By: Bridgette McCauley, PharmD; PGY-2 Psychiatry Pharmacy Practice Resident
Mentor: O. Greg Deardorff, PharmD, BCPP; Clinical Pharmacy Manager, Fulton State Hospital – Fulton, MO
Program Number: 2021-01-03
Approval Dates: February 3, 2021 to August 1, 2021
Approved Contact Hours: 1 hour
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Postpartum depression (PPD) is classified as a major depressive disorder occurring “during pregnancy or within four weeks following delivery.”1 In the United States, the prevalence of PPD is estimated to be 11.5% and is the leading cause of maternal mortality.2-5 Within the first-year after giving birth, one in seven deaths is a result of suicide.6 Those at highest risk of developing PPD are those with a history of depression, history of or current tobacco use, have experienced domestic violence, fear childbirth, are of lower socioeconomic status, have gestational diabetes, ≥40 years old, adolescents, unintentional pregnancy, or maternal anxiety.7-12 While the etiology is not clear, there are a few theories thought to cause PPD.
The exact pathophysiology is unknown, but thought to be related to neurotransmitter abnormalities, genetic predisposition, decreased estrogen, hypothalamic dysfunction, thyroid dysfunction, and alterations of reproductive hormones.13-21 One reproductive hormone in particular, allopregnanolone (a progesterone neurosteroid metabolite), is thought to have a role in PPD.18-21 Allopregnanolone is a positive allosteric modulator of GABAA and in animal models has been linked to anxiety and depression.21,24-26 During pregnancy, progesterone rises and is at its highest plasma concentration during the third trimester.22 The concentrations quickly decrease after childbirth.23 If the GABAA receptors do not adapt to the changes in allopregnanolone at child birth, it may trigger PPD.27
Overview of Brexanolone28
Brexanolone (Zulresso®) is a positive allosteric modulator of GABAA receptors, which was approved in 2019 for the treatment of PPD. This was the first medication approved by the FDA for PPD. This medication is given as a continuous infusion over 60 hours and must be administered in a healthcare facility. It is given as 30 µg/kg/h (0-4h), 60 µg/kg/h (4-24h), 90 µg/kg/h (24-52h), 60 µg/kg/h (52-56h), and 30 µg/kg/h (56-60h). If the patient does not tolerate the 90 µg/kg/h infusion, a dose of 60 µg/kg/h may be used instead. Due to the prolonged infusion, all patients are required to have childcare for the time of the infusion.
The most common adverse effects are sedation/somnolence (13-21%), dizziness/presyncope (12-13%), loss of consciousness (3-5%), and flushing/hot flush (2-5%). Due to the loss of consciousness/sedation risk, this medication does have a REMS program. This ensures that patients are monitored with pulse oximetry and physical assessment by staff.
While brexanolone has no contraindications, it should not be used in those with end stage renal disease (ESRD) with an eGFR of <15 mL/min/1.73m2 due to the solubilizing agent, betadex sulfobutyl ether sodium. This agent can accumulate in severe renal impairment. This medication does not require dose adjustments in patients with hepatic impairment.
During the administration of brexanolone, breast feeding is not recommended, but was found to be safe at 36 hours post-infusion. At 36 hours, the concentration in the breast milk was <10 ng/mL in at least 95% of women. Exposure to the medication in breast milk is not expected to be high as the oral bioavailability is low. Therefore, breastfeeding 36 hours post-infusion should be acceptable as relative infant dose is low.
Evidence Supporting Brexanolone29
Two phase 3 studies were performed. In the studies, there were two different brexanolone infusion rates compared (Table 1). Study 1 looked at both the brexanolone 60 µg/kg/h and 90 µg/kg/h infusion groups. This study showed that at 60 h, the least squares mean reduction in Hamilton Depression Rating Scale (HAM-D) scores were 19.5 points (SE 1.2) in brexanolone 60 µg/kg/h, 14.0 points (SE 1.2) in brexanolone 90 µg/kg/h, and 14.0 points (SE 1.1) in placebo group. The second study of the phase 3 trials, looked at brexanolone 90 µg/kg/h versus placebo and found the least squares mean reduction in HAM-D scores was 14.6 points (SE 0.9) in brexanolone 90 µg/kg/h vs 12.1 points (SE 0.8) in placebo. The phase 3 trial did show that brexanolone was superior to placebo in treatment of postpartum depression at 60 h and showed responses were sustained up to 30 days. Of those that responded to treatment at 60 h, 94% of patients did not relapse at 30 days post-infusion.
