UMKC School of Pharmacy
As usual, we have been very busy at the UMKC School of Pharmacy! While it would be impossible here to describe all that has been going on, I would like provide a brief update on recent activities at the school.
UMKC School of Pharmacy at MSU: After six years of hard work by UMKC and MSU faculty and staff, as well as support from the state of Missouri and many hard-working legislators, we have come through on our promise to provide pharmacy education in Southwest Missouri. Our first cohort of 31 students graduated from our Springfield location in May. Prior to graduation, most of the students had secured jobs in and around Southwest Missouri. This group of outstanding students included many who would not have been able to pack up and move to our sites in Kansas City or Columbia in order to attend pharmacy school. Special thanks go to all who made this happen, but especially our friends and colleagues at Missouri State University. President Clif Smart and Provost Frank Einhellig and all of the folks there who worked with us to make dreams come true.
“APhA-ASP National Champions”. If ESPN would cover pharmacy student competitions, then the entire country, even those outside the pharmacy world, would know the dominance of the UMKC chapter of the American Pharmacists Association-Academy of Student Pharmacists (APhA-ASP)! This year, our chapter was once again recognized as the number one chapter in the country! This is the second time since 2012 that our chapter has been recognized by APhA as the number one chapter, and every year in between they have been among the top seven or four chapters in the nation. Our students are clearly having a huge impact on the health and wellness of people in our country, and especially throughout central and southwestern Missouri as well as the Kansas City area. We are proud that they continue to bring such positive national attention to UMKC. We also had national APhA awards provided to individual UMKC student pharmacists including: Sara Massey (Class of 2018) received the John A. Gans Scholarship from the APhA Foundation; Sierra Woods (Class of 2019) received the APhA Good Government Student Pharmacist of the Year.
Outstanding Faculty Advisors. I often get asked by other deans of pharmacy around the country about the keys to the success of our student chapter of APhA-ASP, and the answer is simple: it’s clearly the outstanding faculty advisors they have. Special thanks go to the mentorship provided by Drs. Kelly Cochran, Kathryn Holt, Lisa Cillessen, Angela Brownfield, Sarah Cox, Heather Taylor, Andrew Bzowyckyj, and Cameron Lindsey. All of these faculty are well-known nationally for leading our students, but we are particularly pleased that Dr. Valerie Ruehter received the APhA-ASP Outstanding Chapter Advisor Award—the top advisor in the country!
Other National Student Awards. Our students received many other national awards. Marian Lyford (Class of 2018) was recognized by the United States Public Health Service with the 2018 Excellence in Public Health Pharmacy Award. Also, Dion Tyler (Class of 2018) and his interprofessional team of health care student finished 3rd at the annual CLARION National Competition at the University of Minnesota.
Faculty and Staff Focus on Student Success! While we are absolutely elated that our students rake in all the national awards, the truth is their greatest accomplishment is graduation. For that ultimate measure of student success, we are forever grateful for the hard work and dedication of our staff and faculty. We are also proud of our student success numbers where 94.4 % of the students who entered our program in 2014 graduated on time in 2018. While we do not yet have NAPLEX pass rates from them, we do know that for 2017 graduates—97.5 % of whom graduated on time—92% passed the NAPLEX on first sitting.
Faculty Accolades. Many of our faculty have received substantial accolades in the last year, far too many to list all here. Among our clinical faculty, some of the accomplishments included: Dr. Andy Smith was named a Fellow of the American College of Clinical Pharmacy; Dr. Heather Taylor became a Board-Certified Pharmacotherapy Specialist; Dr. Heather Lyons-Burney was named MPA Faculty Member of the Year and received the Jefferson Award, a national program started by Jacqueline Kennedy in 1972 that honors everyday heroes in our community; Dr. Paul Gubbins published a book as Editor entitled Drug Interactions in Infectious Disease: Mechanisms and Models of Drug Interactions, 4th Ed.; Dr. Maureen Knell co-authored a publication in Pain Medicine this year that is receiving significant attention locally and nationally for understanding opioid prescribing patterns; Drs. Angela Brownfield, Paul Gubbins, and Valerie Ruehter received the Award for Excellence in Scholarship in Experiential Education from the American Association of Colleges of Pharmacy; and Dr. Kendall Guthrie was elected to serve on the Board of Directors of the MPA.
There are many other great accomplishments of our students faculty in the past year. If you can make time to come by and see us, we’d be happy to tell you all about it. You are all welcome to visit the school anytime at our sites in Kansas City, Columbia, and/or Springfield. We also appreciate your assistance in identifying any students who might be interested in pursuing pharmacy careers. Just let us know, we love to talk to anyone about our great profession!
Best wishes to everyone in MSHP!
Russell B. Melchert, Ph.D.Dean of Pharmacy and Professor
UMKC School of Pharmacy - SSHP
Authors: Anna Parker and Jordyn Williams, UMKC SSHP Chapter Presidents
The spring and summer semesters at the UMKC School of Pharmacy are a little more relaxed than our fall semester. In February, our Columbia campus teamed up with MMSHP and the Ronald McDonald House to prepare meals for patients and families receiving care at the Women and Children's Hospital. It was a great time serving the local community through the event. The Columbia campus also participated in a pull tab collection competition with local hospitals to raise money for the Ronald McDonald House. All together, they were able to collect over 30 pounds of pull tabs. Aside from that, we held our monthly general meetings during the spring semester with visiting speakers to share their experiences working as health-system pharmacists. Dr. Rachel Howland from Truman Medical Center visited during one of our last meetings and presented a very unique patient case. All of the attendees enjoyed hearing how Dr. Howland handled the case with her healthcare team and was able to provide appropriate pharmacological care. The meeting and case presentation helped show students the vital role a clinical pharmacist can play in patient care.
This summer the SSHP executive team is busy gearing up for our main events that happen in the fall semester. Residency program directors should be on the lookout for their invitation to attend Residency Roundtable, which will take place on September 29th at each UMKC campus. Our Clinical Skills Competition and membership drive will also be taking place this coming fall.
The Kansas City campus would like to extend a warm welcome to Dr. Jeremy Hampton, who will be serving as our new advisor this year. We would also like to thank Dr. Tatum Mead and Dr. Stephanie Schauner for their time serving as advisors in Kansas City. We are thankful for your involvement with SSHP and wish you the best! All three campuses are excited to start the new school year in August and are ready to see our chapter grow, serve, and learn.
Pharmacogenomics in Pain Management
Author: Lance Schneider, PharmD, PGY2 Internal Medicine Pharmacy Resident, University of Missouri Health Care, Columbia, MO
Preceptor: Ryan Camden, PharmD, BCPS, PGY2 Internal Medicine Residency Program Director, University of Missouri Health Care, Columbia, MO
Program Number: 2018-07-16
Approval Dates: August 1, 2018 - November 1, 2018
Approved Contact Hours: One (1) CE(s) per LIVE session.
1. Describe what pharmacogenomics is and how it relates to medication therapy management.
2. Review the Centers for Disease Control and Prevention guideline for prescribing opioids for chronic pain.
3. Discuss current pharmacogenomic dosing guidelines.
4. Evaluate current literature regarding utilization of pharmacogenomics for opioid prescribing.
Conventional clinical use of drug therapy is based primarily on a ‘one size fits all’ model, meaning medications are utilized and prescribed based off of population outcomes from clinical trials. Pharmacogenomics is the study of how personal genetic traits affect an individual’s response to drug therapy. Clinically, this is the direction medicine is heading and can have a huge impact on patient care. By testing a patient’s DNA for certain genetic variations and combining that information with available medication databases clinicians can personalize a medication regimen to maximize efficacy and safety. For example, approximately 20-40% of the population will have a suboptimal response to clopidogrel due to variations in the CYP2C19 gene.1 Knowing a patient has this variation prior to medication initiation would allow physicians to start an alternative and more efficacious antiplatelet agent. Currently, utilization of pharmacogenomics for patient specific medication regimens is not widespread. Antimicrobials, chemotherapy, and psychotropics are the drug classes with the most pharmacogenomic information available. Opioids have not been in the forefront of pharmacogenomic testing, however, with the recent Centers for Disease Control and Prevention (CDC) campaign to help control the prescription opioid epidemic pharmacogenomics could play an important role in pain management.
CDC Guideline for Prescribing Opioids for Chronic Pain
In response to the quintupling of opioid prescriptions in the U.S. from 1999 to 2016 the CDC has developed a campaign to help combat misuse and overprescribing of opioids. Not coincidentally, prescription opioid overdose deaths during this time-frame similarly increased without an overall change in the amount of pain reported.2 More than 40% of all U.S. opioid overdose deaths in 2016 involved a prescription opioid with more than 46 people dying every day from overdoses involving prescription opioids.3 The CDC sought out to improve opioid prescribing safety and efficacy through the development of clinical practice guidelines. These guidelines, which can be found online at https://www.cdc.gov/drugoverdose/pdf/Guidelines_Factsheet-a.pdf, provide twelve recommendations for health-care providers. These recommendations are broken into three separate sections: determining when to initiate or continue opioids for chronic pain, opioid selection, dosage, duration, follow-up, and discontinuation, and assessing risk and addressing harms of opioid use.4 As pharmacogenomics is still a relatively new field with a limited amount of data, especially regarding opioids, the CDC has yet to implement any recommendations regarding pharmacogenetic testing for opioid utilization.
