By: Sarah Cook, PharmD, BCPS; Clinical Pharmacy Specialist, SSM Health St. Joseph Hospital – St. Charles

Opioid Use Disorder (OUD) is defined as “a problematic pattern of opioid use leading to problems and distress” according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.¹ Per the American Medical Association, approximately 3-19% of people who take an opioid pain medication will develop OUD, and 45% of those who use heroin first started abusing prescription opioids. Dependence to opioids can develop in as little as 4-8 weeks, and in patients who use opioids chronically, the absence of opioids can lead to withdrawal symptoms (generalized pain, nausea/vomiting, diarrhea, dilated pupils, restlessness, anxiety, insomnia, chills, cravings) which promotes further opioid use to avoid such discomfort.² Due in part to the significance of withdrawal symptoms, many patients with OUD are unable to effectively cease using opioids without additional assistance. Medication-assisted treatment (MAT) for OUD is a strategy that can increase the likelihood of individuals abstaining from inappropriate opioid use, which can translate into reduced mortality, decreased rates of blood borne illnesses, and other clinical benefits.³

Since 1999, overdose deaths due to opioids in the United States have increased by approximately 6 times, with over 47,000 deaths due to opioid overdoses occurring in 2018.⁴ It is estimated that approximately 10.³ million people misused prescription opioids and 2 million people had an OUD in 2018.⁵ In response to this alarming trend, the U.S. Department of Health and Human Services declared the opioid crisis a public health emergency in 2017 and outlined 5 priorities, two of which were to “improve access to prevention, treatment, and recovery support services” and to “target the availability and distribution of overdose-reversing drugs.”⁶ One area that has been a focus of these efforts has been emergency departments, as they are often the location where people engage with the medical system following an overdose or when in opioid withdrawal. Although harm-reduction strategies such as distribution of naloxone, an opioid reversal agent, have become more common in emergency departments, initiation of MAT for OUD is far less common and has faced significant barriers and resistance to implementation.⁷

Medications for OUD

Medications that are FDA-approved for the treatment of OUD include methadone, naltrexone, and buprenorphine. Naltrexone is a competitive antagonist of the mu opioid receptor, which is the primary receptor responsible for the pain relieving, euphoric, and respiratory depression effects of opioids. By blocking this receptor, naltrexone prevents patients from experiencing the effects of opioids when they are used (unless they are used in especially high quantities), which may discourage use over time; it may also somewhat decrease cravings for opioids, although the exact mechanism for this is unknown. Naltrexone does not have restrictions on what providers are able to prescribe it, but patients must abstain from opioids for 7-10 day prior to initiating naltrexone therapy to avoid precipitating significant opioid withdrawal symptoms, which makes this medication generally inappropriate for initiation in the emergency department. Methadone, on the other hand, is a long-acting full agonist of the mu opioid receptor with a moderate binding affinity. It effectively reduces cravings, prevents withdrawal symptoms, and does not cause euphoric effects in patients tolerant to it. Unfortunately, however, methadone is quite dangerous if used to overdose, and due to a propensity for inappropriate use, it is only able to be dispensed for OUD in specially designated clinics in the United States. Since it only has moderate binding affinity, it does not effectively block the binding of more potent opioids, such as fentanyl. Due to some of the downfalls of naltrexone and methadone, buprenorphine is the ideal medication to use to initiate MAT for OUD in emergency departments.⁸

Buprenorphine differs from other prescription and non-prescription opioids as it is a partial agonist of the mu opioid receptor rather than a full agonist. As a partial agonist, buprenorphine does have pain-relieving effects, but unlike other opioids, it has a ceiling effect in relation to respiratory depression and euphoria which makes buprenorphine much safer to use. In addition, buprenorphine has much higher affinity for the mu opioid receptor than most other opioids, making it significantly more difficult to overdose with other opioids if buprenorphine is in a person’s system as it will be unable to be displaced from the receptor; however, this high affinity also causes buprenorphine to displace other opioids currently in a person’s system from the receptor which can at times precipitate withdrawal symptoms. Buprenorphine is indicated for use in both acute and chronic pain as well as OUD, and it comes in a variety of formulations, including oral and sublingual tablets, sublingual films, transdermal patches, long-acting injections, and subcutaneous implants. Some of these formulations also contain naloxone, the opioid reversal agent, which is only activated if the medication is not taken via the intended route – this is included to deter patients from abusing buprenorphine.⁹ In order to prescribe buprenorphine for OUD, providers have to obtain a Drug Addiction Treatment Act 2000 waiver (also known as an X-waiver) – although this is not nearly as restrictive as prescribing methadone, it historically required 8 hours of training for physicians (or 24 hours of training for mid-level providers) and currently restricts providers to having 30 active prescriptions for buprenorphine at a time during the first year, with increased capacity in subsequent years. However, a rule by the DEA also allows buprenorphine to be administered in an emergency department for up to three consecutive days by providers who do not have an X-waiver.¹⁰ (Recent changes to X-waiver requirements will be discussed later in this article.)

Buprenorphine in the Emergency Department

Although evidence existed for using buprenorphine maintenance therapy for OUD that showed benefits including decreased cravings, reduced all-cause mortality, decreased overdose mortality, improved quality-of-life, and reduced incidence of blood borne illnesses such as HIV and hepatitis C,¹¹ evidence for its use in the emergency department setting did not start accumulating significantly until the past decade. One clinical trial showed that buprenorphine could be safely used in the emergency department for opioid withdrawal and resulted in a fewer emergency department visits when compared to symptomatic treatment alone.¹² The ground-breaking study that drew significant attention to buprenorphine’s use in the emergency medicine setting was published by D’Onofrio and colleagues at Yale in 2015. In this study, patients with opioid dependence who reported non-medical use of prescription opioids or heroin use in the last 30 days were randomized into three treatment groups. The first group (“referral group”), which contained 104 patients, received a screening and referral to treatment using a handout containing information on addiction treatment providers arranged according to insurance coverage. The second group (“brief intervention group”), containing 111 patients, received a screening, a 10-15 minute manual-driven brief negotiation interview (BNI), and a coordinated referral including review of insurance eligibility and transportation assistance. The third group (“buprenorphine group”) contained 114 patients who received a screening, a BNI, treatment with buprenorphine if they exhibited moderate-to-severe opioid withdrawal, and a referral to the hospital’s primary care center with an appointment made within 72 hours. A sufficient supply of buprenorphine was prescribed to patients to continue their treatment until follow up. The primary outcome of this study was engagement in addiction treatment at 30 days, with 37% of patients in the referral group, 45% of patients in the brief intervention group, and 78% of patients in the buprenorphine group being engaged in treatment for OUD at 30 days, which was statistically significant. The buprenorphine group also showed a statistically significant reduction in the mean number of days of illicit opioid use per week. The results of this study, with almost double the amount of patients receiving buprenorphine maintained in treatment at 30 days, highlighted the potential for emergency-department initiated buprenorphine to play a key role in improving outcomes for patients struggling with OUD.¹³

Since the study by D’Onofrio and colleagues was published, a number of protocols for emergency-department initiated buprenorphine for OUD have been developed and shared. The Yale protocol, which is based off of the treatment strategy for the buprenorphine group in the study led by D’Onofrio, can be seen in Figure 1.¹⁴ The CA Bridge initiative which was inspired by the work being done at Yale¹⁵ has an extensive library of resources and protocols. This initiative has expanded upon the Yale protocol by expanding the treatment options for patients to include higher total doses of buprenorphine to be given in the emergency department, which has the potential to allow for a longer period of relief from opioid withdrawal symptoms and cravings when an X-waivered provider is not available to write a prescription to bridge patients to their outpatient follow-up appointment. See the Figure 2 for more details.16 Both protocols, as well as others that have been developed, involve screening for inappropriate opioid use as well as an assessment for opioid withdrawal, such as the Clinical Opioid Withdrawal Scale (COWS). If an individual does not yet have notable withdrawal symptoms, buprenorphine should not be administered at that time as it may cause precipitation of worse withdrawal symptoms by displacing other opioids that are bound to the mu opioid receptor. Additionally, naloxone distribution is included as a part of these protocols as a harm-reduction strategy in the event that an individual would continue to use illicit opioids after emergency department discharge. Finally, these protocols are primarily intended to be used by X-waivered providers who will be able to prescribe buprenorphine to be used as an outpatient to bridge patients until their follow-up appointment, but they are written in such a way that they could also be used by non-X-waivered providers in certain situations.^14,16 By improving engagement in treatment and therefore increasing the likelihood of long-term abstinence from illicit opioid use, MAT with buprenorphine for OUD being initiated in emergency departments is a key strategy to combating the opioid crisis.

Figure 1 - Yale Protocol for Buprenorphine Initiation in the Emergency Department¹⁴

(Reprinted from https://medicine.yale.edu/edbup/treatment/.)

Figure 2 - CA Bridge Buprenorphine Hospital Quick-Start Algorithm¹⁶

(Reprinted from https://cabridge.org/tools/resources/.)

Addressing Challenges to Buprenorphine Use for OUD

Despite growing evidence on the benefits of initiating buprenorphine in the emergency department and development of evidence-based protocols that can be translated to a variety of different situations, there remains significant resistance to implementation. A large amount of resistance comes from stigma that is held by healthcare providers, the public, and patients themselves.⁷ Despite evidence to the contrary, some clinicians still do not see addiction as a medical disease but rather as a moral failing of the individual. Additionally, even those who do understand addiction to be a medical disease may view buprenorphine use as simply replacing one addiction for another. However, when used as directed for the indication of opioid use disorder, buprenorphine is being used as a medication with evidence to support its benefits and not as a substance of abuse.¹¹ Also, as previously described, buprenorphine is generally safer than other opioids as it is a partial agonist with ceiling effects on respiratory depression and as it can block the binding of other opioids which may decrease risk of overdose if illicit opioids are used.¹⁰ Other concerns with implementing a program in the emergency department stem from clinicians’ lack of formalized training and knowledge regarding the diagnosis and treatment of OUD, false perceptions that starting MAT for OUD is outside the scope of practice for emergency medicine providers, and actual or perceived lack of resources to effectively implement a program.¹⁷ As MAT for OUD is most effective when used as maintenance therapy, prompt connection to treatment post-discharge is especially of concern.⁸ Fortunately, health system resources, grant funding, and government resources can help address some of these concerns.

A variety of strategies can be undertaken by health systems to assist with the implementation of buprenorphine programs in emergency departments. Key to any of these strategies, effective programs will have the support of hospital leadership to allocate both educational and administrative resources to the program.¹⁷ By increasing clinician’s understating of the science behind addiction and of the diagnosis and treatment of OUD through educational initiatives and advocacy, stigma may slowly be changed to compassion and motivation for some providers, leading to a culture change in the organization.^3,7 A variety of educational resources are openly available online, including from Yale, CA Bridge, Project SHOUT: Supporting Hospital Opioid Use Treatment and others, but development of organization-specific materials regarding community treatment resources is also imperative to success.¹⁰ Additionally, clinicians who complete X-waiver training have been shown to be more comfortable in providing treatment with buprenorphine,¹⁷ so incentivizing providers to obtain this training and obtain an X-waiver can be an effective strategy to help increase participation and bolster the effectiveness of a buprenorphine program by expanding treatment options.¹⁸ Having local clinical experts provide guidance and share their expertise can also increase comfort levels with prescribing buprenorphine in the emergency department and can help drive changes in practice. Development of evidence-based, organization-specific protocols and order sets with clinical decision support also increase provider readiness and comfort in initiating buprenorphine.¹⁷ Finally, although access to continued treatment for opioid use disorder is of concern and often is reliant on many factors outside an individual health care organization, taking a multidisciplinary approach in implementing buprenorphine in the emergency department, including recovery coaches if possible, may help improve the likelihood of effectively connecting patients to continued treatment.^8,18 As implementation of many of these strategies relies on buy-in and support from hospital leadership, presenting evidence on the research-based financial implications of potential cost savings may be beneficial in garnering support; studies show that multiple programs have been initiated with a cost of only approximately $100 per patient and that emergency department programs for treatment of OUD may save from $2000 to $6000 per patient year for patients covered by Medicaid.¹⁰ Funds obtained through both government and non-government grants can also alleviate the initial financial burden of program development and implementation for a health care organization.