Prior to the approval of brexanolone, the mainstay of treatment for PPD was antidepressants.30-32 Most commonly, selective serotonin reuptake inhibitors (SSRIs) were the treatment of choice for PPD. SSRIs do not have a rapid onset of action and may take up to 6-12 weeks to see the full resolution of symptoms.33 A matching-adjusted indirect comparisons and network meta-analysis of brexanolone with SSRIs by Cooper et al demonstrated that brexanolone 90 µg/kg/h showed a greater change from baseline than SSRIs when looking at both HAM-D and Edinburgh Postnatal Depression Scale.34
Eldar-Lissai et al, estimated the average cost of a course of brexanolone to be $34,000, while SSRIs are relatively cheap.35 They estimated that direct maternal medical costs for brexanolone treated patients was $65,908 vs $73,653 for SSRIs over 11 years. This study showed the incremental cost effectiveness ratio of brexanolone was $106,662 per quality adjusted life years over 11-years versus SSRIs. In addition, women treated with brexanolone averaged 6.230 quality adjusted life years vs 5.979 for SSRIs. This study showed that while brexanolone is expensive, it is cost-effective for the treatment of PPD.
Brexanolone is a novel treatment for PPD and has shown promising results. While the long-term effects are not yet known, it has shown itself to be effective for the treatment of PPD and is a viable option for patients suffering with PPD.
By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain
We are in the People Business.
Every day, we go to work to take care of people. Pharmacists are in the business of protecting, educating, persuading, and serving people. It’s what we do, as we interact with patients, nurses, doctors, and other health care professionals. Today I’d like to ask for your help in educating, persuading, and serving a different group of people: Lawmakers!
Politicians Are People Too
As I have written in other articles, pharmacists, technicians and interns have to play according to the rules, and those rules have their foundation in the laws that are passed in Jefferson City. Part of MSHP’s 2021 strategic plan is to increase the amount of education and guidance we provide to the lawmakers who are working hard to create good laws that keep the Missouri public safe. That takes time, and it takes focus, and it takes effort. We can’t do it by ourselves. Will you help?
Three Ways to Help
We have a Public Policy committee that meets monthly to provide updates and discuss our options for getting engaged. We are also forming work groups to focus on provider status, reimbursement for cognitive services, and MSHP advocacy and education on legislative topics. If you would like to add your listening ear and your voice, please email me so that you can join our committee.
We are getting ready for the annual Legislative Day, which will be 3/30. This is a time for Jefferson City to focus on pharmacy, and it provides an opportunity for the Missouri Pharmacy Association and Missouri Society of Health System Pharmacists to come together with one voice to remind our lawmakers of the important role we play in caring for patients. It is a Tuesday, and usually there are events scattered throughout the day, so you will need to make a plan in order to be able to participate. Of course the event will look different this year, so stay tuned. We are not ready for signups, but if you are interested in receiving updates, please email me and I will keep you informed.
If you are not available on 3/30, that is no problem at all! There are 51 other weeks this year where you can reach out to your senator or representative and begin the process of building relationships with them and educating them on pharmacy-related topics. With the COVID vaccine in the news, all eyes are on pharmacy right now. This is a great time to begin the process of meeting the person who represents you so that you can provide them with important information when they need it. Don’t know who your lawmakers are? You can find them here in less than a minute. Send them an email to get on their email list. Don’t feel equipped to speak on behalf of Missouri Pharmacy? Email me and I will provide you with some talking points and agenda items to discuss.
Caring For Lawmakers
Remember, we are in the people business, and our lawmakers are people who need our expertise and care. Let’s make 2021 the year when we start making a difference in our patients by caring for our lawmakers!
Don’t Miss What the Public Policy Committee Has Done!
Advocacy 101 Webinar:
This is a 1 hour webinar that gives the basics about advocating for our patients at the legislative level and at the regulatory level. It is a brief tutorial of ‘how things work.’ Link
Public Policy Updates:
By: Jackie Harris, PharmD, BCPS; Executive Director, MSHP Research and Education Foundation; Christian Hospital
MSHP R&E Foundation is currently accepting submissions and nominees for several awards.