What is Pharmacogenomics?
Pharmacogenomics is the study of how a person’s genetic makeup (-genomics) can affect their response to a drug (pharmaco-), leading to variations in efficacy and adverse drug effects.5 The idea of pharmacogenomics is far from new, with documentation of landmark discoveries dated from at least the 1950s. However, the rate of new discoveries has significantly increased since the completion and publication of the Human Genome Project (HGP) in 2003.6 The HGP was a collaborative research program with the goal to complete the mapping and understanding of all the genes of human beings. It has truly carved a new path into the future of medicine, giving insights that will help to treat, cure and prevent diseases.7
There are approximately 20,500 genes that make up the human genome. Everyone has two copies of each gene, one inherited from each parent, which are the codes that direct cells how to make proteins. Variations in this genetic code through various mechanisms such as single nucleotide polymorphisms (SNPs), copy number variations (CNVs), insertions, or deletions can lead to differences in response to a medication. Alterations in safety and efficacy arise when these genetic variations occur in genes that code for proteins that effect the pharmacokinetics of medications – absorption, distribution, metabolism, and excretion.1
Pharmacogenomic Dosing Guidelines
The lack of clinical prescribing information regarding pharmacogenomics is a primary contributor to the hesitancy of utilization by health-care providers. For example, the U.S. Food and Drug Administration (FDA) has put out a reference of pharmacogenomic biomarkers in drug labeling with over 100 different medications, but only some of them have actionable recommendations based on the biomarker information. One of the best, and most complete references is PharmGKB. PharmGKB is a National Institute of Health (NIH) funded resource that provides information about how human genetic variation affects response to medications. It incorporates multiple dosing guidelines from various professional societies including the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Royal Dutch Association for the Advancement of Pharmacy – Pharmacogenetics Working Group (DPWG), and the Canadian Pharmacogenomics Network for Drug Safety (CPNDS). Drug label information and primary literature are also included to provide genotype-specific dosing recommendations. 1
Opioids with Pharmacogenomic Information
Pharmacogenomic information is scarce regarding opioids and most data come from case control studies and case reports. Codeine and tramadol are the only two opioid medications with pharmacogenomic biomarkers in the drug labeling. The pharmacogenomic information on these medications are in relation to CYP2D6.8 CPY2D6 is an enzyme within the cytochrome P450 (CYPs) superfamily of microsomal drug-metabolizing enzymes. CYPs possess many physiological functions including synthesis of steroid hormones, cholesterol and other fatty acids, and bile acids, and metabolism of exogenous and endogenous substances including drugs and toxins.9 There have been 57 cytochrome P450 genes identified in humans with a small number appearing to contribute to the metabolism of drugs, mainly CYP1, CYP2, and CYP3 families.10 Each CYP gene is given a number associated with a specific group within the gene family, a letter representing the gene’s subfamily, and a number assigned to the specific gene within the subfamily. Therefore, CYP2D6 is the cytochrome P450 gene in group 2, subfamily D, and gene 6.9
Codeine is metabolized by CYP2D6 into morphine, a much more potent opioid. An individual carrying a normal CYP2D6 genotype, also known as an extensive metabolizer (77-92% of patients), will have normal morphine formation and thus the label recommendations for dosing may be followed. Genetic polymorphisms of the CYP2D6 gene result in clinically significant phenotypes: ultra-rapid metabolizer (1-2% of patients), intermediate metabolizer (2-11% of patients), and poor metabolizer (5-10% of patients). Poor metabolizers will lack efficacy while ultra-rapid metabolizers are at a higher risk of toxicity due to the increased formation of morphine following codeine administration. The FDA Label has been updated to include the safety concerns related to ultra-rapid metabolizers; respiratory depression, extreme sleepiness, and confusion. Additionally, death has occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism. Lastly, ultra-rapid metabolizing women who are breastfeeding will have higher than expected serum morphine levels leading to potentially high levels within the breastmilk. For these reasons, codeine is not recommended in ultra-rapid metabolizers. 1,8
Tramadol, similar to codeine, is metabolized by CYP2D6 into a more potent active metabolite, O-desmethyltramadol (M1). Tramadol has the same considerations as codeine in regards to the different genotypes. In addition to ultra-rapid metabolizers, tramadol has FDA labeling information regarding poor metabolizers. A phase 1 pharmacokinetic study in healthy subject poor metabolizers revealed an approximately 20% higher serum concentration of tramadol with a 40% lower serum concentration of M1. An important consideration for both tramadol and codeine is drug-drug interactions with CYP2D6 inhibitors such as fluoxetine. With the known alterations from varying genotypes safety and efficacy of these opioids could be affected greatly with the concomitant use of CYP2D6 inhibitors, even in extensive metabolizers. 1,8
Opioid Pharmacogenomics in Cancer Patients
Opioid analgesics are widely used for the treatment of chronic pain in patients with cancer. Efficacy and safety of these opioids vary widely between patients, and despite their utilization a significant number of patients still experience moderate to severe pain.11 These factors contribute to cancer patients being an optimal population for opioid pharmacogenomic research.
Andreassen et al. identified CYP2D6 polymorphisms in patients being treated with oxycodone for cancer pain to evaluate an association between observed pharmacokinetic alterations and the pharmacodynamic response. CYP2D6 is responsible for metabolizing approximately 11% of the parent compound oxycodone into the more potent oxymorphone.12 The study included 27 poor metabolizers (PM), 413 extensive metabolizers (EM), and 10 ultra-rapid metabolizers (URM). PM patients had a statistically significant lower serum concentration oxymorphone to oxycodone ratio than EM and URM (0.0028, 0.0172, and 0.244; p = <0.05). This pharmacokinetic difference did not correlate with pharmacodynamic outcomes. The median pain intensity was 4 on the numerical rating scale for PM and URM, and 3 for EM with a non-significant difference between groups (p = 0.8). Differences in pain intensity (p = 0.7), nausea (p = 0.6), and cognitive function (p = 0.8) were also non-significant.13
In 2015, Bell et al. performed a clinical review of current pharmacogenomic studies in patients with cancer pain. This review focused on the four most studied pharmacogenomic markers in opioid therapy. Adenosine triphosphate-binding cassette, sub-family B, member 1 (ABCB1), also known as P-glycoprotein, is a transporter that facilitates absorption, distribution, and elimination of opioids within the body including transport across the blood-brain barrier. CYPs, as previously described, are responsible for the metabolism of medications. Specifically, CYP3A4 plays an important role in methadone, oxycodone, hydrocodone, and fentanyl, while CYP2D6 influences codeine, hydrocodone, oxycodone, and tramadol. Another enzyme involved in metabolism is the catechol-O-methyltransferase (COMT) enzyme responsible for metabolizing catecholamines, which play an integral role in pain modulation. Lastly, the µ-opioid receptor gene (OPRM1) is the primary binding site for endogenous opioid peptides and opioid analgesics, thus making it a good target to evaluate for genetic variations and opioid response. The summary of select genetic variants within these targets associated with response in cancer pain have varying outcomes (Table12). Several studies included in the review indicated certain polymorphisms, such as OPRM1 A118G, require statistically different opioid dosages, while other studies looking at the same polymorphism demonstrated no difference. This lack of reproducibility is one of the major flaws associated with opioid genetic research. 12
In the largest study to date in this population, Klepstad et al. set out to validate previously tested SNPs associated with cancer pain and opioid efficacy, such as OPRM1 A118G. This was a 17 center study in 11 European countries in adult patients who were using an opioid for moderate to severe pain (step III at the World Health Organization [WHO] treatment ladder for cancer pain). Of the 2201 patients included in analysis, the primary opioids were morphine (n = 827), oxycodone (n = 445), fentanyl (n = 695), or other opioids (n = 234). The median opioid dose per patient was 180 mg morphine equivalence/24 hours. One-hundred and twelve SNPs from 25 genes were tested with none showing a statistically significant association with opioid dose requirements. 11
Utilization of pharmacogenomics has grown substantially in recent years and will continue to develop as additional information becomes available in the near future. Improvement in clinical outcomes utilizing patient specific medication therapies through pharmacogenomics is promising and is already being observed in several fields such as infectious diseases, oncology, and psychiatry. Utilization of pharmacogenetic testing for opioid prescribing in pain management is not routinely recommended due to limited evidence demonstrating disparate results. Further research is needed to elucidate the clinical relevance and cost-effectiveness of pharmacogenetic testing for opioid therapy.
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1. M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417.
2. Centers for Disease Control and Prevention. Opioid Overdose: Prescribing Data. https://www.cdc.gov/drugoverdose/data/prescribing.html. Accessed May 22, 2018.
3. Centers for Disease Control and Prevention. Opioid Overdose: Prescription Opioid Overdose Data. https://www.cdc.gov/drugoverdose/data/overdose.html. Accessed May 22, 2018.
4. Centers for Disease Control and Prevention. Opioid Overdose: CDC Guideline for Prescribing Opioids for Chronic Pain. https://www.cdc.gov/drugoverdose/prescribing/guideline.html. Accessed May 22, 2018.
5. U.S. Food and Drug Administration. Pharmacogenomics: Overview of the Genomics and Targeted Therapy Group. https://www.fda.gov/Drugs/ScienceResearch/ucm572617.htm. Accessed May 23, 2018.