Regulatory Issues and the Future of the X-waiver

Government resources and regulatory changes are also imperative to expansion of MAT programs for OUD in emergency departments. Since the opioid crisis was declared a public health emergency, a large amount of federal grant funding has been made available to states and health organizations to improve access to OUD treatment and services.⁶ Additionally, it has been shown that Medicaid expansion resulting from the Affordable Care Act of 2008 increased access to care and treatment utilization for OUD,⁷ with better access to MAT and a 6% decrease in the rate of opioid overdose deaths in expansion states compared to non-expansion states.^19,20

The federal government is currently considering changing the regulatory requirement for providers to have an X-waiver to prescribe buprenorphine. In the meantime, as of April 2021, federal guidelines have been updated to remove the educational requirements for practitioners to obtain an X-waiver if they only desire to treat up to 30 patients at a time. Practitioners still must have a valid DEA registration to prescribe buprenorphine and need to file a Notice of Intent to obtain an X-waiver, but the barrier of completing training has been removed if clinicians do not intend to treat large numbers of patients.²¹ Further information regarding these changes and answers to frequently asked questions in regards to the new federal guidelines are available on the Substance Abuse and Mental Health Services Administration website.²²

In the future, government agencies will need to continue to consider the implications and efficacy of requiring an X-waiver for prescription of buprenorphine for OUD. Replacing the X-waiver with broad requirements for the inclusion of education regarding diagnosis and treatment for substance use disorders in medical training programs and continuing education requirements for licensure to further improve access to MAT for OUD may be more effective in providing safe, widely-available OUD treatment.^7,23 In France, where restrictions on buprenorphine prescribing were removed in 1995, increased use of buprenorphine for treatment of OUD was seen and opioid overdose deaths decreased by 79% within 3 years, which supports the concept of decreased government regulation of buprenorphine.²⁴ Additionally, states and insurance payers that require coverage of buprenorphine to be contingent on concomitant counseling therapy should consider removing this requirement, as it limits access to care and the benefits of buprenorphine can be seen even in the absence of counseling; these restrictions especially impact rural areas where counseling services are less common.^7,8

Conclusion

It is as important as ever for health systems and government agencies to dedicate resources to effectively implement buprenorphine programs in emergency departments, thereby improving outcomes for individuals struggling with OUD by increasing engagement in treatment. The emergency department is an ideal location to focus resources on as it is a common place for patients to present to following opioid overdose or in opioid withdrawal, and buprenorphine has been shown to be a safe and effective treatment option in this setting as well as for maintenance treatment of OUD. Although there are many barriers to implementation of buprenorphine programs in emergency departments, there are multiple evidence-based strategies to overcoming these barriers, and easing of training requirements to obtain an X-waiver will hopefully ease some of these barriers as well. Especially considering that provisional data from the CDC indicates that overdose deaths increased by over 25% from the previous year as of August 2020,²¹ there is an urgent need to expand this evidence-based treatment with buprenorphine in emergency departments nationwide.

References

1. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 (5th ed.). American Psychiatric Publishing.
2. American Psychiatric Association. (2018, November). Opioid Use Disorder. American Psychiatric Association (APA). https://www.psychiatry.org/patients-families/addiction/opioid-use-disorder/opioid-use-disorder#:~:text=The%20Diagnostic%20and%20Statistical%20Manual,a%20longer%20period%20than%20intended.
3. Strugar-Fritsch, D. (2019, August). MAT for Opioid Use Disorder: Overcoming Objections. California Health Care Foundation. https://www.chcf.org/wp-content/uploads/2019/06/MATOpioidOvercomingObjections.pdf
4. Centers for Disease Control and Prevention. (2020, March 19). Data Overview | Drug Overdose | CDC Injury Center. Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/drugoverdose/data/index.html
5. Assistant Secretary of Public Affairs (ASPA). (2019, September 4). About the Epidemic. HHS.Gov. https://www.hhs.gov/opioids/about-the-epidemic/index.html
6. U.S. Department of Health and Human Services. (2018, May 23). HHS Acting Secretary Declares Public Health Emergency to Address. HHS.Gov. https://www.hhs.gov/about/news/2017/10/26/hhs-acting-secretary-declares-public-health-emergency-address-national-opioid-crisis.html
7. Madras, B. K., Ahmad, N. J., Wen, J., Sharfstein, J., & Prevention, Treatment, and Recovery Working Group of the Action Collaborative on Countering the U.S. Opioid Epidemic. (2020). Improving Access to Evidence-Based Medical Treatment for Opioid Use Disorder: Strategies to Address Key Barriers Within the Treatment System. NAM Perspectives, 1–37.
8. Strayer, R. J., Hawk, K., Hayes, B. D., Herring, A. A., Ketcham, E., LaPietra, A. M., Lynch, J. J., Motov, S., Repanshek, Z., Weiner, S. G., & Nelson, L. S. (2020). Management of Opioid Use Disorder in the Emergency Department: A White Paper Prepared for the American Academy of Emergency Medicine. The Journal of Emergency Medicine, 58(3), 522–546.
9. Ling, W. (2012). Buprenorphine for opioid addiction. Pain Management, 2(4), 345–350.
10. Cisewski, D. H., Santos, C., Koyfman, A., & Long, B. (2019). Approach to buprenorphine use for opioid withdrawal treatment in the emergency setting. The American Journal of Emergency Medicine, 37(1), 143–150.
11. Velander, J. R. (2018). Suboxone: Rationale, Science, Misconceptions. The Oschner Journal, 18(1), 23–29.
12. Berg, M. L., Idrees, U., Ding, R., Nesbit, S. A., Liang, H. K., & McCarthy, M. L. (2007). Evaluation of the use of buprenorphine for opioid withdrawal in an emergency department. Drug and Alcohol Dependence, 86(2–3), 239–244.
13. D’Onofrio, G., O’Connor, P. G., Pantalon, M. V., Chawarski, M. C., Busch, S. H., Owens, P. H., Bernstein, S. L., & Fiellin, D. A. (2015). Emergency Department–Initiated Buprenorphine/Naloxone Treatment for Opioid Dependence. JAMA, 313(16), 1636.
14. Yale School of Medicine. (2018, September 24). ED-Initiated Buprenorphine. https://medicine.yale.edu/edbup/treatment/
15. Goodnough, A. (2018, August 20). This E.R. Treats Opioid Addiction on Demand. That’s Very Rare. New York Times. https://www.nytimes.com/2018/08/18/health/opioid-addiction-treatment.html
16. CA Bridge. (2021, May). Resources to Treat Substance Use Disorders. https://cabridge.org/tools/resources/
17. Hawk, K. F., D’Onofrio, G., Chawarski, M. C., O’Connor, P. G., Cowan, E., Lyons, M. S., Richardson, L., Rothman, R. E., Whiteside, L. K., Owens, P. H., Martel, S. H., Coupet, E., Pantalon, M., Curry, L., Fiellin, D. A., & Edelman, E. J. (2020). Barriers and Facilitators to Clinician Readiness to Provide Emergency Department–Initiated Buprenorphine. JAMA Network Open, 3(5), e204561.
18. Lowenstein, M. (2019, March 13). Starting Opioid Use Disorder Treatment in the Emergency Department. Leonard Davis Institute of Health Economics at the University of Pennsylvania. https://ldi.upenn.edu/healthpolicysense/starting-opioid-use-disorder-treatment-emergency-department
19. Kravitz-Wirtz, N., Davis, C. S., Ponicki, W. R., Rivera-Aguirre, A., Marshall, B. D. L., Martins, S. S., & Cerdá, M. (2020). Association of Medicaid Expansion With Opioid Overdose Mortality in the United States. JAMA Network Open, 3(1), e1919066.
20. Sharp, A., Jones, A., Sherwood, J., Kutsa, O., Honermann, B., & Millett, G. (2018). Impact of Medicaid Expansion on Access to Opioid Analgesic Medications and Medication-Assisted Treatment. American Journal of Public Health, 108(5), 642–648.
21. Practice Guidelines for the Administration of Buprenorphine for Treating Opioid Use Disorder. Federal Register. (2021, April 28). https://www.federalregister.gov/documents/2021/04/28/2021-08961/practice-guidelines-for-the-administration-of-buprenorphine-for-treating-opioid-use-disorder.
22. Become a Buprenorphine Waivered Practitioner. SAMHSA. (2021, May 5). https://www.samhsa.gov/medication-assisted-treatment/become-buprenorphine-waivered-practitioner.
23. Fiscella, K., Wakeman, S. E., & Beletsky, L. (2019). Buprenorphine Deregulation and Mainstreaming Treatment for Opioid Use Disorder. JAMA Psychiatry, 76(3), 229.
24. Auriacombe, M., Fatséas, M., Dubernet, J., Daulouède, J.-P., & Tignol, J. (2004). French Field Experience with Buprenorphine. American Journal on Addictions, 13(s1), S17–S28.

By: James Unverferth, PharmD, BCPS; Pharmacist Clinical Specialist

SSM Health St. Mary’s Hospital – St. Louis

Background

Feedback and how to effectively provide feedback is a topic becoming ever more relevant as the years go on mostly due to the “millennial” generation filling the roles of students and residents. Supporting the portrayal of millennials on TV and social media, studies have shown that millennials desire frequent coaching and feedback.³

Feedback is important because it helps learners to identify areas of weakness in which they can build on foundational skills and knowledge. If done correctly feedback should help students to establish goals and evaluate performance so that over time they become sufficient enough to rely only on themselves for evaluation and motivation. Additionally, preceptor feedback is a topic that is frequently cited on accreditation surveys for residency programs. Accreditation standards specify that this feedback needs to be specific and criteria-based. To lend guidance on how preceptors can help learners achieve this goal, ASHP has developed a 3 part competency-based approach (Figure 1) to evaluate resident performance of a program’s educational goals and objectives, resident self-assessment of their performance, and of the program itself.¹ This approach, while effective, is mostly tailored towards residency programs and may not be completely applicable to all learning situations, so I have developed a 6-part approach to establish a process of providing quality feedback to any learner. I hope this process helps you realize the importance of providing constructive feedback and its relationship to growth of a learner.

Six-part Approach for Providing Effective Feedback

Part 1: Establishing Expectations

The first step in my 6-part approach is to establish expectations. This stage of the process of providing quality feedback can begin even before a learner starts on rotation. Knowing past experiences of learners and what stage they are in in their studies or career can help shape expectations for the preceptor. For example — expectations for a rotation are going to be different for a resident on their last rotation compared to an APPE student on their first rotation, compared to an IPPE student on their first ever experiential rotation. Regardless, it is important to involve the learner in the process of establishing expectations. Before a learner starts a rotation have them develop SMART goals for the rotation.

By: Megan Musselman, PharmD, MS, BCPS, BCCCP, MSHP Research & Education Foundation

At the MSHP/ICHP Spring Meeting, the R&E Foundation presented Kat Lincoln, PharmD, BCPS, BCIDP with the MSHP Best Practice Award for her project entitled “Daptomycin weight-based dose optimization”. Olathe Medical Center implemented a dose optimization intervention that utilized adjusted body weight (AdjBW) for patients ≥ 130% of their ideal body weight (IBW) and actual body weight (ABW) for those < 100% IBW. The primary outcome was to determine if implementation of a weight –based dose optimization intervention was effective for the treatment of severe gram-positive infections infection. Secondary outcomes included adverse effects and costs associated with the new dosing protocol. The goals and specific aims for the program were to determine safety and efficacy of dosing daptomycin using AdjBW, decrease cost associated with this dosing strategy, and to develop criteria for use of daptomycin.

At the conclusion of the study, the average patient age was 60 years old with an average ABW of 97.25 kg. Of the patients included, 52.5% had a BMI ≥ 30 kg/m2 and 16.6% had a BMI > 40 kg/m2. The infection classification for daptomycin dosing is found in Table 1. In addition, 20% of patients were readmitted within 90 days due to infectious indications. Severity and type of infection attributed to persistence and higher rates of readmission.

