceftolozane/tazobactam (TOL/TAZ) is a cephalosporin/beta-lactamase inhibitor combination FDA approved for the treatment of complicated intra-abdominal infections (cIAIs), in combination with metronidazole, and complicated urinary tract infections (cUTIs), including pyelonephritis. TOL/TAZ demonstrated superiority to levofloxacin in the outcomes of composite cure and microbiological eradication in cUTI. It was non-inferior to meropenem in the outcome of clinical cure of cIAI.⁵ It is highly potent against P. aeruginosa, most Enterobacteriaceae and also ESBL-producing GNB, but provides little activity against Acinetobacter baumannii.^5,7 Common mechanisms of resistance in P. aeruginosa are ineffective against ceftolozane/tazobactam. TOL/TAZ provides most of its utility in practice towards treating Pseudomonas and ESBL producing GNB infections while sparing carbapenems. It has been referred to as the most potent antibiotic against Pseudomonas.⁷

Ceftazidime/avibactam (TAZ/AVI) is a cephalosporin/beta-lactamase inhibitor combination FDA approved for cUTI, cIAI (in combination with metronidazole), healthcare-associated pneumonia (HAP) and VAP.⁷ The addition of avibactam restores activity of ceftazidime to a variety of organisms, including ESBL producing GNB and some, but not all, carbapenemase producing GNB, including Pseudomonas aeruginosa.^4,5,7 In comparison to TOL/TAZ, the presence of avibactam leads to retention of activity against GNB that produce Klebsiella pneumoniae carbapenemases (KPC).⁶ In clinical trials, TAZ/AVI plus metronidazole was compared with meropenem in patients with cIAIs and nosocomial pneumonia, and proved non-inferiority. An open-label trial comparing TAZ/AVI to best available therapy in cUTI or cIAI caused by ceftazidime-resistant Enterobacteriaceae or P. aeruginosa showed utility as an alternative to carbapenems.⁷ The Consortium of Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) database demonstrated that therapy for CRE infection with TAZ/AVI had significantly lower mortality than therapy with colistin. Current data does not support the use of TAZ/AVI as monotherapy when MDR GNB are suspected. Use of local antibiograms should be employed to pair its use with an aminoglycoside, fosfomycin, tigecycline, or colistin.⁷

Meropenem/vaborbactam is the first carbapenem/beta-lactamase inhibitor combination product available. Addition of vaborbactam restores activity of meropenem against some, but not all, carbapenemase producing GNB.⁷ It was FDA approved for cUTI, including acute pyelonephritis, after demonstrating non-inferiority to piperacillin/tazobactam.^4,7 On a negative note, one study found that the addition of vaborbactam did not increase in vitro activity against P. aeruginosa or Acinetobacter spp. in comparison to meropenem alone.⁴ Real-life clinical data is lacking at this point, which will be necessary to define its place in clinical practice.⁷

Plazomicin is the newest agent in the aminoglycoside class and is active against MDR Enterobacteriaceae due to its stability against AMEs.^4,7 Plazomicin spectrum of activity includes Enterobacteriaceae (including CRE, ESBL, and MDR isolates) as well as methicillin-resistant Staphylococcus aureus (MRSA) irrespective of resistance to currently available aminoglycosides. Moreover, plazomicin has demonstrated favorable in vitro activity against polymyxin-resistant Enterobacteriaceae, including mcr-1 producing isolates.^4,9 FDA approval was achieved for cUTI based on comparisons of plazomicin with meropenem or colistin with concurrent tigecycline or meropenem, in which non-inferiority was demonstrated. Favorable lung penetration, in comparison to colistin, may hold some promise as to future adjunctive therapy for VAP. Plazomicin potentially has utility as part of combination therapy for XDR GNB along with novel beta-lactams.⁷

Eravacycline, a synthetic fluorocycline with similarities to tigecycline, has activity against GNB and gram positive cocci. It inhibits peptide elongation by binding to the 30s subunit of the bacterial ribosome and inhibiting addition of amino acids to the growing peptide chain. Many mechanisms of resistance, such as ESBL production, do not affect the activity of eravacycline. While it does not inhibit P. aeruginosa, it is active against MRSA and vancomycin-resistant enterococcus (VRE). Its advantages over tigecycline include more potent in vitro activity, excellent oral bioavailability, lower potential for drug interactions, and greater activity in biofilms. Of note, it extensively concentrates in alveolar macrophages, indicating potential utility in pneumonias caused by MDR bacteria. It is the most potent antibiotic against carbapenem resistant A. baumannii. Eravacycline is FDA approved for cIAI based on 2 clinical trials that demonstrated non-inferiority to ertapenem and meropenem.