6. Felcone LH. Pharmacogenomics: Where Will It Take Us? Biotechnology Healthcare. 2004;1(3):18-28.
7. An Overview of the Human Genome Project. National Human Genome Research Institute (NHGRI). https://www.genome.gov/12011238/an-overview-of-the-human-genome-project/. Accessed May 23, 2018.
8. Center for Drug Evaluation and Research. Science & Research (Drugs) - Table of Pharmacogenomic Biomarkers in Drug Labeling. U S Food and Drug Administration Home Page. https://www.fda.gov/Drugs/ScienceResearch/ucm572698.htm. Accessed May 25, 2018.
9. What is pharmacogenomics? - Genetics Home Reference. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/primer/genomicresearch/pharmacogenomics. Accessed May 25, 2018.
10. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352(21):2211–21.
11. Klepstad P, Fladvad T, Skorpen F, et al. Influence from genetic variability on opioid use for cancer pain: A European genetic association study of 2294 cancer pain patients. Pain. 2011;152(5):1139-1145. doi:10.1016/j.pain.2011.01.040.
12. Bell GC, Donovan KA, Mcleod HL. Clinical Implications of Opioid Pharmacogenomics in Patients with Cancer. Cancer Control. 2015;22(4):426-432. doi:10.1177/107327481502200408.
13. Andreassen TN, Eftedal I, Klepstad P, et al. Do CYP2D6 genotypes reflect oxycodone requirements for cancer patients treated for cancer pain? A cross-sectional multicentre study. European Journal of Clinical Pharmacology. 2012;68(1):55-64. doi:10.1007/s00228-011-1093-5.
Bell GC, Donovan KA, Mcleod HL. Clinical Implications of Opioid Pharmacogenomics in Patients with Cancer. Cancer Control. 2015;22(4):426-432. doi:10.1177/107327481502200408.
Pharmacists’ Role in Pain Management and Combatting the Opioid Epidemic
Authors: Samantha Breckenridge, Pharm.D. Candidate 2019, UMKC School of Pharmacy
Bradley Erich, Pharm.D. Candidate 2019, UMKC School of Pharmacy
Maureen Knell, Pharm.D., BCACP, UMKC School of Pharmacy
Turn on your television or scroll through the internet, it won’t take long to see headlines related to the “opioid epidemic” or “opioid addiction”. Take a step further, a google search of “opioid” suggests topics such as crisis, abuse, and dependence, to note a few. Behind the media stir lies a deeply rooted issue that requires intervention from many angles. Since 1999, the number of opioid prescriptions in the United States has quadrupled.1 While one may think this indicates better pain control, the amount of pain reported by Americans has remained the same. In that same time frame, 165,000 deaths have been attributed to prescription opioid overdose alone.1
There are many Americans dealing with severe pain due to various causes, each deserving of safe and adequate pain relief. Opioid painkillers are known to be effective in the acute treatment of severe pain, but there is little to no evidence to support their long-term usage.1 With an increased duration of exposure to these medications comes an increased risk of dependence and addiction.1 The Centers for Disease Control and Prevention evaluated data from roughly 1.3 million patients who underwent or are currently undergoing opioid therapy. Patients were more likely to continue opioid pain reliever therapy when the first, acute prescription exceeded 10 or 30 days.2 The Centers for Disease Control and Prevention guidelines advocate that sufficient pain relief in an acute setting is often achieved with a three-day supply of an opioid prescription and that patients rarely require more than seven days.1 Having extra, unused opioid pills not only leads to an increased risk that the patient will consume more than needed, but it also leads to the risk of friends and/or family having access to a prescription not intended for them. In 2013 and 2014, there were 10.7 million people aged 12 or older who misused prescription painkillers. Of those, 50.5% reported having obtained the medications through a friend or family member for free.3
Increasing awareness of the opioid epidemic has led to speculation on who is to blame and demands for a quick fix to the problem. However, this is a nationwide issue that will require thoughtful problem-solving by various entities working together to enhance future safety while providing adequate pain management. As of April 2018, twenty-eight states have enacted legislation regarding opioid limits, requirements, or guidance.4 Prescription health plans around the country are also implementing similar quantity limits. The Food & Drug Administration (FDA) is encouraging the drug industry to develop abuse-deterrent opioid dosage forms.5 Lastly, the Drug Enforcement Administration (DEA) is decreasing Annual Production Quotas (APQs) of opioids by 20% to be made in 2018.6
Although there are multiple efforts being made to curb opioid abuse via various mechanisms, these efforts are not without flaws. For instance, many hospitals and health systems are experiencing critical shortages in injectable opioids which may effectively delay patient care and leave patients in pain before action can be taken. According to the American Society of Health Systems Pharmacists (ASHP)7, intermittent shortages of specific injectable opioid products may lead to substitution with other more readily available products. Unfortunately, opioids are not all interchangeable, making improper conversions and substitutions possible, which may lead to risking patient safety. While opioid side effect profiles remain similar, there may be differences between medications. Therefore, patient monitoring is of paramount importance during this conversion to avoid severe side effects such as respiratory depression.
Another challenge for patients, pharmacists, and other members of the healthcare team is quantity limits and formulary restrictions that may force providers to change a patient’s well controlled chronic pain regimen. During this transition, the patient could suffer from opioid withdrawal from chronic therapy, in addition to poor pain control.
The aforementioned concerns and considerations that have arisen throughout the opioid epidemic raise the question: What can healthcare professionals such as pharmacists do about it?
In terms of injectable opioids, ASHP makes recommendations for pharmacists in order to help mitigate this impact. These steps include switching therapy to a clinically appropriate oral or enteric opioid formulations, whenever possible; Engage the institution’s experts on pain and palliative care to further develop guidance and formulate strategies for dealing with intermittent shortages; And ensure relevant institutional pain medication guidelines are up to date, to name a few.7 Additionally, there are programs such as ASHP’s Pain Management Certificate program that equip pharmacists with the skills to provide appropriate and effective pain management for patients suffering from chronic pain. Programs like these provide pharmacists with proficiency in pain management including treatment with non-opioids that can ensure proper pain control while reducing the risk for inappropriate use of opioids.12
Pharmacists in the community and ambulatory care setting have a unique opportunity to work with prescribers and patients to assess opioid pain management. They can provide education for appropriate use, assess for dangerous use, and offer innovative options such as tapering opioid plans and finding the lowest effective opioid dose when quantity limits or access to opioids becomes an issue. In these settings, pharmacists can also make an impact by showing empathy to patients who have relied on opioids for a long time for pain management and are not aware of other options that can help control their pain safely and effectively. Through advanced knowledge about pain control learned in schooling, residencies, and unique opportunities like ASHP’s Pain Management Certificate program, pharmacists in these settings are also able to offer alternatives to opioids such as non-opioid pharmacologic agents and non-pharmacologic therapies to help in controlling chronic or acute pain.
Pharmacists also play an integral role in pain management through transitions of care. Some of these roles include medication reconciliation, drug monitoring and assessment during hospitalizations, patient and healthcare provider education, discharge counseling, post-discharge follow-up and counseling. These roles in transitions of care can help in potentially minimizing medication errors while ensuring safe, appropriate, and effective use of medications throughout the patient care continuum.8
Additionally, pharmacists in Missouri are able to dispense naloxone, a competitive opioid antagonist, to patients who are eligible through screening. This Missouri law authorizes pharmacists to dispense nasal or intramuscular naloxone without a prescription by standing order issued by the Missouri Department of Health and Senior Services or by protocol with a physician.9 The law offers pharmacists a unique role in screening eligible patients for potential naloxone use, education regarding the risk factors for overdose, signs and symptom of overdose, overdose response steps, and the administration of naloxone.9 Naloxone is also fully or partially covered by many insurances including Medicare, Medicaid, and commercial insurance carriers.13,14
Missouri pharmacies may now voluntarily collect medications from the public for destruction that are in compliance with CSR 2220-2.095. While this law does not apply to controlled substances (e.g. opioids), it is a step in the right direction for disposal of medications after they are expired or no longer needed to avoid diversion. Pharmacists may also provide patients with information on disposal of opioids through rxdrugbox.org or medreturn.com, which offer locations such as community pharmacies and law enforcement agencies to dispose of their medications (including controlled substances) safely. The United States FDA also provides guidance on disposal of medications, as there can be misconceptions about the disposal of various formulations and types of medications.15 There are also multiple innovative ways to dispose of controlled substances that do not have to be flushed or thrown away in other household garbage. In early 2018, Wal-Mart began using a technology called DisposeRx that they dispense with opioid prescriptions. According to the manufacturer, when this powder is poured into a prescription bottle with warm water, it ultimately enables patients to dispose of leftover medications in their other household garbage.10 Mallinckrodt Pharmaceuticals provides medication disposal pouches that contain active carbon that inactivates any medication when mixed with water. Mallinckrodt provides a complimentary six pouches to patients who request through their website, in addition to providing pouches to local health departments and other community outreach programs.11
While there is no single way that pharmacists, patients, and other healthcare professionals can tackle the opioid epidemic, there are multiple ways that all who are involved can take action. Pharmacists play an integral role in educating patients and communicating with other healthcare professionals on the proper use of opioids and other pain medications, in addition to ensuring appropriate medication use. Patients also have opportunities to take action, from properly disposing their unneeded/unused medications, to storing their medications safely and securely in a locked medication box or other storage area where they cannot be diverted or accidentally ingested by children. Patients also have the opportunity to carry naloxone for a family member or friend who may need it in the case of an overdose emergency. Collectively, these actions can aid in decreasing the inappropriate use of opioids while still ensuring adequate pain control for patients.