The cost of daptomycin powder for injection is $0.11/mg. Patients with BMI ≥ 30 mg/k2 using AdjBW had a cost savings of $8,000 over 11 months. Patients treated using AdjBW accounted for 53% of orders, but only accounted for 27% of the total cost (Figure 1). The second most common dosing strategy used during the study period was ABW (27.1%) followed by 19.9% of patients being dosed by IBW (Figure 2).

In conclusion from this research project, patients treated using the dose optimization protocol were adequately dosed for treatment and pathogen eradication with minimal 90 day readmission rates. The following daptomycin dosing protocol maintained effectiveness and safety while reducing costs:

• ABW < 100% of patient IBW: Daptomycin dosed using ABW

• ABW ≥ 100-129% of patient IBW: Daptomycin dosed using IBW

• ABW ≥ 130% of patient IBW: Daptomycin dosed using AdjBW

If you have any questions about how Dr. Lincoln implemented her project, please email her at Kathryn.burnett@olathehealth.org.

By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain

“The best time to plant a tree is 20 years ago. The second best time to plant a tree is today.”  -Unknown

The 2021 Missouri Legislative Session has ended.  We could look at that fact and think that we are too late and missed an opportunity.  A more productive mindset is that we are right on time to get started for the 2022 session.  Now is the perfect time to begin learning or continue learning about the various processes that lead to change.  There are many ways to get involved, at the local, state, and Federal level.  This is true for the legislative process, for the regulatory process, and also for the associations in which we participate.  Here are some simple and practical ways that you can increase your ability to get involved for the next year and the next 20 years.

Local Involvement:

It is my opinion that you should know your mayor and your city council leaders.  Mark some time on your personal calendar to click around on your local government’s web site to learn who your mayor and City Council members are.  Find out when the meetings are, and consider attending one this year.  This may not have much of an impact on pharmacy, but I have found that the local government often has the biggest impact on our daily lives.  And learning about the government processes at the local level is a good training ground for the next level. 

State Involvement:

You should also know your state representative, your state senator, and your governor. The state government won’t be in session until January of 2022, but you can learn about your state representatives and senators right now.  Simply click on this link and type in your home address in the “Find Your Representative” box.  You could also look up the address of your workplace, so that you know the house and senate districts for both locations.  I recommend that you copy and paste this information into the document that you save in a folder marked “Involvement.”  You can use this document to capture information and ideas and keep it all in one place.  Then spend a few minutes clicking on the government web sites of your senator and representative to learn about their background, their committee membership, and the legislation they have sponsored or cosponsored.  If you are feeling very brave, you can spend 5 minutes making a phone call to their office.  In most cases you will speak to a staff member at their front desk or leave a voicemail.  Simply say that you are a hospital pharmacist, and you believe that patients will benefit any time that they are given greater access to the care that pharmacists can provide.  Then offer to be a resource for the senator or representative if they ever have a question about pharmacy related issues.  These small steps will help you to get involved, and they will show our elected officials that pharmacists are interested in the process.

If you have ideas for ways that the laws need to be changed so that you can take better care of patients, please let us know.  This is the time for brainstorming and information sharing, because bills generally need to be filed by December 1st.  We can be talking with our partners to see what will fit into the priorities for 2022. 

Federal Involvement:

You should know your representative and both of your senators, and you can find this information at the same website.  You can reach out to these leaders as well, but they’re certainly a little less available than the state leaders.  The best way to engage with the Federal centers and representatives is through the ASHP website.  Please take 5 minutes today to enroll on this website so that you can be poised and ready to respond when our responses are needed.

MHSP Involvement:

As we are kicking off the 2022 preparation, we would love to have your input.  If you aren’t already active on a committee please reach out.  We have a lot of exciting plans and a lot of goals we want to accomplish this year.  In the public policy committee we have formed task forces to accomplish these aims:

1.    Work toward obtaining pharmacist prescriptive authority
2.    Identify and disseminate advocacy topics
3.    Develop MSHP position statements for pertinent legislation
4.    Provide professional development

If you are interested in joining, please contact us! 

ASHP Involvement:

Each year the ASHP House of Delegates reviews a variety of policy statements.  You can see these policies here, and you can provide your input to the public policy committee or to the delegates directly.  There are also a lot of other ways to get involved out with your section or at ASHP Connect.

Plant Today!

Even if you didn’t get involved with legislative day this year, you can easily get involved next year.  If you missed your opportunity to weigh in on PBM restrictions, the PDMP bill, or various bills that allow patients better access to medications, you can rest assured that there will be plenty of opportunities next year.  Like trees, our progress as professionals can best be measured by the decade.  Make this the year where you begin to grow and change and step outside your comfort zone to make an impact for patients and our profession!  You may be surprised how much you can accomplish if you do. 

Don’t Miss What the Public Policy Committee Has Done!

http://www.moshp.com/Public-Policy/

By: Amanda Bernarde, PharmD; PGY-1 Pharmacy Resident

University of Missouri Health Care

Abbreviations: RSI = rapid sequence intubation; KPA = ketamine propofol admixture; ED= emergency department; SBP= systolic blood pressure; OR= odds ratio; CI= confidence interval; NEAR= National Emergency Airway Registry; TBI= traumatic brain injury; MAP = mean arterial pressure

Rapid sequence intubation (RSI) is a mainstay in critical care and emergency medicine to secure a patient’s airway.^1,2 Endotracheal intubation may be indicated if the patient: 1) cannot protect his/her airway, 2) has a risk of aspiration, 3) fails to adequately ventilate or oxygenate, or 4) has anticipated further or rapid decompensation leading to any of the other indications. To facilitate endotracheal tube placement, RSI requires use of sedatives and paralytics to minimize consciousness and to blunt the pathophysiologic response of airway manipulation, respectively. Ideal sedatives produce deep anesthesia with a rapid onset of 30 seconds or less.³ The paralytic agent should have a similar duration. Midazolam, propofol, ketamine, and etomidate are among some of the most common sedatives used in RSI. Though the goal of sedative medications is to augment easy manipulation of the airway, they are not without their own adverse effects, including peri-intubation hypotension.

Concerns for peri-intubation hypotension limit sedative options due to the potential increased risk of cardiac arrest, need for vasopressor support, and in-hospital and post-discharge mortality.^3-5 Etomidate, the gold standard sedative, displays hemodynamic neutrality when administered at a dose of 0.2-0.3 mg/kg, whereas midazolam and propofol have known risks of hypotension. Etomidate has potential adverse effects of adrenal suppression and lowering the seizure threshold, which makes it a suboptimal choice during RSI induction in patients presenting with sepsis, epilepsy, or traumatic brain injury (TBI) patients. Increased interest in exploring other RSI sedation options, particularly ketamine only and ketamine-propofol admixture (KPA) regimens, have been analyzed for use in these patient populations.

Mechanistically, ketamine at doses of 0.5-1 mg/kg increase catecholamine release while prohibiting its reuptake in the synaptic cleft.^3,6,7 In patients with sufficient circulating catecholamines, this leads to increased blood pressure. In contrast, patients with autonomic dysfunction, such as in sepsis, diabetic ketoacidosis, and myocardial infarction, exhibit decreased myocardial contraction and heart rate.⁸ Recent literature of ketamine use for sedation during RSI in hemodynamically unstable patients has shown mixed results (Table 1).

Table 1. Summary of hemodynamic effects of ketamine alone compared to other sedatives.

Ischimaru et al was the first study to establish ketamine’s potential hemodynamic neutrality during intubation of hemodynamically unstable patients.⁶ This prospective observational study from Japan found a statistically significant decrease in ketamine-induced hemodynamic derangement, defined as SBP ≤ 90 mmHg or ≥ 20% decrease in SBP, when compared with the combined comparator of either midazolam or propofol administration. Statistical significance held after adjustments for differences in demographics, primary indication (except in trauma patients), premedication use, and paralytic choice between the two study groups. From this analysis, authors concluded ketamine is superior to midazolam or propofol in maintaining stable hemodynamics during intubation. Of note, etomidate was not compared to ketamine in this study because it is not approved for use in Japan. Due to this difference, additional studies comparing ketamine to etomidate were required to potentially change practice in the United States.

A single large-scale, prospective, multicenter, observational cohort study was conducted by April et al comparing the incidence of peri-intubation hypotension of ketamine to etomidate for any indication.⁹ Using the NEAR study dataset, ketamine was found to have a statistically significant increase in peri-intubation hypotension incidence in comparison to etomidate. Doses chosen by the practitioner did not impact this outcome. This indicated that ketamine may not provide hemodynamic neutrality as the above study suggested. There were several challenges that limit this study’s generalizability to all populations, including the propensity to choose ketamine over etomidate for sepsis and traumatic brain injury (TBI) patients.

A subgroup analysis of NEAR study participants examined current use of etomidate compared to other sedatives and intubation-associated hypotension incidence of etomidate and ketamine.10 Etomidate was the most frequently used sedative in sepsis patients despite the concerns for its potential adrenal suppression. However, etomidate administration decreased and ketamine administration increased in sepsis patients when compared to nonsepsis patients. In this patient population, patients receiving ketamine did experience intubation-related hypotension more often than those administered etomidate. The hypotension was not sustained or significant as there was no statistical difference in need of vasopressor therapy or peri-intubation cardiac arrest between the two medications. The TBI patient cohort had similar findings that showed significant intubation-associated hemodynamic instability with ketamine when compared to other sedatives.¹¹ Unfortunately, analysis of emergency department or in-hospital use of ketamine for RSI in TBI patients is limited. Overall, in the setting of sepsis or TBI, ketamine does not provide beneficial hemodynamic outcomes, with mixed translation to need for vasopressors and incidence of peri-intubation cardiac arrest.

A novel approach to RSI induction was explored by Smischney et al in the KEEP-PACE trial.¹² Reduced dose etomidate (0.15 mg/kg) was compared to a ketamine-propofol admixture (KPA; 0.5 mg/kg of each component) for hemodynamic stability. Because of the novelty of this admixture, the purpose was to establish KPA’s superiority over reduced dose etomidate and reanalyze the mixture against the full etomidate dose if superiority was found. The primary endpoint, the change in mean arterial pressure (MAP) from baseline at 5 minutes post-induction, was not statistically significant (KPA vs etomidate: -3.3 mmHg vs -1.1 mmHg; p= 0.385). Additionally, there was no difference at 10 minutes, 15 minutes, or in average MAP area under the curve. Due to the lack of efficacy, KPA has not been compared to full-dose etomidate.

Despite the initial positive results suggesting ketamine as an alternative to etomidate for hemodynamically unstable patients during RSI, several multicenter, large-scale observational cohort studies have concluded otherwise. At present, etomidate remains the gold standard for induction, particularly in patients who are hemodynamically unstable or have RSI-indications that could quickly decompensate. Nevertheless, the need remains for a hemodynamically neutral induction agent that does not manipulate the adrenal system or lower the seizure threshold, which continues to be the main concerns with universal etomidate use.