Omadacycline is a semisynthetic derivative of minocycline within the tetracycline class. It is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) as well as community-acquired pneumonia (CAP). Coverage includes gram-positive, including MRSA and VRE, gram-negative, anaerobic and atypical pathogens. FDA approval was obtained for ABSSSIs based on the results of 2 trials demonstrating non-inferiority to linezolid. Approval for CAP was obtained based on a trial comparing omadacycline to moxifloxacin, in which omadacycline demonstrated non-inferiority.⁸

Imipenem/cilastatin/relebactam (IMI/REL) is a carbapenem/beta-lactamase inhibitor that gained FDA approval in July 2019 for complicated UTIs, including pyelonephritis, and cIAIs, both due to a set of susceptible organisms. The addition of relebactam restores activity against KPC type carbapenemases, but not the other carbapenemases. IMI/REL was compared to imipenem alone in patients with cIAIs and cUTIs and demonstrated non-inferiority, but the trials were not selective for MDR infections. It is expected that IMI/REL will provide an additional therapeutic option against KPC producing GNB.⁴ In vitro analysis show that 32% of imipenem non-susceptible P. aeruginosa strains from the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program remain resistant with the addition of relebactam.¹² A trial comparing IMI/REL to piperacillin/tazobactam in patients with pneumonia has been completed, but the results are not currently available.

Conclusions

While the rapid development of resistance, particularly in gram-negative bacteria, is concerning, the development of novel agents and their appropriate use has the potential to spare us from a global crisis. Antimicrobial stewardship will be critical to ensure that these agents remain active against MDR bacteria in the future. Clinicians should be well aware of their local antibiograms to help guide empiric antimicrobial therapy. While these newer agents have been able to overcome many modalities of bacterial resistance, no single agent can be employed that will be active against all MDR GNB. Table 1 shows the activity of these new agents against several types of resistance. Of note is that no single agent can work against all types of CRE. Additionally, MDR Acinetobacter poses a significant problem as no agent can be considered a “drug of choice” due to its extensive list of resistance mechanisms. Real-world data will become available as these agents are used in practice, and this data will help illuminate the niche uses that each agent likely possesses. 

Figure 1.

Ruppé E. Ann. Intensive Care. 2015; 5:21.

Table 1.

References

1. Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. 2014
2. Exner M, Bhattacharya S, Christiansen B, et al. Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria? GMS Hyg Infect Control. 2017;12:Doc05. doi: 10.3205/dgkh000290
3. Ruppé E, Woerther P, Barbier F. Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann. Intensive Care. 2015; 5:21. doi: 10.1186/s13613-015-0061-0
4. Petty LA, Henig O, Patel TS, et al. Overview of meropenem-vaborbactam and newer antimicrobial agents for the treatment of carbapenem-resistant Enterobacteriaceae. Infect Drug Resist. 2018;11: 1461-1472. doi: 10.2147/IDR.S150447
5. Toussaint KA, Gallagher JC. β-Lactam/β-Lactamase Inhibitor Combinations: From Then to Now. Ann Pharmacother. 2015; 49(1): 86-98. doi: 10.1177/1060028014556652
   
6. Van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations. Clin Infect Dis. 2016;63(2):234–41. doi: 10.1093/cid/ciw243
   
7. Karaiskos I, Lagou S, Pontikis K, et al. The “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How. Front. Public Health. 2019; 7(151).  doi: 10.3389/fpubh.2019.00151
8. Baker DE. Omadacycline. Hosp Pharm. 2019;54(2):80-87. doi: 10.1177/0018578718823730
9. Denervaud-Tendon V, Poirel L, Connolly LE, et al. Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. J Antimicrob Chemother. 2017; 72: 2787–2791 doi:10.1093/jac/dkx239
10. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed July 11, 2019.
11. Snesrud E, Maybank R, Kwak YI, et al. Chromosomally encoded mcr-5 in colistin nonsusceptible Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2018;62(8). doi: 10.1128/AAC.00679-18.
12. 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(150). doi: 10.1186/s12866-019-1522-7 
    

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