1. Factsheet CDC Guideline for Prescribing Opioids for Chronic Pain. Centers for Disease Control and Prevention website. www.cdc.gov/drugoverdose/pdf/guidelines_at-a-glance-a.pdf Updated August 29, 2017. Accessed June 10, 2018.
2. Shah A, Hayes CJ, Martin BC. Characteristics of initial prescription episodes and likelihood of long-term opioid use — United States, 2006–2015. MMWR Morb Mortal Wkly Rep 2017; 66: 265–269. DOI: http://dx.doi.org/10.15585/mmwr.mm6610a1
3. Lipari RN, Hughes A. How people obtain the prescription pain relievers they misuse. The CBHSQ Report. 2017. URL: www.samhsa.gov/data/sites/default/files/report_2686/ShortReport-2686.html
4. Prescribing Policies: States Confront Opioid Overdose Epidemic. National Conference of State Legislatures website. http://www.ncsl.org/research/health/prescribing-policies-states-confront-opioid-overdose-epidemic.aspx Published April 5, 2018. Accessed June 11, 2018.
5. Abuse-Deterrent Opioid Analgesics. U.S. Food & Drug Administration website. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm600788.htm Updated April 23, 2018. Accessed June 11, 2018.
6. Quotas - 2017. DEA Diversion Control Division. https://www.deadiversion.usdoj.gov/fed_regs/quotas/2017/fr1108.htm. Published November 8, 2017. Accessed June 11, 2018.
7. Injectable Opioid Shortage FAQ. ASHP. 2018. https://www.ashp.org/Drug-Shortages/Shortage-Resources/Injectable-Opioid-Shortages-FAQ. Accessed June 11, 2018.
8. Sourial M. The Pharmacist's Role in Pain Management During Transitions of Care. U.S. Pharmacist – The Leading Journal in Pharmacy. https://www.uspharmacist.com/article/the-pharmacists-role-in-pain-management-during-transitions-of-care. Published August 18, 2017. Accessed June 11, 2018.
9. Board of Pharmacy. Missouri Department of Agency. https://www.pr.mo.gov/pharmacists-naloxone.asp. Accessed June 11, 2018.
10. Solving the Problems of Drug Disposal. DisposeRx™. https://disposerx.com/. Accessed June 11, 2018.
11. Safe Medication Disposal. Inclusion and Diversity at Mallinckrodt Pharmaceuticals. http://www.mallinckrodt.com/corporate-responsibility/safe-drug-disposal. Accessed June 11, 2018.
12. New ASHP Certificate Program Offers Advanced Training in Pain Management. ASHP. March 2018. https://www.ashp.org/news/2018/03/16/new-ashp-certificate-program-offers-advanced-training-in-pain-management. Accessed June 11, 2018.
13. NARCAN® NASAL SPRAY AFFORDABILITY. NARCAN®(naloxone HCl) Nasal Spray. https://www.narcan.com/affordability. Accessed June 20, 2018.
14. EVZIO2YOU. EVZIO®. https://www.evzio.com/patient/evzio2you/. Accessed June 20, 2018.
15. Center for Drug Evaluation and Research. Safe Disposal of Medicines - Disposal of Unused Medicines: What You Should Know. US Food and Drug Administration Home Page. https://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/EnsuringSafeUseofMedicine/SafeDisposalofMedicines/ucm186187.htm. Accessed June 21, 2018.
Medication Saving Behaviors in Older Adults: Identifying and Managing a Barrier to Effective Healthcare
Authors: Kristin Hegna, PharmD, St. Louis College of Pharmacy, Resident at UnityPoint – Meriter
Melanie VanDyke, PhD, St. Louis College of Pharmacy, Associate Professor and Licensed Psychologist
Medication hoarding in older adults is a barrier to effective healthcare that is difficult to define, identify, and manage. The DSM-5 classifies hoarding disorder as a problem with discarding possessions (regardless of their value) because of feeling the need to save things and experiencing distress about their disposal. Hoarding disorder is further characterized by clutter that interferes with the use of living space and clinically significant distress or functional impairment.1 Excessive clutter may create an unsafe living environment and pose both tripping and fire hazards. Medication hoarding differs somewhat from generalized hoarding behavior: medications have inherent value, and medication hoarding may not substantially contribute to household clutter. However, the accumulation of unused or expired medications in the home carries the additional risk of accidental (or intentional) medication misuse and diversion.2
In order to identify and manage medication hoarding, healthcare providers have a new tool: the Medication Saving Behaviors (MSB) scale. The 6-item MSB scale was developed and validated with a population of women who manage medications for their older family members.3 Key components of MSB include distress in acquiring, storing, and discarding medications; avoidance of medication disposal; and difficulties with medication management due to the quantity of medications in the home. Of note, this accumulation of medication may impact both the patient and their family.
Identifying MSB in the Health-System Setting
The ability to identify problematic medication accumulation is challenging in the inpatient setting, where medications are handled by hospital staff and providers may not have knowledge of the patient’s household supply of medication. However, medication reconciliation serves as an opportunity to identify at-risk patients. In line with the 2017 Joint Commission’s National Patient Safety Goals, medication reconciliation is critical in identifying and resolving discrepancies in medication use.4 Ideally, providers should contact their patients and the family members involved in patient care. This communication provides insight into the difficulties associated with medication management, including the acquisition, storage, and disposal of drugs.
In addition, a Brown Bag Review of a patient’s supply of medications provides an important safety check. A potential “red flag” for identifying MSB is the presence of expired and leftover (no longer prescribed) medications, as MSB are correlated with the quantity of expired and leftover medications in community dwelling older adults. However, the number of prescribed medications is not associated with MSB,3 so a patient should not be identified as at-risk for medication hoarding based solely on having more medications prescribed. Therefore, a thorough review of all of the medications in the patient’s home is recommended to assess the risks of MSB.
Clinical Implications of MSB
Older adults are at a higher risk of adverse events due to increased use of medications, and older adults with hoarding disorder report a greater number of chronic medical conditions and a higher risk of falls.5 Since MSB are significantly related to generalized hoarding behaviors,6 the potential for exposure to unsafe medications is particularly relevant in older adults with hoarding disorder. Therefore, healthcare providers may consider asking patients with a history of hoarding behaviors about their current MSB.
Additionally, MSB are significantly correlated with medication adherence problems.6 The Adherence to Refills and Medications Scale (ARMS) is an important tool for patients with chronic diseases states and low literacy levels. For instance, research using the ARMS demonstrates that patients with coronary heart disease who have better medication adherence show significantly better blood pressure control over patients who are less adherent. 7 Medication nonadherence is a known barrier to effective healthcare, resulting in higher rates of morbidity, mortality, and an estimated annual cost of $100-$300 billion USD.8 Due to the relationship between MSB and medication adherence problems, medication hoarding may worsen health outcomes and increase healthcare costs.
Management of MSB in the Health-System Setting
Just as it is difficult to identify MSB during an inpatient visit, the management of MSB within the health-system setting is likely to be challenging. Hoarding and other chronic conditions require long-term follow-up after hospitalization. When a patient identifies hoarding behaviors, a health-system pharmacist may ask follow-up questions about medication storage and adherence. During transitions of care, it may be helpful to counsel all patients who are prescribed risky medications, such as opioids, about safe storage and disposal practices. This communication is not consistently practiced: a study of more than 1000 adults with recent opioid medication use found that just over half of the patients recalled receiving information on safe storage (51%) or proper disposal (55%), with pharmacists being the medical professional most likely to address these issues.9
In addition to direct patient care, a health-system pharmacist may provide additional services to support family caregivers, particularly when frequent medication changes are made. Medication regimens that were adjusted four or more times in the previous year were significantly related to decreased adherence.10 Another factor related to MSB and poor adherence is caregiver self-efficacy. Caregivers who are less confident in their ability to handle medication-related hassles reported more MSB, worse medication adherence, and more medication-related hassles.6 Pharmacists have the opportunity to reduce caregiver burden by providing thorough discharge counseling, clear medication instructions, safe storage and disposal information, and positive feedback to caregivers about specific strategies they use successfully. By supporting family caregivers, pharmacists may ultimately reduce MSB and improve health outcomes.
Further research is required to create a standardized approach for identifying and managing patients with MSB. By recognizing the risk factors of MSB, providers can target at-risk patients and their families for appropriate interventions. Healthcare providers may improve medication adherence and reduce the risk of medication misuse and diversion by successfully addressing MSB.
Pharmacists who are interested in discussing medication hoarding or want an updated version of the scale, please contact Melanie.VanDyke@stlcop.edu.
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013
2. Disposal of unused medicines: What you should know. U.S. Food and Drug Administration website https://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/EnsuringSafeUseofMedicine/SafeDisposalofMedicines/ucm186187.htm. Updated June 13, 2018. Accessed June 26, 2018.