References

1. Chong ID, Sandefur BJ, Rimmelin DE, et al. Long-acting neuromuscular paralysis without concurrent sedation in emergency care. Am J Emerg Med. 2014;32(5):452-456.
2. Driver BE, Klein LR, Prekker ME, et al. Drug order in rapid sequence intubation. Acad Emerg Med. 2019;26(9):1014-1021.
3. Hamilton JP. Rapid-sequence intubation and the role of the emergency department pharmacist. Am J Health Syst Pharm. 2011;68(14):1320-1330.
4. Strollings JL, Diedrich DA, Oyen LJ, Brown DR. Rapid-sequence intubation: a review of process and considerations when choosing medications. Ann Pharmacother. 2014;48(1):62-76.
5. April MD, Arana A, Reynolds JC, et al. Peri-intubation cardiac arrest in the emergency department: a National Emergency Airway Registry (NEAR) study. Resuscitation. 2021;S0300-9571(21)00097-6.
6. Ishimaru T, Goto T, Takahashi J, et al. Association of ketamine use with lower risks of post-intubation hypotension in hemodynamically-unstable patients in the emergency department. Sci Rep. 2019;9(1):17230.
7. White PF, Way WL, Trevor AJ. Ketamine—its pharmacology and therapeutic uses. Anesthesiology. 1982;56(2):119-136.
8. Goldberger JJ, Arora R, Buckley U, Shivkumar K. Autonomic nervous system dysfunction: JACC focus seminar. J Am Coll Cardiol. 2019;73(10):1189-1206.
9. April MD, Arana A, Schauer SG, et al. Ketamine versus etomidate and peri-intubation hypotension: a National Emergency Airway Registry study. Acad Emerg Med. 2020;27(11):1106-1115.
10. Mohr NM, Pape SG, Runde D, Kaji AH, Walls RM, Brown CA. Etomidate use is associated with less hypotension than ketamine for emergency department sepsis intubations: a NEAR cohort study. Acad Emerg Med. 2020;27(11):1140-1149.
11. Fouche PF, Meadley B, St Clair T, et al. The association of ketamine induction with blood pressure changes in paramedic rapid sequence intubation of out-of-hospital traumatic brain injury. Acad Emerg Med. 2021. Epub ahead of print.
12. Smischney NJ, Nicholson WT, Brown DR, et al. Ketamine/propofol admixture vs etomidate for intubation in the critically ill: KEEP PACE randomized clinical trial. J Trauma Acute Care Surg. 2019;87(4):883-891.

By: Andrew Vogler, PharmD; PGY1 Pharmacy Resident

Mentor: Daniel Hansen, PharmD; Clinical Pharmacy Specialist

Mercy Hospital Springfield

Program Number: 2021-05-0

Approval Dates: June 1, 2021 – December 1, 2021

Approved Contact Hours: 1 hour 

Learning Objectives:

1.    Define a bacteremia based on infectious pathogen and source of infection
2.    Identify correct indication and duration of oral antibiotics for gram-negative bacteremia
3.    Discuss the utility of follow-up blood cultures for gram-negative bacteremia

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Background

There are approximately 2 million cases and 250,000 deaths annually from sepsis due to bacteremia with approximately 45% due to a gram-negative pathogen in North America and Europe.¹ With the prevalence of gram-negative bacteremia so high and no current guideline discussing proper treatment regimens or duration, it is important to have a clear understanding of bacteremia before one can start a proper treatment regimen.² Bacteremia is defined as bacteria in the blood and can often be asymptomatic or transient becoming a blood stream infection if the immune system becomes overwhelmed. Bacteremia should be differentiated from sepsis or septicemia. The Surviving Sepsis Campaign defines sepsis as, “life-threatening organ dysfunction caused by a dysregulated host response to infection.”³ Septicemia is a narrower term for sepsis that is caused by bacterial spread into the blood stream. Throughout this article the discussion of sepsis will be kept separate from the discussion of bacteremia, as they are not interchangeable terms.

Bacteremia can vary in source of infection and infectious pathogen. Though bacteremia can occur due to direct inoculation into the blood stream, it typically occurs as the result of an infectious pathogen spreading to the blood from another source. Bacteremia is classified by 3 main criteria: infectious pathogen, the source of infection, and whether the bacteremia is complicated or uncomplicated. The source of infection can either be primary or secondary. A primary bacteremia is caused from direct inoculation of pathogen into the bloodstream. A secondary bacteremia is caused by a pathogen entering the body from a site other than direct inoculation such as bacteremia secondary to pneumonia or urinary tract infection.⁴

During the initial Gram-stain phase, pathogen-based classification of bacteremia is typically either Gram-positive or Gram-negative. The most common cause of gram-positive bacteremia is Staphylococcus aureus (S. aureus), which is due to the organism’s ability to produce the enzyme coagulase, which can convert fibrinogen in the blood to fibrin causing the blood to clot.¹ The infectious emboli then stick to different areas of the body like blood vessels or heart valves, making a bacteremia very difficult to clear. Other Gram-positive bacteria such as enterococcus and coagulase-negative staphylococcus can form biofilms making them difficult to treat, as well. In comparison to Gram-positive bacteria, Gram-negative bacteria do not produce coagulase and are often easier to treat, with patients often being able to clear infection with oral antibiotics and shorter durations of therapy.

The severity of bacteremia is classified as either complicated or uncomplicated based on the likelihood of a timely resolution of infection. To be considered an uncomplicated bacteremia, the patient must be afebrile within 72 hours of initial treatment, have a negative repeat blood cultures obtained 2-4 days after initial set, and not have endocarditis or metastatic infection. Complicated bacteremia is often treated for longer durations with IV antibiotics due to severity of illness, high inoculum of infection, lack of treatment response, seeding of infection, or a combination there of. Morpeth and colleagues looked at the rate of endocarditis in 2761 patient cases with species other than Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, or Kingella species (non-HACEK) Gram-negative bacteremia. The study determined the risk of complicated bacteremia due to Gram-negative endocarditis is extremely low at approximately 1.8% with a high percentage of those patients having some sort of implanted endovascular device (29%).⁶

The Infectious Disease Society of America (IDSA) for the treatment of Methicillin-Resistant S. aureus (MRSA) bacteremia. They do not address bacteremia due to organisms other than MRSA. The rate of mortality for MRSA bacteremia with endocarditis (upwards of 37%) is higher than that of gram-negative bacteremia (12.5%).⁷ For MRSA bacteremia, IDSA recommends at least 14 days of IV anti-MRSA antibiotics following negative blood cultures. Historically Gram-negative bacteremia has been treated using IV antibiotics for 7 to 14 days, primarily based on expert opinion. The following discussion of the evidence supporting shorter treatment durations and opportunities for oral antibiotic therapy for uncomplicated Gram-negative bacteremia will better prepare the pharmacists in managing patients and in antibiotic stewardship.

Prevalence of Infectious Pathogen

Gram-negative bacteremia is most often secondary to another source of infection. Likely pathogens for secondary bacteremia are variable based on source of infection and location of onset. From the results of three studies, Table 2 depicts the likely pathogens for community, hospital, and ICU acquired Gram-negative bacteremia.^8-10 Manzoni and colleagues looked at 2,924 different microorganisms from 16 different hospitals in northern Italy over the course of 2 years for community acquired gram-negative bacteremia.⁸ The study found that the majority of community acquired Gram-negative bacteremia were caused by cephalosporin susceptible Escherichia coli in this study population. The most likely source for bacteremia with this organism is a urinary-tract infection, although the study did not report sources of infection.⁸ There is an increase in more drug-resistant organisms when infection onset occurs in the hospital and intensive care unit setting setting.^9,10 Shorr and colleagues looked at data from 6,697 patient from 59 different hospitals in the United States with hospital acquired Gram-negative bacteremia defined as a first positive blood cultures drawn >2 days after admission.⁹ The study found a wider variety of infectious pathogens than was found in the study  of community acquired bacteremia with only 18% of infections due to Escherichia coli and 56% being from various spp. For ICU acquired Gram-negative bacteremia, 2 studies by Sligl and colleagues looked at 18,146 admissions over a 5-year period from 1999 to 2003 and an 8-year period from 2004 to 2012 seeing consistent occurrence rates of infectious pathogen, over the 13 year period.^5,10 Swamy and colleagues looked at 406 cases of Gram-negative bacteremia and broke down source of infection by percent, the results can be found in figure 1.¹⁷ Swamy and colleagues found the majority of gram-negative bacteremia were due to a urinary source, which remains consistent to the other studies discussed. They found the majority of community acquired Gram-negative bacteremia were due to Escherichia coli. Based on prevalence data presented, the majority (up to 90% in community acquired) of Gram-negative bacteremia is the result of bacteria from the Enterobacterales (formerly Enterobacteriaceae) family such as E. coli, Klebsiella, Enterobacter, and Citrobacter.⁸

Intravenous vs Oral Treatment

Once an infection is suspected, empiric therapy is initiated, and cultures should be obtained. As blood cultures begin to result, one may begin targeting therapy to treat the source of infection. A clinician often does not know they are treating a bacteremia until the blood cultures result. Once a causative pathogen is identified, treatment considerations such as de-escalation to oral therapy can be considered. The transition of a patient’s antibiotic therapy from IV to oral is not only a cost avoidance measure for the hospital system and the patient, provided it is done appropriately. Conversion to oral antibiotics lowers the number IV administrations decreasing a patient’s risk for infection and often allows for earlier discharge. There is evidence to support patients transitioning to highly bioavailable antibiotics after 1 to 5 days of IV therapy for gram-negative bacteremia. Listed in table 3 are common highly bioavailable antibiotics listed from highest to lowest:

*IV dosing 400mg vs PO dosing 500mg accounts for decreased bioavailability

Uncomplicated MRSA bacteremia treatment must be IV for a duration of at least 14 days per IDSA guidelines.¹ The transition to oral therapy for Gram-negative bacteremia can be considered for the treatment of Enterobacteriaceae. Two different studies found treatment failure for highly bioavailable antibiotics was 2% or less when evaluating uncomplicated Enterobacterales bacteremia of urinary source.^12,13 One of the studies by Kutob and colleagues looked at the rate of treatment failure for 362 patients being treated with high, moderate, and low bioavailable oral antibiotics. The study showed treatment failure rates of 2% (n=106), 12% (n=179), and 14% (n=77), respectively. Treatment failure for the purpose of this study was defined as all-cause mortality or recurrent infection within 90 days of the initial episode of bacteremia. Levofloxacin was the only highly bioavailable antibiotics investigated, and all 3 groups received an average of 4.7 days IV therapy prior to oral conversion. These results are further bolstered by 2019 meta-analysis from Punjabi and colleagues, which investigated 2289 patients from 14 studies.¹⁶ The studies evaluated oral vs IV step-down therapy for Enterobacterales bacteremia. The analysis found 65% of patients transitioned to oral fluoroquinolone, 7.7% to TMP-SMX, and 27.2% to oral beta-lactam, and again showed overall treatment failure for transitioning patients to oral antibiotic was low when using a highly bioavailable antibiotic. The results did find that recurrence of infection occurred more often when transitioned to oral beta-lactam than fluoroquinolone (OR 2.15; 95% CI, 0.93-4.99), however inadequate dosing was cited as a possible reason for this finding. All of these studies evaluated transitioning patients to oral after day 3-4 of IV therapy. While these studies show positive results for fluoroquinolone efficacy in this setting, it is noteworthy that resistance amongst Enterobacterales to fluoroquinolones is increasing limiting their use. In addition, black box warnings around toxicities of these drugs make them less than optimal choices in many patients. Fortunately, newer data have shown positive results for alternative agents as well. Two retrospective studies found that the rate of treatment failure for oral beta-lactams were similar to oral fluoroquinolones.^13,14 The first study by Rieger and colleagues, looked at 241 patients with uncomplicated urinary Enterobacterales bacteremia treated with oral antibiotics. The study found no statistically significant difference in treatment failure between IV only and IV to oral treatment (3.8% vs 8.2%; p=0.19). Treatment failure was defined as a change in antibiotic regimen due to worsening clinical status, escalation back to IV antibiotics from oral, or readmission for the same infection within 30 days of discharge. The primary oral regimens used were, ciprofloxacin (65.3%), oral beta-lactams (19%) and trimethoprim-sulfamethoxazole (9.1%).¹³ The second study was by Mercuro and colleagues.14 The study reviewed 224 patients with uncomplicated urinary Enterobacterales bacteremia comparing clinical success of oral beta-lactam step-down therapy vs oral fluoroquinolone. Rates of clinical success were found to be similar among both groups (86.9% vs 87.1%; p>0.05) with higher rates of therapy completion in the beta-lactam group (91.7% vs 82.1%; p=0.049).¹⁴ A prospective study by Sutton and colleagues released in 2020 was much larger and evaluated 4089 patients who received an oral beta-lactam compared with a highly bioavailable fluoroquinolone or trimethoprim-sulfamethoxazole (TMP-SMX). The study found a 30-day mortality rate of 3% (n=29) vs 2.6% (n=82) and a recurrence rate of 1.5% (n=14) vs 0.4% (n=12), respectively.¹⁵ Based on the findings of these studies, a highly bioavailable fluoroquinolone should be considered an adequate choice for step-down therapy for an uncomplicated Enterobacterales bacteremia of urinary source after at least 2-days IV therapy. In addition, it appears that in many cases an oral beta-lactam can be considered an acceptable, side-effect minimizing substitution to a highly bioavailable fluoroquinolone provided the dosing regimen is optimized based on pharmacokinetic parameters and the patient has completed 3-4 days of IV therapy.