MSHP R&E Best Practice Award
The Best Practice Award program recognizes innovation and outstanding performance in a pharmacy directed initiative. The theme for the 2021 award focuses on Adapting to New Circumstances. Submission deadline is January 11, 2021.
A poster of the program will be highlighted during the Spring Meeting Poster Session. The award recipient will be honored at a Reception during the Spring Meeting and have the opportunity to provide a brief podium presentation detailing the implementation and impact of the project to the attendees.
Applicants will be judged on their descriptions of programs and practices currently employed in their health system based on the following criteria:
Applicants must be active MSHP members practicing in a health-system setting such as a large or small hospital, home health, ambulatory clinic or other health care system. More than one successful program from a health system may be submitted for consideration.
Award recipient will receive half off their meeting registration, a plaque and a $250 honorarium.
Submission Instructions: A program summary not to exceed 400 words must be submitted with the application and include the following information.
MSHP R&E Best Residency Project Award
The Best Residency Project Award recognizes innovation and outstanding performance in a pharmacy residency project. A poster of the program will be highlighted during the Spring Meeting Poster Session. The award recipient will be honored at a Reception during the Spring Meeting and have the opportunity to provide a brief podium presentation detailing the implementation and impact of the project to the attendees. Submission deadline is January 11, 2021
Applicants will be judged based on the following criteria:
Applicants must be active MSHP members completing a residency in a health-system setting such as a large or small hospital, home health, ambulatory clinic or other health care system.
Email your submission to firstname.lastname@example.org with Best Residency Project Award Submission in the subject line.
The Garrison award was established in 1985, named after Thomas Garrison for his long standing support of MSHP (past-president 1974-1976), ASHP (past-president 1984) and numerous professional and academic contributions to Pharmacy.
The Garrison Award is presented each year to a deserving candidate who has been nominated in recognition of sustained contributions in multiple areas:
Email your nomination to email@example.com with Garrison Award Submission in the subject line.
Submission Deadline for Garrison Award is January 11, 2021.
Tonnies Preceptor Award
MSHP R&E Foundation is pleased to honor a health system pharmacist for outstanding service to the profession as a preceptor to pharmacy students and/or residents. Below are the Criteria and Procedures to nominate a preceptor for the award.
The Tonnies Preceptor award was established in 2020, named after Fred Tonnies, Jr. for his long standing support of MSHP (past-president 1976-1978), Mid-Missouri Society of Hospital Pharmacists (MMSHP) (past-president 1988) and numerous professional and academic contributions to Pharmacy. He was one of the founding members of MSHP and MMSHP, and has over 35 years of precepting experience.
The Tonnies Preceptor Award is presented each year to a deserving candidate who has been nominated in recognition of sustained contributions in multiple areas:
The award will be presented to a health system pharmacist that consistently exemplifies the core values (Professionalism, Desire to educate and share knowledge with students, Willingness to mentor, Willingness to commit the time necessary for precepting, Respect for others, Willingness to work with a diverse student population) and the following characteristics:
Each letter of nomination must include:
Support for Nomination: Please briefly explain (in no more than 500 words) the ways in which the nominee models these core values. The winner will be selected by the Board of Directors of the MSHP Research and Education Foundation. Email your submission to firstname.lastname@example.org with Tonnies Preceptor Award Submission in the subject line.
Submission Deadline for Tonnies Preceptor Award is January 11, 2021.
Best Practices Award Winner – A Pharmacist-Driven Penicillin Allergy Overhaul
Becca Nolen, Infectious Diseases and Antimicrobial Stewardship Pharmacist at SSM Health-St. Mary’s Hospital received the Best Practices Award during the Virtual KCHP/MSHP Spring Meeting for her project entitled “A Pharmacist-Driven Penicillin Allergy Overhaul.”
One of the most commonly reported allergies in the United States is to penicillin. Historically, cross-reactivity between penicillin and other beta-lactam antibiotics has been estimated at 10%, but recent literature has shown that the beta-lactam ring does not confer cross-reactivity, and the true likelihood of cross-reactivity is significantly lower than previously reported (approximately 1%).