3. VanDyke MM, Steffen A. Medication savings behaviors of older adults: Scale developed to assess family caregiver perspectives. Clin Gerontol. 2017;40(4):258-267. doi: 10.1080/07317115.2016.1276114
4. National patient safety goals effective January 2017: Hospital accreditation program. The Joint Commission website https://www.jointcommission.org/assets/1/6/NPSG_Chapter_HAP_Jan2017.pdf. Accessed June 26, 2018.
5. Diefenbach GJ, DiMauro J, Frost R, et al. Characteristics of hoarding in older adults. Am J of Geriatr Psychiatry. 2013;21(10). doi: 10.1016/j.jagp.2013.01.028.
6. VanDyke MM, Chow M, Dinh A, et al. Presentation: Medication hoarding: Women managing medications for older family members identify a hoarding-related risk factor. Poster presented at: Anxiety and Depression Association of America and St. Louis College of Pharmacy Student Research Symposium; 2018 Apr; Washington D.C. and St. Louis, Missouri.
7. Kripalani S, Risser J, Gatti ME, et al. Development and evaluation of the Adherence to Refills and Medications Scale (ARMS) among low-literacy patients with chronic disease. Value Health. 2009;12(1):118-123. doi: 10.1111/j.1524-4733.2008.00400.x.
8. Neiman AB, Ruppar T, Ho M, et al. CDC Grand Rounds: Improving Medication Adherence for Chronic Disease Management — Innovations and Opportunities. MMWR Morb Mortal Wkly Rep 2017;66. DOI: http://dx.doi.org/10.15585/mmwr.mm6645a2.
9. Kennedy-Hendricks A, Gielen, A, McDonald E, et al. Medication Sharing, Storage, and Disposal Practices for Opioid Medications Among US Adults. JAMA Intern Med. 2016;176(7):1027-1028. doi:10.1001/jamainternmed.2016.2543.
10. Choe E, VanDyke M, Griggs, et al. Presentation: Assessing potential caregiver strategies associated with improved medication adherence in a community-based sample of older adults. Poster presented at: St. Louis College of Pharmacy Student Research Symposium; 2017 Apr; St. Louis, Missouri.
Saint Louis College of Pharmacy SSHP
Author: Hubert Kusdono, St. Louis College of Pharmacy SSHP Chapter President
Throughout the Spring Semester of the 2017-2018 academic year, the STLCOP SSHP chapter aimed to build upon and expand its initiatives with regards to community outreach and health-system service, professional development, and networking opportunities for its student members.
To kick off its Community Outreach Initiative, STLCOP SSHP introduced a new fundraising event called Pants with a Purpose – an event which would eventually be an outstanding highlight in the chapter’s many successes throughout the semester. This fundraising event was publicized to STLCOP students and faculty, in which for every pair of sweatpants purchased, another pair would be donated to the St. Patrick’s Center for the Homeless. Other essential items and basic necessities were also donated to help improve the health of the less fortunate in the St. Louis community. Through this community outreach event, the chapter was able to donate about $1800 in clothing and household needs. The Ronald McDonald House Community Outreach Event was another fundraising opportunity for STLCOP SSHP members, which was held in collaboration with SIUE SSHP. During this event, students volunteered their services to cook and prepare meals for patients’ families at the Ronald McDonald House. Blankets for Cancer Patients was another health-system service and volunteer opportunity for students to make tie-knot blankets for oncology patients in St. Mary’s Hospital. The Sweet Babies Volunteer event was an opportunity for students to volunteer at St. Mary’s Neonatal Intensive Care Unit, as well as take a tour of the facility. Cancer Care Packages was another well-received, recurring event where students were able to make cancer-care packages and hand-deliver them to patients at Siteman Cancer Center. This provided students, who haven’t already done so already, with the opportunity to tour Siteman’s outpatient infusion center and learn about oncology pharmacy from the pharmacists who worked there.
As part of the Community Outreach Initiative, the STLCOP chapter held numerous health and vaccination clinics throughout the spring semester, where students were able to talk to patients regarding their medication adherence, diabetes, asthma, hypertension management, and vaccination history. These series of health clinics was a great opportunity for students, who were learning about how to administer blood pressure in some of their classes, to implement and enhance their skills by obtaining blood pressure from real patients in the community. Additionally, the chapter held a series of vaccination clinics and training sessions for students who wanted to practice administering vaccines. These clinics were held across various Shop N’ Save and Walgreens pharmacies throughout the greater St. Louis area, and students were given the opportunity to promote the importance of yearly flu shots and timely vaccinations, such as the Shingrix vaccine for Shingles. Students were thus able to implement what they had learned regarding how to administer vaccinations in a real-life setting, where they were able to interact with patients while doing so and impart their knowledge to the community.
As part of the chapter’s spring semester initiatives for professional development, STLCOP SSHP held a Residency Preparation Program which included a CV Review event and Mock Interview. Students were able to have their CV’s and resumes reviewed and critiqued by various faculty members. STLCOP SSHP believes that it is important for students to develop their CV’s and resumes early in their professional years, as it can only benefit them as they may apply to various jobs and internship opportunities throughout their years in pharmacy school. During the Mock Interview Practice Sessions, students were able to partake in a residency, fellowship, or job interview simulation conducted by various pharmacy practice faculty. This gave students the opportunity to sharpen their interviewing skills and know what kind of questions to expect in a potential residency interview. Faculty provided feedback to students and also answered questions regarding their potential career path into different pharmacy specialties.
STLCOP SSHP also aimed to continue providing students with ample networking opportunities with practicing pharmacists. During the Practice Advancement Initiative (PAI) Week in February, the chapter expanded its yearly series of health-system panels by introducing a Residency Director's Roundtable for the first time. Students were able to network and connect with directors from residency programs and hospitals throughout the St. Louis area. This provided students with a unique opportunity to learn about what residency programs seek and expect from their candidates. The chapter also arranged a Clinical Roundtable networking event, where students were able to learn about the daily duties and roles of a clinical pharmacist, the impact that clinical pharmacists make in patient-centered care, and the different pharmacy specialties that students can pursue in pharmacy. The chapter also hosted several panels, seminars, and Lunch N’ Learns, where students were able to hear about interesting and important topics in healthcare such as hypertension management, skin cancer, and home infusion pharmacy.
Overall, the STLCOP SSHP chapter was successful in introducing new events and expanding upon previously successful ones in light of its new initiatives for community outreach and service, professional development, and networking. The chapter hopes to build upon every aspect in its ultimate goal to introduce and prepare student pharmacists for the residency preparation process that lies ahead, and hopes that it can continue to serve as a resource for students who seek to develop their knowledge and skills as aspiring pharmacists.
Saint Louis College of Pharmacy
The 2017-18 academic year came to a close on May 12, as St. Louis College of Pharmacy celebrated the class of 2018 at its 150th Commencement. This year’s ceremony marked a milestone in the College’s history as it recognized the first graduates earning bachelor’s degrees in the College’s integrated Bachelor of Science and Doctor of Pharmacy program. With more than 400 degrees conferred, the 150th Commencement featured the largest class of graduates in the College’s history.
With our historic Commencement behind us, we are reflecting on an exciting year that was highlighted by a wide range of recognition for the College’s faculty, facilities and programs.
During the academic year, we were also thrilled to welcome Thomas Burris, Ph.D., FAAAS, FAHA, to campus as the Alumni Endowed Professor in the College’s Center for Clinical Pharmacology and President’s Senior Research Advisor. With a research background focused on using chemical biology approaches to examine the physiological roles of nuclear hormone receptors and developing drugs targeting them for the treatment of conditions including type 2 diabetes, heart disease, cancer and Alzheimer’s disease, Burris brings the Center for Clinical Pharmacology one step closer to becoming a national research leader in pain management and personalized approaches to medication therapy. He joins pharmacists, physicians and researchers at the center who hold academic appointments at both the College and Washington University School of Medicine in St. Louis.
This is an exciting time at St. Louis College of Pharmacy! I invite you to visit campus soon for a first-hand look at the many wonderful things underway as the College continues its work to prepare students for expert practice and leadership in pharmacy and health professions careers.
Bruce R. Canaday, Pharm.D., FASHP, FAPhADean of Pharmacy and Professor
Summer Tenet - Have Fun
Aaah, summer - that long anticipated stretch of lazy, lingering days, free of responsibility and rife with possibility. It's a time to hunt for insects, master handstands, practice swimming strokes, conquer trees, explore nooks and crannies, and make new friends.
- Darell Hammond
While you are doing your best to stay cool from the summer heat, I hope you are able to take time for yourself and your family, enjoy some summer fun, and perhaps even a nice vacation with those you love. Integrating fun into your life, at home and at work, is an essential part of the personal and professional balance we are all trying to find. Take some time, chat with your co-workers, tell a joke, go get some ice cream, and enjoy the ride on this crazy journey called life!
Summer has arrived and so has a new year for many including universities, residency programs, health systems and of course MSHP. We started our year with our annual Strategic Planning Meeting which was held in Mid-June in Kansas City. I am happy to report that we had a good turnout, a productive meeting, and set straightforward, measurable goals for our society this year. Highlights include efforts to achieve full prescribing authority with recognition as mid-level providers in the state of Missouri, continued support for technician advancement initiatives ongoing in the state, increase the utility of our members’ only section of our Society website, and improve communication to the membership at large. While fun may not be the best word to describe our experience during this meeting, there were a few laughs, everybody left with a smile on their face, and a good feeling about the plan for the year.