Evidence for the use of oral antibiotics outside of treating Enterobacterales is lacking. Fluoroquinolones are the only oral agents with reliable activity against Pseudomonas aeruginosa due to high intrinsic resistance to oral beta-lactams. This means there are significantly less options for oral step-down therapy.¹⁶ As a result, there is an overall lack of evidence to support routine transition to oral therapy for MDR-bacteremia including Pseudomonas aeruginosa.¹⁶ However, in a study by Fabre and colleagues of 249 patients treated for uncomplicated urinary Pseudomonal bacteremia, 17 (6.8%) transitioned to an oral fluoroquinolone.¹⁷ A reported median time to transition was 5 days after initiating therapy. All 17 patients had source control, defined as the removal of infected hardware or devices, resolution of biliary or urinary obstruction, or drainage of infected fluid collections, and no difference in outcomes were reported. Thus, while routine transition of all patients with Pseudomonas bacteremia would not be recommended, the high bioavailability of fluoroquinolones along with the small retrospective study by Fabre and colleagues does support consideration of oral fluoroquinolones in uncomplicated urinary pseudomonal bacteremia where source control is achieved, and the patient has a rapid clinical response to antibiotics. The use of oral fluoroquinolone step-down therapy for pseudomonal bacteremia should be made on a case-by-case basis. There is also a lack of evidence to support the use of oral antibiotics for non-urinary source uncomplicated Gram-negative bacteremia. The meta-analysis by Punjabi and colleagues cited 6 studies which evaluated non-urinary sources of bacteremia in addition to urinary sources. These studies reported positive outcomes supporting the use of oral therapy for bacteremia of any source, but the results of these studies are likely skewed as the majority (>60%) of cases were secondary to a urinary tract infection.¹⁸

Considerations for Duration of Treatment

Once targeted therapy has been chosen for an infection, a proper duration of therapy must be determined to reduce excessive use of antibiotics and risk of adverse events. Whether a bacteremia is complicated or uncomplicated as well as the source of infection are the primary factors in determining treatment duration. If the infection is complicated, an extended duration of treatment of up to 14 days or more should be considered following resolution of complicating signs and symptoms.¹⁹ For uncomplicated Gram-negative bacteremia, the majority of cases are derived from a urinary infection with a catheter related source the second most common, and then unidentified source.¹⁹ In the study by Swamy and colleagues discussed above in which the majority of Gram-negative bacteremia cases were the result of a urinary tract infection, the achievement of clinical response at the end of therapy for short (7 days or less), intermediate (8 to 14 days) and long (more than 14 days) courses of treatment for gram-negative bacteremia showed no difference in clinical responses. (78.6% vs 89% vs 80.6%, respectively; p=0.2). In addition, the study failed to find a correlation between identified pathogen type, source of infection (urinary vs non-urinary), and time to defervescence (≤72 hours, >72 hours) with clinical failure at the end of therapy. However, the study was underpowered and patients with delayed clinical response may require longer durations of treatment.¹⁹ Another study by Yahav and colleagues compared 7 vs 14 days for uncomplicated Gram-negative bacteremia.²⁰ The study, which looked at a 90 days composite of all-cause mortality, relapse, suppurative, or distant complications, found a 7 day duration to be non-inferior to a 14 day duration of treatment (45.8% vs 48.3%). The majority of patients had a urinary sourced infection (68%) caused by a Enterobacterales (90%).²⁰

Unlike data surrounding IV to oral conversion, treatment durations for multi-drug resistant pathogens such as Pseudomonas aeruginosa or Acinetobacter baumannii may be reduced. Of the studies cited above recommending a reduced duration of 7 days for uncomplicated bacteremia, there was a relatively low percent of patients included with multi-drug resistant pathogens.19,20 The study by Yahav and colleagues only evaluated 28 (4.6%) patients with pseudomonal bacteremia and 2 (0.3%) patients with Acinetobacter bacteremia.²⁰ The study by Swamy and colleagues only included 7% of patients treated for a pseudomonal bacteremia and 4% of patients treated with an Acinetobacter bacteremia.¹⁹ A retrospective study by Fabre and colleagues of 249 patients with uncomplicated Pseudomonas bacteremia found patients treated for approximately 10 days had similar outcomes to those treated with longer durations.¹⁷ There are too few patients in these studies with MDR Gram-negative bacteremia to recommend a reduced duration of therapy for this patient population.

The Use of Follow-up Cultures

Follow-up cultures are necessary for adequate treatment duration for Gram-positive bacteremia. In GNB, the utility of follow-up cultures is more ambiguous. Canzoneri and colleagues looked at 383 cases of GNB where follow-up cultures had been drawn and found positive follow-up cultures for a Gram-negative bacteria in 8 cases.²¹ Only one of the positive cultures was indicative of a possible treatment failure, suggesting follow-up cultures for uncomplicated GNB are not needed.

Conclusion

The treatment of a GNB can range from 7 to 14 days. For complicated GNB a full 14-day duration following resolution of complicating factors would be ideal, as the risk for recurrence is likely high. For MDR pathogens such as Pseudomonas or Acinetobacter, there is evidence to support a reduced duration of 10-days IV antibiotics for uncomplicated bacteremia. Enterobacterales can be treated with a short 7-day course of either IV treatment for non-urinary sourced bacteremia or oral step-down therapy for urinary sourced bacteremia. Provided the patient sees clinical improvement, the use of follow-up blood cultures is not needed for GNB. The flow sheet in figure 2 depicts when to consider treatment duration reductions and IV to oral conversion for Gram-negative bacteremia based on infectious pathogen, source of infection, and complications of bacteremia. The use of shorter oral antibiotic regimens when appropriate will aid in better antibiotic stewardship and patient care.

Figure 2: Treatment Duration Flowsheet

*Recommendations should be considered on a case-by-case basis

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References

1. Liu C, Bayer A, Cosgrove SE, and colleagues. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children [published correction appears in Clin Infect Dis. 2011 Aug 1;53(3):319]. Clin Infect Dis. 2011;52(3):e18-e55. doi:10.1093/cid/ciq146
2. Biedenbach DJ, Moet GJ, Jones RN. Occurrence and antimicrobial resistance pattern comparisons among bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (1997-2002). Diagn Microbiol Infect Dis. 2004;50(1):59-69. doi:10.1016/j.diagmicrobio.2004.05.003
3. Smith DA, Nehring SM. Bacteremia. [Updated 2020 Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441979/
4. Harald Seifert, The Clinical Importance of Microbiological Findings in the Diagnosis and Management of Bloodstream Infections, Clinical Infectious Diseases, Volume 48, Issue Supplement_4, May 2009, Pages S238–S245, https://doi.org/10.1086/598188
5. Sligl WI, Dragan T, Smith SW. Nosocomial Gram-negative bacteremia in intensive care: epidemiology, antimicrobial susceptibilities, and outcomes. Int J Infect Dis. 2015;37:129-134. doi:10.1016/j.ijid.2015.06.024
6. Morpeth S, Murdoch D, Cabell CH, and colleagues. Non-HACEK gram-negative bacillus endocarditis. Ann Intern Med. 2007;147(12):829-835. doi:10.7326/0003-4819-147-12-200712180-00002
7. Singer M, Deutschman CS, Seymour CW, and colleagues. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287
8. Luzzaro F, Viganò EF, Fossati D, and colleagues. Prevalence and drug susceptibility of pathogens causing bloodstream infections in northern Italy: a two-year study in 16 hospitals. Eur J Clin Microbiol Infect Dis. 2002;21(12):849-855. doi:10.1007/s10096-002-0837-7
9. Shorr AF, Tabak YP, Killian AD, Gupta V, Liu LZ, Kollef MH. Healthcare-associated bloodstream infection: A distinct entity? Insights from a large U.S. database. Crit Care Med. 2006;34(10):2588-2595. doi:10.1097/01.CCM.0000239121.09533.09
10. Sligl W, Taylor G, Brindley PG. Five years of nosocomial Gram-negative bacteremia in a general intensive care unit: epidemiology, antimicrobial susceptibility patterns, and outcomes. Int J Infect Dis. 2006;10(4):320-325. doi:10.1016/j.ijid.2005.07.003
11. Michael Smith, MD, MSCE, Samir Shah, MD, MSCE, Matthew Kronman, MD, MSCE, Sameer Patel, MD, MPH, Cary Thurm, PhD, Adam L Hersh, MD, PhD, Route of Administration for Highly Orally Bioavailable Antibiotics, Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Pages S498–S499, https://doi.org/10.1093/ofid/ofx163.1291
12. Kutob LF, Justo JA, Bookstaver PB, Kohn J, Albrecht H, Al-Hasan MN. Effectiveness of oral antibiotics for definitive therapy of Gram-negative bloodstream infections. Int J Antimicrob Agents. 2016;48(5):498-503. doi:10.1016/j.ijantimicag.2016.07.013
13. Rieger KL, Bosso JA, MacVane SH, Temple Z, Wahlquist A, Bohm N. Intravenous-only or Intravenous Transitioned to Oral Antimicrobials for Enterobacteriaceae-Associated Bacteremic Urinary Tract Infection. Pharmacotherapy. 2017;37(11):1479-1483. doi:10.1002/phar.2024
14. Mercuro NJ, Stogsdill P, Wungwattana M. Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones versus β-lactams. Int J Antimicrob Agents. 2018;51(5):687-692. doi:10.1016/j.ijantimicag.2017.12.007
15. Sutton JD, Stevens VW, Chang NN, Khader K, Timbrook TT, Spivak ES. Oral β-Lactam Antibiotics vs Fluoroquinolones or Trimethoprim-Sulfamethoxazole for Definitive Treatment of Enterobacterales Bacteremia From a Urine Source. JAMA Netw Open. 2020;3(10):e2020166. Published 2020 Oct 1. doi:10.1001/jamanetworkopen.2020.20166
16. Hale AJ, Snyder GM, Ahern JW, Eliopoulos G, Ricotta D, Alston WK. When are Oral Antibiotics a Safe and Effective Choice for Bacterial Bloodstream Infections? An Evidence-Based Narrative Review. J Hosp Med. 2018;13(5):328-335. doi:10.12788/jhm.2949
17. Fabre V, Amoah J, Cosgrove SE, Tamma PD. Antibiotic Therapy for Pseudomonas aeruginosa Bloodstream Infections: How Long Is Long Enough?. Clin Infect Dis. 2019;69(11):2011-2014. doi:10.1093/cid/ciz223
18. Punjabi C, Tien V, Meng L, Deresinski S, Holubar M. Oral Fluoroquinolone or Trimethoprim-sulfamethoxazole vs. ß-lactams as Step-Down Therapy for Enterobacteriaceae Bacteremia: Systematic Review and Meta-analysis [published online ahead of print, 2019 Aug 14]. Open Forum Infect Dis. 2019;6(10):ofz364. doi:10.1093/ofid/ofz364
19. Swamy, Siddharth PharmD; Sharma, Roopali BS, PharmD, AAHIVP, BCPS(AQ-ID) Duration of Treatment of Gram-Negative Bacteremia, Infectious Diseases in Clinical Practice: May 2016 - Volume 24 - Issue 3 - p 155-160 doi: 10.1097/IPC.0000000000000362
20. Yahav D, Franceschini E, Koppel F, and colleagues. Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial. Clin Infect Dis. 2019;69(7):1091-1098. doi:10.1093/cid/ciy1054
21. Canzoneri CN, Akhavan BJ, Tosur Z, Andrade PEA, Aisenberg GM. Follow-up Blood Cultures in Gram-Negative Bacteremia: Are They Needed?. Clin Infect Dis. 2017;65(11):1776-1779. doi:10.1093/cid/cix648

By: Jacklyn Harris, PharmD, BCPS, Christian Hospital/St. Louis College of Pharmacy

We had another great virtual Spring Meeting this year! We hope that you enjoyed the programming as much as we did and hope that you were able to view this year’s posters. Our poster presenters did not disappoint- they did a great job completing their research and recording a short 5-minute video review of their poster. Our poster winners this year are listed below.