This program consists of pharmacist-led interventions at SSM Health St. Mary’s Hospital – St. Louis, including education of providers when beta-lactams may be appropriate in penicillin-allergic patients, beta-lactam allergy questionnaires, and penicillin skin testing in patients who have penicillin allergies and are not on a penicillin or cephalosporin for treatment of infection. A real-time best-practice alert (BPA) that identifies patients for the Antimicrobial Stewardship pharmacist to review and assess which of the aforementioned interventions would be most appropriate. Patients are excluded if they are on antibiotics for surgical prophylaxis, duration of antibiotics is <48 hours, or if they are on appropriate antibiotics that were not a penicillin or cephalosporin. Data were collected during a pilot of the project from November 2018 to February 2019, though the project is still on-going.
During the study period, 297 BPAs were generated and 214 patients were excluded, mostly for being on antibiotics less than 48 hours. 83 patients were on appropriate antibiotics that were not a penicillin or cephalosporin. Recommendations to switch antibiotics were made on 30 patients, and one penicillin skin test was completed during the study period. Interventions were accepted in 90% of patients, and no patients had adverse drug reactions or required supportive care after switching to a penicillin or cephalosporin. Since the study time period, 12 penicillin skin tests have been performed.
This project has helped educate our providers on the appropriate management of infected patients with reported penicillin allergy, as well as to expand the role of pharmacist. The utilization of unnecessary broad-spectrum antibiotics has been reduced, which could potentially lead to shorter hospital stays and less repeated use of broad-spectrum antibiotics in penicillin -allergic patients.
If you have any questions about this project, please contact Becca Nolen at Rebecca.Nolen@ssmhealth.com.
By: Abbey Jin, PharmD Candidate 2021, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Alexandria Wilson, Pharm.D., BCPS (AQ-ID); Associate Professor, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Clinical Pharmacy Specialist, Infectious Diseases, Washington University Infectious Disease Clinic
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread rapidly across the world since the first known cases arose out of Wuhan, China in late 2019.1 Coronavirus disease 2019 (COVID-19) was declared a pandemic on March 11th, 2020.2,3 As of the writing of this paper, there have been over 43 million confirmed cases of COVID-19 worldwide, with over 1 million deaths.4 Patients with underlying health conditions may have different outcomes than patients without comorbidities.5,6 In particular, people living with Human Immunodeficiency Virus (PLHIV) have been labelled as a COVID-19 high-risk group due to immunosuppression.7 In a report from Kanwugu et al., published on July 21st 2020, there have been 378 reported cases of COVID-19 among PLHIV worldwide.8 This review will summarize the clinical characteristics, HIV management, and outcomes of PLHIV who are infected with SARS-CoV-2.
Epidemiology of COVID-19 in PLHIV
The first published case of HIV and SARS-CoV-2 coinfection was reported in Wuhan, China in early 2020.8 Mirazaei et al. published a systematic review of 252 cases of HIV and SARS-CoV-2 infections in July 2020.2 The majority of those cases were male (80.9%) with a mean age of 52.7 years on antiretroviral therapy (ART) (98%).2 Many patients also had other chronic health conditions known to increase the risk of COVID-19, such as hypothyroidism, asthma, hyperlipidemia, hypertension, obesity, diabetes, and lung disease. 2,5 Slightly over 20% of the patients in the systematic review were smokers. 2
Clinical Features and Courses of COVID-19 in PLHIV
Upon admission, coinfected patients presented with similar signs and symptoms of COVID-19 to HIV- uninfected patients. Many coinfected patients had upper or lower respiratory infections, fever, cough, headache, dyspnea, malaise, sore throat, arthralgia, gastrointestinal upset, myalgia, lymphopenia, and lung changes, i.e. opacities upon X-ray imaging.2,5,9,10
The following table compares the results of Mirazaei et al.’s systematic review of COVID-19 in PLHIV (percentages calculated from available data) to the largest COVID-19 cohort available as of November 3rd, 2020 (>44,000 patients) and United States (US) COVID-19 case surveillance data of hospitalization and intensive care unit (ICU) admission rates from January 22, 2020 to May 30, 2020. 2,11-13
This data suggests that PLHIV who develop COVID-19 have more severe and critical illnesses, hospitalizations, and ICU admissions than HIV negative patients. A majority (86.9% of 176) of patients had high CD4 counts of at least 200 cells/mm.3 Similarly, a HIV-1 RNA of no more than 1000 copies/mL was seen in a majority (99.1% of 233) of patients with viral load data.2 There have also been some reports of PLHIV presenting with Pneumocystis jirovecii pneumonia and COVID-19.14