Lastly, I want to update you on a new and fun opportunity that will take place on September 6-9th, 2018 in Branson, MO. We are working with the Missouri Pharmacy Association (MPA) on a co-branded fall meeting. This is a new effort for our organizations and we hope it is the first step in a collaborative effort that will continue into the future. Content for the meeting will be presented by both MSHP and MPA members and will cover both community and health systems perspectives on various topics. I encourage anyone who is interested to participate to join me for some fun in Branson this fall. Information and registration details can be found at https://www.morx.com/conference.
Enjoy your summer, have as much fun as you can, and get those new residents trained. I look forward to updating you in the fall with what I hope will be early success on a few of the strategic priorities mentioned above.
Immunotherapy and Management of Immune-Related Adverse Effects: A Focus on the Immune Checkpoint Inhibitors
Authors: Mallory Crain, PharmD: PGY-2 Oncology Resident Barnes-Jewish Hospital and Sara K. Butler, PharmD, BCPS, BCOP: Barnes-Jewish Hospital
Program Number: 2018-04-10Approval Dates: 6/6/18 - 9/6/18Approved Contact Hours: One (1) CE(s) per LIVE session.
ObjectivesUnderstand the general mechanism of immune checkpoint inhibitors and specific mechanisms of action for the individual agents.
BackgroundImmunotherapy is quickly becoming a mainstay treatment option for numerous malignancies, and multiple immunotherapy agents have been approved by the US Food and Drug Administration (FDA). In general, immunotherapy agents work by using the immune system to fight off cancer, which can be done through various mechanisms.1 The immune checkpoint inhibitors, a specific class of immunotherapy agents, upregulate the immune system by blocking proteins that inactivate the immune system. This class of agents can be very effective against malignancies that express these inactivating proteins.2-9
Immune Checkpoint InhibitorsThe immune checkpoint inhibitors are a group of agents that target specific proteins that help control the immune response, called the immune checkpoint proteins. There are three different checkpoint proteins that are currently targeted by available agents: cytotoxic T-lymphocte-associated-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1). CTLA-4 and PD-1 are expressed on the surface of T-cells. These inactivating proteins interact with CD80/CD86 and PD-L1, respectively, on tumor or antigen presenting cells. When this interaction occurs, T-cell activation is inhibited resulting in malignant cells evading T-cell-mediated death. Immune checkpoint inhibitors are able to block the interaction between PD-1 and PD-L1 or CTLA-4 and CD80/CD86. When this occurs, T-cells are activated and able to fight off malignancy.2-9
There are currently six different immune checkpoint inhibitors that are FDA approved (table 1). The first agent to gain FDA-approval was ipilimumab, the only agent that inhibits CTLA-4.10 Following ipilimumab, two PD-1 inhibitors, pembrolizumab and nivolumab, were both approved.11,12 The newest immune checkpoint inhibitors, atezolizumab, avelumab, and durvalumab, all inhibit PD-L1.13-15 All of these agents are FDA-approved for a variety of solid malignancies and Hodgkin’s lymphoma.10-15 In addition, there is a vast amount of ongoing clinical trials evaluating the immune checkpoint inhibitors for other solid and hematologic malignancies.
Introduction to Immune-Related Adverse EffectsSince immune checkpoint inhibitors result in a non-tumor-specific activation of T-cells, there is potential for immune-related adverse effects to occur. This is a result of the immune system attacking non-tumor cells, which can cause organ damage. The immune-related adverse effects can occur in any organ system. However, the most frequent immune-related adverse effects seen in clinical practice involve the gastrointestinal (GI) tract, endocrine glands, skin, and liver. Although infrequent, the central nervous system, cardiovascular, and pulmonary systems can also be involved.6-9,16-19 There is some evidence supporting a higher incidence of specific immune-related adverse effects depending on the location of the primary malignancy. For instance, pneumonitis may be more common in patients with lung cancer compared to other types of malignancy.20
Immune-related adverse effects usually develop within the first few weeks to months of exposure to checkpoint inhibitors, but can occur at any time point, even after treatment discontinuation. In general, prolonged treatment or higher doses have not been associated with an increased incidence of immune-related adverse effects.6-8 Ipilimumab is the exception to this since literature comparing 3 mg/kg to 10 mg/kg found increased immune-related adverse effects in the patients who received 10 mg/kg.21 In addition, patients who receive combination therapy with ipilimumab and nivolumab do have an increased frequency of immune-related adverse effects compared to monotherapy with either agent.22 There is currently conflicting evidence surrounding whether development of an immune-related adverse effect is associated with efficacy. However, patients that do not develop an immune-related adverse effect can still achieve response with immune checkpoint inhibitor therapy.8
Depending on the mechanism of the immune checkpoint inhibitor, immune-related adverse effects can occur at different frequencies (table 2).10-15 Evidence shows that patients who receive CTLA-4 inhibitors have increased grade 3 or higher immune-related adverse effects compared to PD-1 and PD-L1 inhibitors.23 The frequency is increased further when a CTLA-4 inhibitor is used in combination with a PD-1 inhibitor.22 In addition, even though PD-1 and PD-L1 inhibitors have the same mechanism for efficacy, these agents can have different safety profiles. This is because both PD-L1 and PD-L2 interact with PD-1 to cause T-cell inactivation. When PD-1 is inhibited by an immune checkpoint inhibitor, both PD-L1 and PD-L2 are unable bind to PD-1. However, when just PD-L1 is blocked, PD-L2 can still bind to PD-1.24 This is thought to result in fewer immune-related adverse effects with PD-L1 inhibitors compared to PD-1 inhibitors.
Management of Immune-Related Adverse EffectsThe management of immune-related adverse effects is highly dependent on the organ system involved and the severity of the adverse effect. The severity of immune-related adverse effects is graded by the common terminology criteria for adverse events (CTCAE).25 In general, for most mild immune-related adverse effects, therapy with an immune checkpoint inhibitor can usually be continued. For moderate to severe immune-related adverse effects, therapy usually needs to be held in addition to administration of systemic corticosteroids. There are some situations that may require administration of other immunosuppressants such as infliximab, cyclophosphamide, or mycophenolate mofetil.6-8 Since the management of immune-related adverse effects is very dependent on the specific adverse effect and severity, below are specific recommendations for management of common immune-related adverse effects encountered in clinical practice.
Cutaneous Toxicities:Cutaneous toxicities are reported in 30-50% of patients who receive immune checkpoint inhibitor therapy and are the earliest immune-related toxicities to present.26 These toxicities are less frequently reported with PD-1 and PD-L1 inhibitors compared to ipilimumab, but all agents have the same incidence of grade 3 or higher toxicities around 1-3%. Skin toxicities include rash/inflammatory dermatitis, bullous dermatoses, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). Since rash/inflammatory dermatitis is the most common immune-related skin toxicity, this is the only specific management recommendations included (table 3). For grade 1 toxicities, the immune checkpoint inhibitor can be continued with topical emollients and/or corticosteroids applied for treatment. For grade 2-4 toxicities, it is recommended to hold immune checkpoint inhibitor therapy and administer systemic corticosteroids at 1-2 mg/kg of (methyl)prednisolone or equivalent. Topical emollients and corticosteroids along with oral antihistamines should also be given for grade 2-3 toxicities.6-9
Gastrointestinal (GI) Toxicities:GI toxicities are common immune-related adverse effects that occur with immune checkpoint inhibitor therapy. The two main GI immune-related adverse effects are colitis and hepatitis. Other serious GI immune-related adverse effects, such as pancreatitis, have been reported in the literature. The incidence of these adverse effects depends on the therapy given. In regards to colitis, 8-27% of patients may experience this adverse effect, with higher frequencies reported with dual anti-CTLA-4 and anti-PD-1 therapy and monotherapy with CTLA-4 inhibitors. Hepatitis is much less common compared to colitis, occurring in 2-10% of patients treated with immune checkpoint inhibitor monotherapy. Similar to colitis, the incidence increases with combination therapy up to 25-30%, with 15% of cases categorized as at least grade 3. Colitis most often occurs within the first 5-10 weeks after immune checkpoint inhibitor initiation. The general onset of hepatitis is similar to colitis at 6-12 weeks after immune checkpoint inhibitor initiation.9,27 Since colitis and hepatitis are both fairly common immune-related adverse effects, it is important to understand the management of each of these toxicities (tables 4 & 5).