• Original Research: Kennedy Moore, Pharm.D, Susan Burros, Pharm.D, BCACP, Amy Cummings, Pharm.D, BCACP, Lauren Wilde, Pharm.D, Sarah Will, Pharm.D., BC-ADM for “Integration of Patient-Aligned Care Team (PACT) Clinical Pharmacy Specialist (CPS) Involvement in the Interdisciplinary Management of COPD”
• Encore Research: Lavinia Salama, Pharm.D for “Evaluation of Cost Savings, Safety and Barriers to Implementing a Biosimilar Interchange Policy in a Community Infusion Center”
• Student Research: Danielle Murdock, Pharm.D Candidate, Heather Lyons-Burney, Pharm.D for “Assessing the impact of a pharmacist-led diabetes prevention program at a clinic for uninsured, medically underserved patients”

If you were not able to view the posters, check them out here http://www.moshp.org/mshp-posters-2021/.

This year’s MSHP R&E Foundation Best Practice theme was ‘Adapting to New Circumstances’. This year’s Best Practice award was presented to Kat Lincoln for her project entitled “Daptomycin-weight-based dose optimization”. Look for a review of her project in the next newsletter!

This year’s Best Residency Project Award was presented to Sara Lauterwasser for her project entitled “Safety comparison of heparin and enoxaparin for venous thrombosis prophylaxis in traumatic brain injury”. We will be scheduling a special webinar for Dr. Lauterwasser to present her project.

The 2nd annual Tonnies Preceptor Award was given out at this year’s meeting. The Tonnies awards was established in honor of Fred Tonnies, Jr for his longstanding support of MSHP, MMSHP, and numerous professional and academic contributions to Pharmacy, including over 35 years of dedicated service to student learners. The award recognizes a pharmacist for their sustained contribution to precepting learners in health-system pharmacy, mentoring students/residents in the research process, activity with pharmacy students throughout the state, and service to the profession through ASHP, MSHP, and/or local affiliates. This year’s Tonnies Preceptor Award was presented to Austin Campbell. Dr. Campbell is Clinical Pharmacy Specialist in Psychiatry at the Missouri Psychiatric Center at the University of Missouri Health Care. His investment in developing future practitioners has been evident for many years.

Our final award was the Garrison Award. The Garrison Award recognizes an individual who demonstrates outstanding accomplishments in health-system pharmacy practice, demonstrates teaching through involvement with pharmacy students and contributions to the professional of pharmacy through involvement with MSHP, ASHP, or local affiliates. This year’s award was presented to Diane McClaskey. Diane is the Assistant Director of Experiential Education and Clinical Assistant Professor for the University of Missouri Kansas City, School of Pharmacy at MSU. She embodies the spirit of the Garrison Award in her continuous efforts in student involvement, research and publications, and leadership. We were honored to award this year’s Garrison Award to Diane! Congratulations!!

Please congratulate each of our award winners!! We look forward to when we can present these awards to each of you in person. Thanks for another great Spring Meeting and continue to push the practice of pharmacy in Missouri!

By: Amanda Bernarde, PharmD; PGY1 Pharmacy Resident, University of Missouri Health Care

Uncontrolled pain in the trauma patient population can lead to a variety of long-term, debilitating effects.^1,2 Most prominently, patients experience impaired healing due to additional production of inflammatory factors, increased risk of infection, and psychological disorders persisting well past the initial injury.³ Due to the subjectivity of pain assessments and confounding factors, including sedating medications that can mask uncontrolled pain, recent exposure to opioids, and chronic versus acute pain etiologies, pain management remains a challenge in all patient populations.

Opioids continue to be the mainstay in pain management for trauma patients. However, due to their adverse effect profile, potential for misuse and abuse, and the ever-evolving drug shortage issues facing health care institutions, additional approaches to medication management are necessary to adequately control patients’ pain.² Multimodal analgesia (MMA) is the concomitant use of both opioid and non-opioid pain medications for synergistic mechanisms of action in an effort to minimize opioid-related adverse effects. This approach combats the two sides of pain patients experience: nociceptive and neuropathic.^2,4 Nociceptive pain is caused by mechanical harm to the body, which is the traditional sense of trauma-related pain and commonly managed by opioids, while neuropathic pain is an effect of inappropriate stimuli to the sensory system and not well controlled by opioids.

In a quasi-experimental study completed by Hamrick et al., investigators demonstrated the positive effects of MMA on cumulative oral morphine equivalents (OME) in critically ill trauma patients.⁵ Patients with three or more mechanisms of medication pain management had an average OME of 116.3 mg, while patients without MMA had an average OME of 479 mg spanning the first five days after injury. Beyond the overall reduction of opioid requirements when using a multimodal pain approach, use of non-opioids in addition to traditional regimens have significantly reduced intubation time and intensive care unit length of stay with a reduction of 2.64 and 4.25 days, respectively.⁶ This impact on both short-term and long-term outcomes can drastically alter a patient’s disease course and management beyond the acute setting.

There are a number of specific medication classes that have been explored in conjunction with opioids, including traditional over-the-counter pain medications, gabapentinoids, α-adrenergic agonists, and ketamine. Trauma patients given scheduled oral acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) in addition to opioids had an average OME reduction 6.34 mg and 10.18 mg, respectively, in the 24-hour period post-MMA.⁴ Though reduction in opioid requirements may have been a natural disease progression, several studies have found similar results in non-trauma patients.^2,7,8 Gabapentin and pregabalin mitigate neuropathic pain and help prevent chronic pain, while α-adrenergic agonists, like dexmedetomidine and clonidine, work both peripherally and centrally to provide analgesia, anxiolysis, and sedation.² Both medication classes have demonstrated effective reduction of OME and coinciding pain scores in non-trauma surgical patients, yet no studies have been conducted in critically ill trauma patients to illustrate the effects in this patient population. Lastly, in a recent systematic review and meta-analysis, ketamine administration in the pre-hospital setting was not found to be less effective at managing pain compared to opioids.⁹ This non-opioid analgesic has proven efficacious in decreasing pain scores and OME for both intranasal administration and intravenous administration in a variety of trauma population subsets.^10,11 Each MMA approach, though successfully protocolized at many institutions, should be individualized to the patient, including end organ function, comorbid conditions precluding use, and baseline use of these medications which may reduce their efficacy in treating the acute pain needs of the patient.

In addition to the non-opioid medication therapies, there are nonpharmacologic approaches that can facilitate to both the physical progress and emotional aspects for trauma patients. One such nonpharmacologic therapy is early initiation of physical therapy. From a physical standpoint, assisted movement restores range of motion, promotes healing of injured tissues, and decreases long-term activation of inflammatory responses.¹² Early mobilization has demonstrated a reduction of pulmonary, vascular, and cardiovascular complications, including pneumonia, pulmonary embolism, acute respiratory distress syndrome, deep vein thromboses, myocardial infarctions, and cardiovascular shock.^12,13 Additionally, a statistically significant decrease in hospital length of stay by 2.4 days was shown when comparing early mobility to the control group (p=0.02). Though ICU length of stay was reduced by 1.5 days, these findings were not statistically significant, attributing the decrease in total length of stay to fewer complications when patients reached the general care floors. The positive effect of early physical therapy have prompted additional research in nonpharmacologic approaches to pain management, including mobilization in the emergency department and use of virtual reality.

The limitations and risks associated with long-term, high-dose opioid use remain a concern in practitioners’ minds in treating critically ill trauma patients. Despite the limited data in this patient population, literature from other non-traumatic surgeries has been extrapolated to trauma patients due to their similar pain management needs. In the studies available and those extrapolated, MMA has shown to significantly decrease opioid and overall analgesic requirements, intubated days, and intensive care unit and hospital length of stay, in addition to minimizing misuse and abuse of opioids by setting the same precedent in the outpatient world.

References:

1. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306.
2. Wampole CR, Smith KE. Beyond opioids for pain management in adult critically ill patients. J Pharm Pract. 2019;32(3):256-270.
3. Karamchandani K, Klick JC, Linseky Dougherty M, Bonavia A, Allen SR, Carr ZJ. Pain management in trauma patients affected by the opioid epidemic: a narrative review. J Trauma Acute Care Surg. 2019;87(2):430-439.
4. Gross JL, Perate AR, Elkassabany NM. Pain management in trauma in the age of the opioid crisis. Anesthesiol Clin. 2019;37(1):79-91.
5. Hamrick KL, Beyer CA, Lee JA, Cocanour CS, Duby JJ. Multimodal analgesia and opioid use in critically ill trauma patients. J Am Coll Surg. 2019;228(5):769-775.e1
6. Zhao H, Yang S, Wang H, Zhang H, An Y. Non-opioid analgesics as adjuvants to opioid for pain management in adult patients in the ICU: A systematic review and meta-analysis. J Crit Care. 2019;54:136-144.
7. Polomano RC, Fillman M, Giordano NA, Vallerand AH, Nicely KL, Jungquist CR. Multimodal analgesia for acute postoperative and trauma-related pain. Am J Nurs. 2017;117(3 Suppl 1):S12-S26.
8. Jibril F, Sharaby S, Mohamed A, Wibly KJ. Intravenous versus oral acetaminophen for pain: systematic review of current evidence to support clinical decision-making. Can J Hosp Pharm. 2015;68(3):238-247.
9. Yousefifard M, Askarian-Amiri S, Rafiei Alavi SN, et al. The efficacy of ketamine administration in prehospital pain management of trauma patients: a systematic review and meta-analysis. Arch Acad Emerg Med. 2020;8(1):e1.
10. Carver, TW, Kugler NW, Juul J, et al. Ketamine infusion for pain control in adult patients with multiple rib fractures: results of a randomized control trial. J Trauma Acute Care Surg. 2019;86(2):181-188.
11. Bouida W, Bel Haj Ali K, Ben Soltane H, et al. Effect on opioids requirement of early administration of intranasal ketamine for acute traumatic pain. Clin J Pain. 2020;36(6):458-462.
12. Chimenti RL, Frey-Law LA, Sluka KA. A mechanism-based approach to physical therapist management of pain. Phys Ther. 2018;98(5):302-314.
13. Clark DE, Lowman JD, Griffin RL, Matthews HM, Reiff DA. Effectiveness of an early mobilization protocol in a trauma and burns intensive care unit: a retrospective cohort study. Phys Ther. 2013:93(2):186-196.

By: Emily Lammers, PharmD, MSLD; PGY2 Ambulatory Care/Academia Resident

Mentor: Lisa Cillessen, PharmD, BCACP; Clinical Assistant Professor, UMKC School of Pharmacy at MSU

Program Number: 2021-03-02

Approval Dates: April 7, 2021 to October 1, 2021

Approved Contact Hours: 1 hour

Learning Objectives:

1. Review the pathophysiology of type 1 and type 2 diabetes.
2. Recognize what a continuous glucose monitor is and the components involved with the device.
3. Identify similarities and differences of continuous glucose monitors on the market.
4. Identify how to interpret readings and trends from a continuous glucose monitor device.
5. Describe insurance coverage eligibility criteria for continuous glucose monitors for patients with diabetes mellitus.