Findings from Specific Cohorts
There have been conflicting outcomes concerning the survival rates of PLHIV with COVID-19 compared to the general COVID-19 population. For instance, in the United Kingdom, a cohort of patients from the OpenSAFELY platform reported 14,882 COVID-19 deaths with 25 cases among PLHIV. The study included a total of 17.3 million patients with 27,480 cases among PLHIV who were three times more likely to have a COVID-19-related death compared to HIV negative patients (Hazard Ratio (HR) 2.90, 95% Confidence Interval (CI) 1.96-4.30). The association was even greater in patients of African ethnicity (HR 3.80, 2.15-6.74, vs. HR 1.64, 0.92-2.90, p-interaction=0.045).15 Similarly, in a study from Western Cape, South Africa with a patient repository of 3,460,932, 16% were PLHIV. Of this 16%, 3,978 PLHIV were diagnosed with COVID-19, and 115 PLHIV with COVID-19 died. It was shown that HIV was associated with COVID-19 mortality. The risk was similar across different levels of immunosuppression and viral loads. Standardized mortality ratio for COVID-19-related deaths in PLHIV was 2.39 (95% CI 1.96-2.86).16 Another multicenter cohort study with 286 patients found that PLHIV and COVID-19 with CD4 count below 200 cells/mm3 had a higher risk for death, ICU admission, mechanical ventilation or hospitalization, regardless of viral suppression.17
However, a large scale study of 7,576 patients conducted by the US Veterans Aging Cohort Study, showed no difference in mortality (adjusted HR (aHR) 1.08, 95% CI 0.66-1.75), hospital admission (aHR 1.09, 95% CI 0.85-1.41), intubation (aHR 0.89, 95% CI 0.49-1.59), or ICU admission (aHR 1.08, 95% CI 0.72-1.62) between PLHIV and HIV negative patients with COVID-19. This study matched PLHIV and HIV negative patients to account for potential confounders.18 Another study in New York with a cohort of 100 PLHV and 4,513 HIV negative patients also supported no difference in mortality rates.19 All of these studies were not included in Mirazaei et al.’s systematic review which reported deaths in 14.3% of 252 coinfected patients.2
HIV Management in COVID-19
For PLHIV, the National Institutes of Health (NIH) guidelines for COVID-19 treatment recommend patients continue taking their ART unchanged, including investigational agents, and medications for opportunistic infections (OI) prophylaxis.14
The Guidelines recommend against changing ART regimens to treat or prevent COVID-19.20 However, clinicians are advised to consult with a HIV specialist if the ART needs to be adjusted or if the patient is on a feeding tube. For PLHIV not on ART, it is currently unknown when is best to start taking the ART. Overall, clinical recommendations for management of coinfected patients do not differ from the general population.14
Cohorts that assessed specific ARTs patients were taking at the time of COVID-19 included combination nucleoside reverse transcriptase inhibitors with an integrase inhibitor, nucleos(t)ide reverse transcriptase inhibitors (NRTIs) with protease inhibitors (PIs), or combination therapy with nonnucleoside reverse transcriptase inhibitors (NNRTIs).5,21
There have also been studies of outcomes in coinfected populations on ARTs. A cohort study of 77,590 PLHIV in which 236 were diagnosed with COVID-19, in Spain looked at outcomes of PLHIV receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC) and other ARTs (3TC in two-drug therapies or NNRTI with PI monotherapy). The results of the study are summarized in the table below. 21
The results of this study suggest a benefit in COVID-19-related outcomes of PLHIV on TDF/FTC compared to other ARTs. The study also suggested ARTs have a protective effect in PLHIV, lessening the risk for serious COVID-19 cases.21 There have been other studies looking at ARTs, like lopinavir/ritonavir and darunavir/cobicistat, for treatment of COVID-19, but have shown no clinical benefit compared to the standard of care or need further investigation, respectively.22,23
Current cases of infection with SARS-CoV-2 in PLHIV present with similar clinical features to HIV uninfected people. Different studies have suggested varied outcomes in PLHIV.15-19 Current COVID-19 treatment guidelines offer the same management recommendations for PLHIV and HIV-patients.14 In PLHIV, there are guidelines for HIV management, which state ARTs should not be changed. In one cohort, the combination of ARTs TDF/FTC showed some benefit compared to other ARTs in COVID-19-related outcomes of PLHIV, but more data is needed.21 Differences in the outcomes observed in the cohorts may be attributed to the retrospective nature of some studies, the differing designs, size of cohort, etc. Due to the novelty of COVID-19, there are still many unanswered questions, including whether CD4 count or viral load in PLHIV are associated with severity of COVID-19, and the impact of different ARTs.2 To make accurate conclusions, there needs to be more data on COVID-19 in PLHIV.