For colitis, unless restricted to grade 1, therapy should be held or permanently discontinued depending on the severity/grade. In addition, patients should receive systemic corticosteroids. In patients that have grade 3-4 colitis, infliximab should be considered if patients have persistent symptoms despite systemic corticosteroids. Another therapy option for colitis is vedolizumab. However, this agent should be reserved to patients who are refractory to, or have contraindications to, infliximab.6-9,28-29
In patients who develop grade 1 hepatitis, immune checkpoint inhibitor therapy can be continued without administration of systemic corticosteroids. Systemic corticosteroids should be administered in patients with at least grade 2 hepatitis. If patients develop severe, grade 3-4 hepatitis, immune checkpoint inhibitor therapy should be permanently discontinued. In addition, if patients have persistent symptoms after three days, mycophenolate mofetil can be added on to systemic corticosteroids.6-9,30 Infliximab should not be used in cases of hepatitis since there is concern for hepatic toxicity.31
Endocrine Toxicities:There are a vast amount of endocrinopathies that can occur with immune checkpoint inhibitor therapy. Some of these include hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, and diabetes. One important step is distinguishing between primary and secondary endocrine toxicity since it is possible that patients could have an endocrinopathy not related to immune checkpoint inhibitor therapy.6-7 Overall, clinically significant endocrine toxicities related to immune checkpoint inhibitors occur in about 10% of patients. The incidence is mostly the same among the different immune checkpoint inhibitor agents.32
Compared to other immune-related adverse effects, the management of endocrine toxicities differs slightly, with some of the specific management strategies reviewed below (table 6). For most endocrinopathies, immune checkpoint inhibitors may be continued as long as the patient is asymptomatic or only has mild symptoms. This is because most endocrine toxicities can be controlled through various supplementations and medications.6-9 An example of this is a patient with immune-related asymptomatic hypothyroidism treated with levothyroxine. As long as patient’s hypothyroidism is controlled, the immune checkpoint inhibitor can be continued.
Pneumonitis:Pneumonitis is an uncommon immune-related adverse effect, occurring in about 2.7% of patients. However, it is a very serious toxicity when it does occur. Unlike most other immune-related adverse effects, pneumonitis is more common with PD-1 and PD-L1 inhibitors compared to CTLA-4 inhibitors, and the incidence increases with combination therapy. In addition, the onset of pneumonitis can vary from two to 24 months after the initiation of therapy, with the median time to onset reported in the literature around three months.20,33 Since pneumonitis can be very severe, it is recommended to hold or permanently discontinue immune checkpoint inhibitor therapy depending on the grade (table 7). For grades 2-4, patients should be started on empiric antibiotics and systemic corticosteroids. In addition, if symptoms persist for 48 hours after systemic corticosteroids, additional immunosuppressant therapy is recommended. There are a variety of agents that could be started at this time including infliximab, mycophenolate mofetil, intravenous immunoglobulin (IVIG), or cyclophosphamide.6-9
Other Immune-Related Adverse Effects:There are numerous other immune-related adverse effects that can occur with immune checkpoint inhibitor therapy. However, for the most part, these are much less common. In addition, all of these toxicities have fairly similar management with holding the immune checkpoint inhibitor and initiating systemic corticosteroids. Some of the toxicities, including musculoskeletal and central nervous system toxicities that require unique management, are discussed below. Other immune-related adverse effects seen with immune checkpoint inhibitors include nephritis, hematologic toxicities (ex. hemolytic uremic syndrome, aplastic anemia, and immune thrombocytopenia), cardiovascular toxicities (ex. myocarditis, arrhythmias, and venous thromboembolism), and ocular toxicities.6-9,16-19
Musculoskeletal toxicities have a wide range of severity. Myalgias and arthralgias are less severe musculoskeletal toxicities and more common after immune checkpoint inhibitor therapy, occurring in up to 40% of patients.34 Inflammatory arthritis and myositis are severe immune-related adverse effects that may require additional immunosuppression, IVIG, or plasmapheresis for severe cases. Similar to musculoskeletal toxicities, central nervous system toxicities also range in severity from neuropathy to myasthenia gravis, Guillain-Barré syndrome, and encephalitis. For severe cases of myasthenia gravis or Guillain-Barré syndrome, IVIG or plasmapheresis is recommended with systemic corticosteroids. When diagnosed with encephalitis, patients should receive empiric antimicrobials, and in severe cases, high-dose systemic corticosteroids (methylprednisolone 1000 mg IV) with or without IVIG.7
Additional Treatment Considerations:One of the main management strategies of immune-related adverse effects involves holding immune checkpoint inhibitor therapy. As clinicians, a common question that may be asked is when therapy can be restarted. The first step is making sure the patient’s immune-related adverse effect has resolved to at least grade 1. The next step is assessing the corticosteroid dose. In general, most practitioners consider prednisone 10 mg (or equivalent) daily an appropriate corticosteroid dose to resume immune checkpoint inhibitor therapy.7
Aside from holding immune checkpoint inhibitor therapy, the other main management strategy for immune-related adverse effects is administration of systemic corticosteroids. Systemic corticosteroids pose numerous supportive care challenges, mainly from adverse effects that require monitoring (table 8).35 In addition to monitoring of adverse effects, patients often require prophylactic medications as well, if the expected duration of systemic corticosteroids is prolonged. Common supportive medications required include Pneumocystis jirovecii pneumonia (PJP) and GI prophylaxis with sulfamethoxazole-trimethoprim and a histamine2-receptor antagonist (H2RA) or proton pump inhibitor (PPI), respectively.7
A common question from patients and practitioners is if corticosteroids decrease the efficacy of immune checkpoint inhibitor therapy. Studies have shown that patients who receive corticosteroids for treatment of immune-related adverse effects have similar objective response rates, time to treatment failure, and overall survival compared to patients who did not receive corticosteroids.36,37 Therefore, evidence supports that corticosteroids do not impact the efficacy of immune checkpoint inhibitor therapy.
ConclusionsThe immune checkpoint inhibitors are a class of immunotherapy agents currently used in a variety of solid malignancies and Hodgkin’s lymphoma. Their use has been rapidly increasing with numerous clinical trials currently open for various solid and hematologic malignancies. The immune checkpoint inhibitors increase the immune system activity through blocking the inactivating checkpoint proteins located on T-cells. This allows the immune system to attack malignant cells, but also puts patients at risk for developing immune-related adverse effects. Management may differ depending on the exact immune-related adverse effect and severity. However, the main management strategies involve holding immune checkpoint inhibitor therapy and administering systemic corticosteroids. Due to the increased use of immune checkpoint inhibitors, it is likely that immune-related adverse effects will become more common in clinical practice. Early recognition of these adverse effects and recommending appropriate management and supportive care strategies are key steps for successful resolution of immune-related adverse effects.
Click here to download and open the Appendix
Appendix includes tables:
Table 1: Immunotherpy Agent OverviewTable 2: Incidence of Immune-Related Adverse Effects
Table 3: Management of rash/inflammatory dermatitis
Table 4: Management of colitis
Table 5: Management of hepatitis
Table 6: Management of endocrine toxicities
Table 7: Management of pneumonitis
Table 8: Immunosuppressants used for management of immune-related adverse effects
Table 1: Immunotherpy Agent OverviewTable 2: Incidence of Immune-Related Adverse Effects
Table 3: Management of rash/inflammatory dermatitis
Table 4: Management of colitis
Table 5: Management of hepatitis
Table 6: Management of endocrine toxicities
Table 7: Management of pneumonitis
Table 8: Immunosuppressants used for management of immune-related adverse effects
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The changes in sepsis guidelines: How do they shape our current practice?
Authors: Paige Hagen, PharmD: PGY-1 Resident SSM Health St. Clare Hospital and Christopher K. Carter, PharmD, BCCCP: SSM Health St. Clare Hospital
Program Number: 2018-04-09Approval Dates: 6/6/18 - 9/6/18Approved Contact Hours: One (1) CE(s) per LIVE session.
Sepsis’ Impact and ImportanceEven with advances in medicine, sepsis remains difficult to define and is associated with high mortality rates. Sepsis accounts for roughly 31.5 million cases annually, resulting in 5.3 million deaths. Patients who survive are at higher risk for long-term physical, cognitive, and psychosocial morbidity, and have an increased mortality rate for up to two years after an event.1
In addition to high mortality rates, sepsis poses a significant burden to our healthcare system due to the cost of treatment. In the United States, sepsis is the number one highest cost of hospitalizations, averaging roughly $24 billion dollars for treatment annually. The average hospital stay costs about $18,400, but depends on when sepsis was detected. If detected early on in the emergency department, it costs about $3,000. If not detected until after admission, the cost of treatment can be as much as $32,000. Additionally, patients with sepsis experience a length of stay that is 75% longer than patients with other disease states. Furthermore, sepsis is the number one cost of readmissions with roughly 62% of patients re-admitted within 30 days. 2
With the high mortality rates and the significant cost burden to our healthcare system, it is important to constantly re-evaluate and re-define the approach to the treatment of sepsis and septic shock.
Timeline of Trials for Early Goal Directed Therapy (EGDT)In 2001, Rivers et al. published striking evidence from their trial looking at early goal directed therapy (EGDT) for the treatment of severe sepsis and septic shock. EGDT involves the measurement of central venous oxygen saturation, central venous pressure, and mean arterial pressure through central venous and arterial catheterization. According to the protocol, patients are administered crystalloid or colloid fluids, vasoactive agents, red blood cell transfusions, and/or inotropic agents in order to meet each monitoring parameter and achieve an optimal balance between oxygen demand and oxygen delivery. This trial was the first attempt at showing benefit from EGDT with the purpose of determining whether EGDT before admission to the intensive care unit (ICU) effectively reduced the incidence of multi-organ dysfunction, mortality, and the use of health care resources among patients with severe sepsis or septic shock. When looking at in-hospital mortality rates, the study found benefit in the EGDT group versus the usual care group (30.5 % vs. 46.5%). Additionally, it found that those who received EGDT at the earliest stages of sepsis and septic shock experience significant short-term and long-term benefits, such as early identification and treatment of patients at high risk for cardiovascular collapse and for early intervention to help restore the balance between oxygen delivery and oxygen demand to the vital organs.3
In 2004, EGDT was incorporated into the Surviving Sepsis Campaign guidelines’ three and six hour treatment bundles.