Background:

Diabetes mellitus is a chronic disease that affects over 34 million children and adults in the United States alone and 422 million people worldwide. This equates to a global presence of diabetes in people aged 18 years and older of 8.5%.¹ In the United States specifically, 10.5% of the population are diagnosed with diabetes which equates to 1 in 10 Americans. Of the people in the United States diagnosed with diabetes, about 5% of the population, or 1.4 million, are diagnosed with Type 1 Diabetes Mellitus (T1DM) and 90- 95% are diagnosed with Type 2 Diabetes Mellitus (T2DM).² These statistics show that diabetes mellitus is a common disease state that healthcare providers will encounter in their patients regardless of the environment in which they work.

Type 1 diabetes mellitus, which typically presents in adolescents and young adults, is characterized by the immune system destroying insulin producing cells in the pancreas causing the pancreatic beta cells completely stop producing insulin. This leaves the patient without an insulin supply. Insulin is responsible for binding to cells to allow glucose into the cells. If you think of a lock and key, insulin is the key that unlocks the cells and allows glucose to enter the cell. If the cells cannot take up glucose, the body cannot use this glucose for energy and the patient will be in a hyperglycemic state. Due to the lack of insulin in the body, patients with T1DM are indicated for insulin therapy as the treatment of choice. This patient population will require two to four injections per day of insulin. In combination with insulin injections, patients with T1DM need to monitor their blood sugar levels multiple times a day.³

Type 2 diabetes mellitus, which typically presents in older, overweight patients, is characterized by decreased beta cell function, insulin secretion and insulin sensitivity. The body still produces some insulin, but cells are not responding to the insulin to allow glucose into the cells. This is what leads to hyperglycemia in these patients and the diagnosis of T2DM. Patients with T2DM can be treated with both oral and injectable medications based on the severity of their disease. Some patients will not require injections, and some will require up to six injections per day. In combination with this, T2DM patients will need to monitor their blood sugars between one to four times daily depending on their treatment regimen and progression of disease.

Whether the patient has T1DM or T2DM, diabetes puts any patient at an increased risk of complications in the future. These complications can include cardiovascular disease, retinopathy, neuropathy, nephropathy, and others. One of the best ways to mitigate these risks is to have good management of the patient's diabetes and blood glucose levels. This includes staying at or below an A1c of 7% and maintaining blood sugars within the fasting (80-130 mg/dL) and postprandial (<180 mg/dL) goals as outlined by the American Diabetes Association. Based on the UKPDS 35 trial, every 1% reduction in A1c is correlated with a 21% decreased risk of diabetic complications.⁴ This trial and other evidence highlight the importance of maintaining proper control of blood glucose. One of the best ways for a patient to know the status of their blood sugars is to test, but many times patients are limited on the amount of times they can test in a day based on their insurance coverage and not wanting to continuously have finger sticks. This is an area where continuous glucose monitors (CGM) can come into play.

In 2016, the Endocrine Society appointed task force created recommendations and guidelines surrounding CGM use for patients with T1DM and T2DM. The task force recommends the use of CGMs in adult patients with T1DM who have A1c levels above target and who are willing and able to use these devices on a nearly daily basis. Secondly, the task force recommends CGM devices for adult patients with well-controlled T1DM who are willing and able to use these devices on a nearly daily basis. Thirdly, the task force recommends short-term, intermittent CGM use in adult patients with T2DM (not on prandial insulin) who have A1c levels 7% or higher and are willing and able to use the device. These recommendations indicate that CGMs place in therapy is growing and patients are benefiting from using CGMs.⁵

Continuous Glucose Monitors (CGM):

A continuous glucose monitor is a device a patient wears externally on either their abdomen or arm or is implanted. The device has a small sensor that will be inserted under the skin and automatically tracks a patient's interstitial blood glucose throughout the day and night. Interstitial fluid is part of the extracellular fluid between a patient’s cells and interstitial glucose values are determined by the rate of glucose diffusion from plasma to the interstitial fluid and the rate of glucose uptake by subcutaneous tissue cells.⁶ Interstitial glucose values can have a delay compared to blood glucose levels, so if a patient is experiencing signs of hypoglycemia, but the CGM device is not showing a hypoglycemic reading, the patient should verify with a blood glucose fingerstick.

CGMs have different components to them that include a sensor, transmitter, and receiver. The sensor is a small wire inserted subcutaneously and is responsible for measuring interstitial blood glucose levels every one to five minutes. The transmitter is a wireless component of the sensor that will transmit blood glucose levels to a receiver, reader, or application (app) on a smartphone.⁷ The sensor and transmitter are combined into a small, compact device that is attached externally to the body for most devices. There is one implantable CGM device on the market. Lastly, the receiver is a device that is separate from the sensor and transmitter. The receiver, which can be a small device or a compatible smart device, will display the transmitted data from the sensor. Different CGM devices are on the market and may have small differences from each other like where to place the sensor or the amount of time before each reading, but each device will have a sensor, transmitter, and receiver. Having the CGM device continuously track blood glucose levels allows patients and providers to see trends throughout the day and night and utilize these numbers to make medication or lifestyle changes.⁸

In recent trials completed in T1DM and T2DM patients, CGM have been shown to decrease hypoglycemic events. The IMPACT trial from 2016, showed patients with T1DM had a 38% reduction of time in hypoglycemia and a 40% nighttime reduction of hypoglycemia (<70 mg/dL)9. The REPLACE trial in 2017, showed that patients with T2DM had a 43% reduction of time in hypoglycemia and a 54% nighttime reduction of hypoglycemia (<70 mg/dL).¹⁰ This reduction provides a safer environment for patients and reduces worry for providers and patients regarding patients experiencing hypoglycemic events.

How many CGMs are on the market?

Pharmacists may have noticed that CGM devices have gained more popularity in recent years with the Freestyle Libre and Freestyle Libre 2 coming to market, but this was not the first CGM to be approved for use in patients with diabetes. Dexcom G6, Guardian Connect with the Guardian Sensor 3, and Senseonics Eversence are other continuous glucose monitors that are available to patients and have been since the early 2000’s.

Dexcom

The Dexcom G6 is the most current model that is available to patients and is equipped with a 10-day wearable sensor and transmitter. A patient will place the sensor and transmitter on their abdomen. The sensor and transmitter device are water-resistant and easy to insert with an auto-applicator. The Dexcom G6 transmitter wirelessly provides a glucose reading every five minutes, or up to 288 times per day to the receiver or a compatible smart device. These readings can be shared with up to ten others via the Dexcom Share feature. If a patient wishes to share data from their device with their healthcare provider, the information can be shared via the Dexcom Clarity software which allows providers to review CGM data at any time. The G6 is also equipped with an alert system for critically low blood sugars. The device monitors glucose trends and if glucose is trending downward, the device will alert a patient with a 20-minute advanced warning of a severe hypoglycemic event (<55 mg/dL). A patient will also have the option to set a “Low Alert” and “High Alert” for when their blood glucose readings are below or above target range. These alerts can be set, changed, or discontinued at any time by the patient. The alert for critically low blood sugars cannot be changed or stopped. The G6 is FDA permitted to make diabetes treatment decisions without confirmatory finger sticks or calibration needed, but if a patient is experiencing symptoms that are not in line with the readings they are receiving, fingerstick blood sugar should be taken to confirm.¹¹

Guardian Connect and Guardian Sensor 3

The Guardian Connect CGM is powered by the Guardian Sensor 3, which can be worn up to seven days and is water-resistant for up to 30 minutes. The sensor measures interstitial blood glucose levels every five minutes. The transmitter will then automatically transfer these readings to the Guardian Connect app. The Guardian Connect app allows patients to set predictive high and low glucose values ranging from 10-60 minutes prior to predicted events happening. With the predictive alerts turned on to 30 minutes before a low, the Guardian Connect system had a 98.5% rate of detecting hypoglycemic events by evaluating if the patient’s glucose is trending downward. This system also allows patients to connect with their healthcare providers via the CareLink system platform. This platform enables providers virtual, remote monitoring of their patient’s glucose levels and trends. Another feature of the Guardian Connect system is the Sugar.IQ Diabetes Assistant cognitive app. This app uses IBM Watson analytics to identify patterns in diabetes data. The app continually analyzes how a patient’s glucose levels respond to their food intake, insulin dosages, and daily routines. This helps patients discover any hidden reasons for highs or low and gives a daily summary of glucose levels to allow patients to see how their blood sugar levels are trending.¹²

Senseonics Eversence

Eversence is the world’s first and only long-term, implantable CGM device. The sensor will be professionally placed by a healthcare provider every 90 days directly under the skin in a patient’s arm. The sensor is 3.5mm x 18.3mm. The sensor remains accurate if compressed and during exercise. The transmitter will sit right above the sensor on a patient’s arm and is removable, rechargeable, and water-resistant up to 30 minutes. A benefit of the transmitter being removable is patients can remove the device for a special occasion and they will not waste a sensor because the sensor and transmitter are not attached. The transmitter will send data to a patient’s smart device every five minutes via Bluetooth. The transmitter will provide on-the-body vibration alerts when a patient’s blood glucose is too high or too low in addition to alerts the patient can see and hear. Eversence is the only CGM on the market that includes vibration alerts. Blood glucose levels are automatically sent to a patient’s smart device from the transmitter, the patient’s smart device will track the real-time glucose measurements with no need for a different receiver. The patient can also track exercise and meals to see them on the graph and aid in identifying trends. The data sent to the smart device can be shared with up to five people of the patient’s choosing and could include members of the healthcare team.¹³

Freestyle Libre 14-day

Freestyle Libre is a 14-day sensor that a patient wears on the upper part of the back of their arm. The sensor filament is less than 0.4mm thick and is water- resistant. The receiver is a separate device that patients can use to scan the sensor to obtain their glucose readings. A patient can also use their smart device with the LibreLink app if preferred. Patients may scan the transmitter as often as they want while they are wearing the sensor and a new reading is available every minute to view with the system storing glucose readings every 15 minutes. It is required that patients do scan the sensor at least once every eight hours or data will be lost for that time period. Each scan will show the patient’s current blood sugar reading, direction sugars are trending, and a trend graph showing the last eight hours of glucose history. The reader will hold up to 90 days of glucose history including daily patterns, time in target, low glucose levels, and 7, 14 and 30-day averages. This data is available to be shared with up to 20 people like family members or healthcare providers via the LibreLinkUp app. Freestyle Libre 2, which was approved Summer 2020, is the most recent version of the Freestyle Libre devices. The Libre 2 has all the features of the previous versions and includes alerts for high and low blood sugars for the patient. Along with that, the Libre 2 has an online portal called LibreView that can be accessed by patients and healthcare providers to share CGM data. The Libre 2 is not currently approved to be used with the LibreLink app, so patients will need to have the receiver accessible to scan the sensor at least once every 8 hours. The receiver can double as a glucose meter if the patient needs to perform a fingerstick blood sugar check.¹⁴

Comparison of Continuous Glucose Monitors

How do I interpret the numbers?

The glucose readings, trend lines, averages, and alerts from a continuous glucose monitor can seem daunting as a healthcare provider trying to figure out what to do with all the information. From a figure used in an article written by Dr. Bergenstal, this article will go through how to interpret all the information from a CGM report.