By: Annalisa Torres, PharmD Candidate 2021; St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy in St. Louis
Mentor: Paul Juang, PharmD, BCPS, BCCP, FASHP, FCCM; Professor, Department of Pharmacy Practice, St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy in St. Louis
SARS-CoV-2 and COVID-19
As 2019 drew to a close, the world saw the emergence of a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease known as Coronavirus disease 2019 (COVID-19). This highly pathogenic coronavirus was originally identified in Wuhan, China and would eventually spread to the rest of the global population resulting in a modern worldwide pandemic. The increased morbidity and mortality associated with COVID-19 resulted in the need for both the rapid manufacturing and global distribution of a safe and effective vaccine that is unparalleled.1 Due to its highly infectious nature that has resulted in numerous mortalities along with the global economic impact, understanding how SARS-CoV-2 enters the cell is an important factor in vaccine development.2
Like its predecessor, severe acute respiratory syndrome coronavirus (SARS-CoV), which resulted in the 2003 SARS outbreak, SARS-CoV-2, is a betacornoavirus that gains entry into the host cell via a spike protein (S2) that is present as a trimer on viral cell surfaces. A receptor binding domain for angiotensin-converting enzyme 2 (ACE2) is located on S protein resulting in the entry of both SARS-CoV and SARS-CoV-2 into the host cell. While the mechanism for entry is the same, slight variations in the receptor binding domain of SARS-CoV-2 result in a higher binding affinity for ACE2 compared to SARS-CoV.2 This mechanism has been the key area of interest related to COVID-19 vaccine development.3
Generally, it takes between 15 and 20 years before a safe and effective vaccine is available for distribution to the public.5,6 But given the need for more rapid vaccine development a public – private partnership known as Operation Warp Speed (OWS) was formed in May 2020. OWS is a partnership between the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector in order to accelerate not only vaccine development but also manufacturing and distribution, in the hopes of being able to provide at least 100 million doses by mid-2021.7
mRNA Vaccines: Moderna and Pfizer/BioNTech
A novel approach to vaccine development, messenger RNA (mRNA) based vaccines work on the notion that mRNA coded for pathogen antigen, in this case SARS-CoV-2, can not only be delivered to human cells but can then be used to produce antigen within the cell. mRNA vaccine technology synthesizes the viral protein by utilizing the human protein translational process. This method of vaccine delivery allows for a robust immune response without the introduction of live or inactivated portions of SARS-CoV-2. Due to its susceptibility to be rapidly degraded by ribonucleases, these vaccines need to be encapsulated with a lipid nanoparticle.5,6 Both Moderna in conjunction with NIAID (National Institute of Allergy and Infectious Disease) and Pfizer in conjunction with BioNTech have developed an mRNA based vaccine that encodes for spike protein found on the surface of SARS-CoV-2. 5,8,9
Adenovirus Vector Vaccines: AstraZeneca and Janssen
The vaccines currently being developed by AstraZeneca in conjunction with University of Oxford and Janssen Pharmaceuticals are known as replication-incompetent vectors. These vaccines have been engineered to express the spike protein found on SARS-CoV-2 while also disabling in vivo replication. Both vaccines are based on adenovirus vectors that deliver the spike protein to human cells. Upon entry into host cells, these vectors will allow for the expression of the spike protein, resulting in an immune response. While these vaccine types have been shown to elicit a good B and T cell response, they are somewhat affected by pre-existing vector immunity. In order to overcome this issue, vector types are either rare in humans, animal derived, or induce low immunity.5,6
Inactive Spike Protein Vaccines: Novavax and Sanofi/GlaxoSmithKline
The vaccine candidates being put forth by Novavax and Sanofi/GlaxoSmithKline utilize inactivated viral vectors to display the SARS-CoV-2 spike protein.5 The benefit of these vaccine types is that they are not only safe in immunocompromised individuals, and they have been extensively utilized in prior viral protein-based vaccines.6 NVX-CoV2373, the vaccine candidate from Novavax, includes the transmembrane domain of the wild-type SARS-CoV-2 spike (S) protein. As mentioned above, S mediates the attachment of SARS-CoV-2 to human cells.10
Table 1, comparing the current available data for the six leading COVID-19 vaccine candidates, is shown below.