Since 2014, there has been a rapid influx of sepsis literature, with the publication of three large trials and updated definitions. The trio of trials was aimed at reproducing the findings by Rivers et al. and to better determine the generalizability of these results.
Protocolized Care for Early Septic Shock (ProCESS)4 was published in May of 2014. It was conducted across the United States and randomly assigned patients with septic shock to one of three groups for six hours of resuscitation: protocol based EGDT, which mimicked the protocol from Rivers et al.; protocol based standard therapy that did not require the placement of a central venous catheter (CVC), administration of inotropes, or blood transfusions; and usual care. The primary endpoint looked at 60-day in-hospital mortality. As a result when comparing EGDT to protocolized standard therapy to usual care, no significant difference was found in mortality rates (21% vs 18.2 % vs 18.9%). However, the protocol-based care groups resulted in increased use of central venous catheterization, IV fluids, vasoactive agents, and blood transfusions.
The Australasian Resuscitation in Sepsis Evaluation (ARISE)5 was published in October 2014 as the second trial aiming to determine if EGDT, as compared with usual care, would decrease 90-day all-cause mortality among patients presenting to the emergency department (ED) with early septic shock in diverse health care settings. This trial was conducted in 51 tertiary care and non-tertiary care metropolitan and rural hospitals across Australia and New Zealand, with several sites in Finland, Hong Kong, and the Republic of Ireland. Patients presenting to the ED with early septic shock were randomly assigned to EGDT or usual care. For the studied primary endpoint of all-cause mortality within 90 days after randomization, no significant difference between the EGDT and usual care groups was found (18.6% vs 18.8%). There were also no differences in 28 day or in-hospital mortality, duration of organ support, or length of hospital stay.
Protocolized Management in Sepsis (ProMISe)6 rounded out the trio of trials with its publication in April of 2015. Its aim was to determine if the 6-hour EGDT resuscitation protocol was superior, in terms of clinical and cost-effectiveness measures, to usual care in patient presenting with early septic shock to National Health Service emergency departments in England. When studying the primary endpoint of all-cause mortality at 90-days, there was no significant difference among those receiving 6 hours of EGDT compared to usual care (29.5 % vs 29.2%). The EGDT group had increased used of central venous catheters, IV fluids, vasoactive drugs, and red-cell transfusion as a result of the treatment protocol. Additionally, ProMISe found that continuous monitoring with ScvO2 and strict protocolization did not show an improvement in overall outcomes.
Finally, in May of 2015, a meta-analysis was published comparing the results of the trio of trials in addition to past trials that used EGDT.7 Eleven trials were reviewed to address the question of whether EGDT, compared with other resuscitation strategies, was associated with a survival benefit. The study’s primary outcome was mortality in patients presenting to the ED with septic shock at 28 days, 90 days, and hospital discharge. The results found no difference between EGDT and usual care (23.2% vs 22.4%). Additionally, EGDT was associated with an increased rate of admission to the ICU and increased the utilization of resources.
It is important to take a step back and analyze these results as a whole. Some may ask, “why is it that Rivers et al. found ground breaking evidence with EGDT in lowering mortality rates, yet the trio of trials and meta-analysis found no difference in mortality outcomes and no benefit of this specific protocol?” One explanation for these results may stem from the improvement of “usual care” from 2001 to 2014. Detection and treatment of sepsis and septic shock has improved dramatically over the years. To this day, usual care is centered on the fundamentals of the Rivers et al. protocol which includes fluid resuscitation, blood cultures, and early initiation of broad-spectrum antibiotics. The only difference is that “usual care” today is not using the parts of EGDT that are extraneous in most patients like inotropes, blood transfusions, and central lines.
Updated Sepsis DefinitionIn February of 2016, there was an update to the definitions of sepsis and septic shock titled “The Third International Consensus Definitions of Sepsis and Septic Shock (Sepsis-3).”8 The definitions had last been revised in 2001 and the aim of the authoring task group was to provide practitioners with more robust criteria to diagnose patients with sepsis and identify patients with a suspected infection that would likely progress to a life-threatening state. From the review and updates, Sepsis-3 found four key findings.
First, the previous definition focused excessively on the inflammatory process, which portrayed a misleading model that sepsis follows a continuum from sepsis to severe sepsis to septic shock. Additionally, Sepsis-3 determined that the systemic inflammatory response syndrome (SIRS) criteria lacked specificity and sensitivity and are present in many hospitalized patients. This likely has then led to an over-diagnosis of sepsis. It was also thought that SIRS criteria do not indicate a dysregulated, life-threatening response as was intended by the 2001 definition. The taskforce therefore defined sepsis as a “life- threatening organ dysfunction caused by a dysregulated host response to infection.” This new definition helps to emphasize the importance of urgent recognition and the severity of mortality with a septic presentation.
Secondly, Sepsis-3 found that there were multiple definitions in use for sepsis, septic shock, and organ dysfunction, which lead to discrepancies in reported incidence and observed mortality. As a result, organ dysfunction was redefined as an increase in the SOFA score of ≥ two points. This assumes that patient’s baseline SOFA score should be zero, unless the patient has pre-existing organ dysfunction. Of note, an increase in SOFA score ≥ two points is associated with in-hospital mortality of greater than 10%.
Furthermore, Sepsis-3 determined that the term “severe sepsis” is redundant since sepsis is now further defined as life-threatening organ dysfunction and eliminated this distinction Septic shock was also further defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. It is clinically identified by a vasopressor requirement to maintain a mean arterial pressure (MAP) ≥65 mmHg and a serum lactate > two mmol/L (>18 mg/dL) in the absence of hypovolemia. Patients with septic shock are associated with in-hospital mortality rates of > 40%.
Finally, Sepsis-3 introduced the QuickSOFA (qSOFA) score that provides simple criteria to identify patients with suspected infection who are likely to have poor outcomes. It can be performed quicker than the SOFA score, as it does not require invasive testing and can be reassessed repeatedly. It is advised that the qSOFA be used to prompt physicians to further investigate for organ dysfunction, initiate therapy as appropriate, and to increase patient monitoring. With the updated definitions and clinical criteria, Sepsis-3 can facilitate earlier recognition and timely management for patients with sepsis or those at risk of developing sepsis.
Surviving Sepsis Campaign’s Response to Sepsis-3In response to the updated Sepsis-3 definitions and the new evidence from the aforementioned trials, the Surviving Sepsis Campaign published new guidelines in 2016. 9,10 These guidelines specifically updated the six-hour sepsis treatment bundle by removing the requirement of a CVC to monitor central venous pressure (CVP) and central venous oxygen saturation (ScvO2) in all patients with septic shock who received timely antibiotics and fluid resuscitation.
SEP-1 Core MeasureIn response to the updated definition and sepsis guidelines, it is important to take into account CMS’ introduction of SEP-1, the sepsis core measure. SEP-1 was implemented October 1, 2015 and uses the 2001 sepsis definition that uses SIRS criteria for sepsis, severe sepsis, and septic shock recognition. The core measure does support bundle compliance as stated in the most recent Surviving Sepsis Campaign guidelines (2016). In order to receive reimbursement from CMS, all measures outlined by SEP-1 must be met. It is important to note that over-diagnosis of sepsis may occur under this core measure due to the use of the 2001 definition instead of the updated definition. This should be considered at an entity level when determining what resources will be required to ensure CMS compliance.
Effect on Current Medical PracticeRivers et al. originally found striking evidence in lowering sepsis mortality rates using EGDT. From there, EGDT was incorporated into the Surviving Sepsis Campaign Guidelines in 2004. When a trio of trials attempted to recreate the finding by Rivers et. al., EGDT was not substantiated or associated with a lower rate of mortality. They also discovered that strict monitoring and measurement of CVP and ScvO2 did not improve mortality outcomes.
Following the publication of ProCESS, ARISE, and ProMISe, the 2001 definition of sepsis was updated with the publication of Sepsis-3. The aim of Sepsis-3 was to update the definition of sepsis and provide greater consistency and clarity for diagnosing sepsis. Additionally Sepsis-3 introduced the QuickSOFA score, allowing for quick recognition of patients with a suspected infection that would likely result in poor outcomes.
From the trial results and the publication of Sepsis-3, the Surviving Sepsis Campaign Guidelines updated the six-hour bundle, removing the requirement for CVP and ScvO2.. Eliminating these requirement will help to decrease the healthcare resource utilization costs and lower rates of ICU admissions.
Even with the rapid influx of sepsis literature, CMS’ SEP-1 core measure still uses the 2001 definition that uses SIRS criteria for sepsis, severe sepsis, and septic shock recognition. With this, over-diagnosis of sepsis may occur across entities to ensure CMS compliance.
In summary, there has been great advancements in sepsis literature since 2001, reshaping our current practices. Even with all of the new discoveries, I believe that the EGDT fundamentals outlined by Rivers et al. for early resuscitation in sepsis and septic shock remain unchanged. The fundamentals are as important today as they were in 2001 which include fluid resuscitation, blood cultures, and early initiation of broad-spectrum antibiotics.
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