This figure is from a FreeStyle Libre device, but many of the CGMs on the market will produce similar data to what is in the image above. The average glucose has a high correlation with A1c, but not as much with glycemic variability or hypoglycemia. If a healthcare provider were to only utilize this number when making a treatment decision it does not give much information around glucose patterns. The glucose management index is a substitution for estimated A1c. This number is calculated from the mean CGM glucose over a specified period of time. The next item to take a look at is the time in range (TIR). This graph shows the time a patient is in target range, above and below. As healthcare providers, we want to try to maximize our patient’s time in range and minimize the time above and below. The image above shows the TIR as a percentage, but some data will show it in minutes or hours in range per day averaged over the allotted time period. TIR will automatically set up to 70-180 mg/dL, but if a patient or provider wants to alter the target levels that is available to do. The time in hypo- and hyperglycemia have specified values and then beyond that will have critical values. These are shown above with <70 mg/dL considered below target range, but then it also specifies what percentage of that time the patient spent <54 mg/dL. These values can be extremely useful for healthcare providers to identify how often a patient is below or above goal. Using this information paired with the graph on time to see when exactly the patient is experiencing the time above or below can aid the provider in making very informed, specific medication regimen changes. The coefficient of variation (CV) is a value that is used to mark glucose variability. It has been studied that a CV of <36% represents low glucose variability and a stable glucose profile and ≥ 36% is vice versa. Standard deviation (SD) highly correlates with mean glucose and A1c. If the SD is less than the mean glucose divided by three, a provider can assume low glucose variability and a stable glucose profile. Lastly, the ambulatory glucose profile with the dark blue line being the median with 50% of glucose levels above and 50% below. The dark blue shading is indicative of 50% of all glucose readings and the light blue is 80% of readings for the specified time. This graph is a visual that healthcare providers can quickly look at to identify how often and at what times a patient is in target range. It is also a great tool to use to identify what times a day a patient is at risk for a hypoglycemic event and can alter medication regimens to mitigate chances of hypoglycemia.¹⁵

A CGM report may seem daunting at first but breaking down each part and understanding what it means in the big picture could be helpful. While this article discussed specifically FreeStyle Libre, this information is transferable to any CGM report that a provider may be interpreting with some small differences present.

What monitor is right for my patient?

Insurance companies play a huge part in identifying which monitor may be right for a patient. Insurance companies issue preferred drug lists that indicate which medications and devices are preferred for that specific insurance company. This does not mean that non-preferred medications will not be covered to some extent but may have a higher copay or require a prior authorization. It is more common that insurance companies will provide coverage for continuous glucose monitor devices for patients with T1DM as these patients typically require more daily finger sticks and are treated solely with insulin which may put them at an increased risk for hypoglycemic episodes.

Each company with a CGM on the market will also have a team available for patients or providers to help with coverage. The pharmaceutical companies want patients using their products, so they offer many resources to help with the processing of paperwork and finding coverage opportunities for patients. Below is a list of insurance coverage and criteria that must be met for common insurances that pharmacists in Missouri may encounter. Commercial insurance companies have similar criteria, so only one has been listed below.

Missouri Medicaid

Missouri Medicaid covers Dexcom G6 for patients who meet certain criteria including:¹⁶

Blue Cross Blue Shield of Missouri

Blue Cross Blue Shield of Missouri covers Freestyle Libre 14 and Dexcom G6 at a tier 2 and ST. The step therapy qualifications are listed below for FreeStyle Libre 14 Day and similar steps are required for Dexcom G6:¹⁷

Medicare

The Medicare National Coverage Determinations Manual has released the following information regarding coverage of a CGM for patients with Medicare insurance.¹⁸

Considering the different eligibility criteria for commonly seen insurance plans in Missouri, it can be hard for patients to gain approval for continuous glucose monitoring devices. There is always the option for patients to pay out of pocket, but that can be a considerable expense for patients. Continuous glucose monitors are great devices that have proven to decrease times in hypoglycemia and overnight hypoglycemia for patients. There is also the benefit of information sharing with friends, family, and the healthcare team. For healthcare providers, it makes our decision-making process more exact when we can identify trends in glucose over time instead of a moment in time blood sugar. With all those benefits being mentioned, cost and eligibility are the largest barriers. To increase accessibility to patients, there needs to be a reduction in cost or loosened eligibility criteria for patients with T1DM and T2DM.

References:

1. World Health Organization. Diabetes. Geneva, Switzerland: World Health Organization; 2020.
2. American Diabetes Association. Fast facts - data and statistics about diabetes. Arlington, VA: American Diabetes Association; 2020.
3. Publishing, H. (n.d.). Type 1 Diabetes Mellitus. Retrieved January 28, 2021, from https://www.health.harvard.edu/a_to_z/type-1-diabetes-mellitus-a-to-z
4. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000 Aug 12;321(7258):405-12. doi: 10.1136/bmj.321.7258.405
5. Endocrine.org. (n.d.). Retrieved January 28, 2021, from https://www.endocrine.org/
6. Cengiz, E., & Tamborlane, W. (2009, June). A tale of two compartments: Interstitial versus blood glucose monitoring. Retrieved January 28, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903977/
7. Cengiz, E., & Tamborlane, W. (2009, June). A tale of two compartments: Interstitial versus blood glucose monitoring. Retrieved January 28, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903977/
8. Cengiz, E., & Tamborlane, W. (2009, June). A tale of two compartments: Interstitial versus blood glucose monitoring. Retrieved January 28, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903977/
9. IMPACT Trial: Bolinder, Jan, et al. Novel glucose-sensing technology and hypoglycemia in type 1 diabetes: a multicentre, non-masked, randomised controlled trial. The Lancet 388.10057 (2016): 2254-2263
10. REPLACE Trial: Haak, Thomas, et al. Flash glucose-sensing technology as a replacement for blood glucose monitoring for the management of insulin-treated type 2 diabetes: a multicenter, open-label randomized controlled trial. Diabetes Therapy 8.1 (2017): 55-73.
11. Dexcom. (n.d.). Retrieved January 28, 2021, from https://www.dexcom.com/
12. Guardian Connect Continuous Glucose Monitoring System. (2020, December 16). Retrieved January 28, 2021, from https://www.medtronicdiabetes.com/
13. Eversense. (n.d.). Retrieved January 28, 2021, from https://www.eversensediabetes.com
14. Continuous Glucose Monitoring System. (n.d.). Retrieved January 28, 2021, from https://www.freestyle.abbott/us-en/home.html
15. Clinical Services Programs. (n.d.). Retrieved January 28, 2021, from https://dss.mo.gov/mhd/cs/
16. Bergenstal, R. (2017). Understanding continuous glucose monitoring data. Endocrine Pract, 23, 629-632.
17. Anthem Blue Cross Blue Shield: Health Insurance, Medicare & More. (n.d.). Retrieved January 28, 2021, from https://www.anthem.com/
18. MCD. (n.d.). Retrieved January 28, 2021, from https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?lcdid=33822

By: Jamie Prashek, PharmD, PGY1 Pharmacy Resident, University of Missouri Health Care

Status epilepticus broadly refers to a seizure with prolonged activity; historically this was defined as a duration of at least 30 minutes.^1-3 Lowenstein et al. further specified this definition as convulsive seizures with at least five minutes of continuous seizure activity or intermittent seizures without recovery of consciousness in-between.^4,5 Current recommendation is for prompt initiation of treatment once activity has reached five-minutes.² A delay in initiation increases the chance for prolonged activity and risk for neuronal injury. Morbidity and mortality increases as seizure time lengthens, with seizures lasting greater than 30 minutes having an increased risk for worse outcomes.^2,5-7

Approximately 150,000 individuals develop epilepsy yearly, with 15% experiencing status epilepticus at some point.⁸ Since “time is brain”, status epilepticus is a medical emergency with immediate and effective treatment being imperative. Benzodiazepines have historically been the agents of choice as first line options.^1,3 However, the exact agent, dose, and route of administration has been up for debate. Different routes of administration include intravenous (IV), intramuscular (IM), rectal, buccal, and intranasal. In addition, another question is which second line treatment agent is appropriate when status epilepticus is refractory to benzodiazepine treatment. The following will review key literature and guidelines to outline recommended and effective treatment in those with status epilepticus.

In 2016, the American Epilepsy Society released a guideline recommending treatment for convulsive status epilepticus in both children and adults.³ As mentioned previously benzodiazepines remain the initial treatment of choice, however, with various benzodiazepines and routes of administration, it is imperative to consider the feasibility of administration when making a selection. Intravenous benzodiazepines have been widely used, but obtaining access during active convulsions is not always feasible and another route must be available. Two pivotal studies discussed below, have helped to guide treatment with benzodiazepines.

The pre-hospital treatment for status epilepticus (PHTSE) study was a randomized, double blind, placebo controlled trial evaluating the safety of intravenous benzodiazepines by emergency medical service (EMS) providers.^9,10 Study intervention included 2mg IV lorazepam, 5mg IV diazepam, or placebo, with the allowance of a one-time repeated dose if necessary. The primary outcome was cessation of status epilepticus prior to arrival to the emergency department (ED). Termination of status was evident in 59.1% in those who received IV lorazepam, 42.6% who received IV diazepam, and 21.1% who received placebo (p=0.001).

Silbergleit et al. compared the use of IM midazolam to IV lorazepam for pre-hospital treatment in those with active status epilepticus.¹¹ The rapid anticonvulsant medication prior to arrival trial (RAMPART) was a randomized, double blind, non-inferiority trial designed to find an alternate efficacious agent.¹¹ Treatment was as follows, patients weighing 40 kg or more received 10 mg IM midazolam followed by IV placebo, or they received IM placebo followed by 4 mg IV lorazepam. With dose adjustments for those between 13 to 40 kg, active drug doses at 5 mg IM midazolam and 2 mg IV lorazepam. The primary outcome of cessation of convulsions prior to ED arrival was evident in 73% of the IM midazolam group compared to 63.4% in the IV lorazepam group (p<0.001).¹¹ Importance for this study was to provide EMS providers an alternative agent to IV lorazepam that was comparable in safety and efficacy. Limitations for IV lorazepam included the potential difficulty in obtaining IV access, along with the limited shelf life of unrefrigerated lorazepam solution.¹²

At the time of the 2016 guidelines, a gap in evidence existed for deciding the best secondary agent when status is refractory to benzodiazepine therapy. Chamberlain et al. with the established status epilepticus treatment trial (ESETT) set out to answer this exact question. ESETT was a double blind, randomized, Bayesian response trial comparing levetiracetam, fosphenytoin, and valproate in those after adequate benzodiazepine administration.¹³ Treatment randomization was in a 1:1:1 ratio with levetiracetam 60 mg/kg (max of 4500 mg), fosphenytoin 20 mg PE/kg (max of 1500 mg PE), or valproate 40 mg/kg (maximum 3000 mg) infused over 10 minutes. The primary outcome was for cessation of clinical seizures and improved responsiveness at 60 minutes without the need for additional anti-seizure medications or endotracheal intubation. Across the different age groups efficacy was evident in roughly half of the patients treated with each agent. Although, the ESETT did not answer the question of which agent is preferred, it does give more reassurance that utilizing levetiracetam, fosphenytoin, or valproate should be effective if dosed accurately.

The 2016 guidelines developed a treatment algorithm helping providers decide what agent is ideal at specific time intervals. See Figure 1 for a modified algorithm and Table 1 for treatment agents and dosing. IV lorazepam dosed at 4 mg is an ideal first line agent. In those without IV access IM midazolam is an appropriate alternative agent. After treatment with benzodiazepines, a plan for immediate treatment with a second phase agent is just as important, with appropriate choices including levetiracetam, fosphenytoin, and valproate.

References:

1. Trinka E, Kälviäinen R. 25 years of advances in the definition, classification and treatment of status epilepticus. Seizure. 2017;44:65-73.
2. Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-1523.
3. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA. 1993;270(7):854-859.
4. Lowenstein DH, Bleck T, Macdonald RL. It's time to revise the definition of status epilepticus. Epilepsia. 1999;40(1):120-122.
5. Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61.
6. Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinants of mortality in status epilepticus. Epilepsia. 1994;35(1):27-34.
7. DeLorenzo RJ, Garnett LK, Towne AR, et al. Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes. Epilepsia. 1999;40(2):164-169.
8. NORD (National Organization for Rare Disorders). 2021. Status Epilepticus - NORD (National Organization for Rare Disorders). [online] Available at: [Accessed 1 February 2021].
9. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus [published correction appears in N Engl J Med 2001 Dec 20;345(25):1860]. N Engl J Med. 2001;345(9):631-637.
10. Lowenstein DH, Alldredge BK, Allen F, et al. The prehospital treatment of status epilepticus (PHTSE) study: design and methodology. Control Clin Trials. 2001;22(3):290-309.
11. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591-600.
12. Gottwald MD, Akers LC, Liu PK, et al. Prehospital stability of diazepam and lorazepam. Am J Emerg Med. 1999;17:333–7.
13. Chamberlain JM, Kapur J, Shinnar S, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020;395(10231):1217-1224.