Moderna. Moderna announces longer shelf life for its COVID-19 vaccine candidate at refrigerated temperatures. Moderna Web site. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-longer-shelf-life-its-covid-19-vaccine. November 16, 2020. Accessed November 17, 2020.
Word Health Organization. Draft landscape of COVID-19 candidate vaccines. Word Health Organization Web site. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. November 12, 2020. Accessed November 17, 2020.
By: Abbey Jin, Ashley Jose, and Miriam Bisada, PharmD Candidates Class of 2021; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Yvonne Burnett, PharmD, BCIDP; Assistant Professor, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Infectious Diseases Clinical Pharmacist, Missouri Baptist Medical Center
Coronaviridae are a diverse family of single-stranded RNA viruses that typically infect mammalian and avian hosts. Structurally, coronaviridae are spherical in nature with protruding spikes on the surface, resembling clubs.1 First discovered in humans in the 1960s, the coronavirus family has since rapidly mutated to include seven different human coronaviruses (hCoV), which can be broken down into four sub-groups: alpha, beta, gamma, and delta, alpha and beta being the most common.2 Notably in the 21st century, three life-threatening coronavirus infections have emerged: Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and Coronavirus Disease 2019 (COVID-19).2
As these viruses are related, there are parallels between the three viruses and clinical disease. SARS, MERS, and COVID-19 are zoonotic diseases that have genetic origins from bats and other mammals.3 Additionally, all three are transmitted via respiratory droplets; however, MERS-CoV may also be transmitted via other bodily fluids. As these usually require close contact with respiratory droplets, they can be easily transmitted, with SARS-CoV-2 being the most easily transmitted, then SARS-CoV and MERS-CoV.3 The clinical presentations are often similar and will be compared below. While there are many similarities between the three viruses, they are distinct, and only SARS-CoV-2, causing COVID-19, has resulted in a worldwide pandemic. This review will compare clinical epidemiological features, clinical presentations and symptoms, and/or treatment recommendations between the MERS, SARS, and COVID-19 coronaviruses.
Severe Acute Respiratory Syndrome (SARS)
SARS-CoV is a beta coronavirus that was first identified in 2002 in Guangdong, China and rapidly spread to other countries/areas, including Canada, Hong Kong, Singapore, and Vietnam.3-5 The incubation period of SARS is typically between 2-10 days, with the mean time from onset of clinical symptoms to admission ranging between 3-5 days.4 According to World Health Organization (WHO), over 8000 people worldwide became infected with SARS-CoV between 2002 and 2003 and, of these, 774 died.6
Clinical Presentation and Diagnostics
SARS commonly presents with symptoms like that of influenza infection, including malaise, headache, fever, diarrhea, chills, and myalgia, similar to MERS and COVID-19.3,4 Patients may also experience dry cough or shortness of breath in the first two weeks of illness; however, rash and neurologic findings are uncommon.4 Symptoms may further progress and result in the development of pneumonia or hypoxia. Patients with SARS have also presented with biphasic infection, where initial improvement is followed by rapid deterioration with noted fever, chest infiltrates and respiratory failure.4
The primary method of diagnosis is molecular PCR testing of nasopharyngeal or oropharyngeal swabs, sputum, blood or stool samples.3,4,7 PCR testing is the most well-developed molecular technique that has been used to evaluate novel infections due to its high sensitivity, specificity and cost effectiveness.8 However, it also comes with the risk of false positive or false negative results. Serological testing, such as antibody testing, can be used to detect the presence of antibodies in the blood due to SARS-CoV infection.6 Per the Centers for Disease Control and Prevention (CDC), antibody testing is not recommended to be used as the sole basis for diagnosis of acute SARS infection; however, it may be useful for detecting exposure to the virus.9 Serologic tests may be misleading, if not used within an appropriate time of disease, antibody development may take up to 3 weeks, until then infected patients may have negative results.10 Lastly, the sensitivity of both PCR and serology testing have been found to be around 80% and close to 100%, respectively.11
To date, there are no guidelines or vaccines to direct the management or prevention of SARS. SARS management is centered around providing supportive care and minimizing infectious spread.4 The combination of ribavirin and corticosteroids have been studied for management of SARS, but were not found to be effective.4 The data surrounding corticosteroid use in SARS is conflicting. One study found methylprednisolone alone lowered oxygen requirement and rapidly resolved lung opacities, while others have reported 20-fold increase in adverse outcomes, including mortality or intensive care unit admission, with the use of corticosteroids.12,13 Convalescent plasma may also be administered in patients who continue to deteriorate, as one preliminary study observed decreased hospital length of stay and mortality in severely ill patients with SARS.14
Middle East Respiratory Syndrome (MERS)
MERS-CoV first presented to humans in 2012 in Jordan, but most cases occurred in the Kingdom of Saudi Arabia. Since then, MERS-CoV has spread to 27 countries.15 While the mortality rate due to MERS is relatively high at 34.4%, this may be due to underreported cases with mild or asymptomatic infection.16 The median incubation period is 5 days, and the median time for hospitalization since illness onset is 4 days.3 Of the three coronaviruses, MERS-CoV has the lowest reported transmission rates.3
MERS infection presents in a progressive manner where, initially, many patients may be asymptomatic or present only with mild influenza symptoms.17 Common presentations include cough, headache, fatigue, fever >38oC, and diarrhea, like SARS and COVID-19.3 Patients may progress to more severe disease, identified by worsening respiratory status, acute respiratory distress syndrome (ARDS), and multi-organ failure. Multi-organ failure and deaths occurred in 20% to 40% of infected patients.15
Like SARS, MERS can be detected via molecular and serologic tests. Molecular tests, such as PCR, diagnose active infection in patients. The MERS-CoV PCR diagnostic sensitivity and specificity were both 100%.18 Serologic testing detects patients who were infected and had an immune response by identifying antibodies to MERS-CoV; however, like SARS and COVID-19, this approach is for investigational use only and not for diagnosis. The CDC recommends two-phase serologic testing due to false-positives, using two screening and one confirmatory test.19
As with SARS, there are no guidelines to direct MERS management. Early supportive therapy is recommended, which includes supplemental oxygen therapy and/or mechanical ventilation depending on respiratory status, conservative fluids (if no evidence of shock), and management of co-morbidities.20
The role of antivirals to treat MERS or SARS is not definitive due to high mortality and morbidity rates; however, antivirals may be considered in addition to supportive care as soon as MERS is diagnosed in severe cases. 21 Antiviral therapies have shown efficacy in laboratory studies, but not in clinical trials.21 A retrospective cohort study in patients with severe MERS-CoV infection showed that combination therapy with ribavirin and interferon-alpha-2a was associated with significantly improved survival at 14 days (typical therapy duration) compared with supportive care alone, but lack additional clinical data due to the high mortality rate.20,22 The dose for ribavirin should be clinically adjusted according to the patient’s renal function and tolerability to its side effects (cytopenia and hemolytic anemia).21 Glucocorticoids, while shown to be beneficial in COVID-19 infection, were not found to reduce mortality in MERS and were associated with delays in viral clearance.23 Convalescent plasma studies are limited due to the low numbers of MERS-CoV survivors, but could be administered within 2 weeks of infection onset in patients with severe MERS that are refractory to antivirals.21 Other agents studied, but not recommended for MERS treatment, include polyclonal anti-MERS-CoV human antibodies, nucleoside viral RNA polymerase inhibitors (e.g. remdesivir), and peptide inhibitors (e.g. HR2P-M2).20 Like SARS and COVID-19, there is currently no FDA approved vaccine, but clinical trials are ongoing.24
The first known cases of COVID-19 were reported in Wuhan, China in late 2019 and rapidly spread across the world infecting millions. COVID-19 was declared an international public health concern on January 30th, 2020, and a pandemic on March 11th, 2020, and continues to affect almost every country worldwide.3,26-29 As of the writing of this paper (October 31st, 2020), there have been over 45 million reported cases globally and over 1.1 million deaths.27 On average, patients exhibit symptoms 5 days following infection, but symptoms may emerge up to 14 days after exposure.30 Patients >50 years have the highest rate of hospitalization.31 Furthermore, chronic kidney disease, obesity, heart failure, coronary artery disease, smoking, sickle cell disease, immunocompromising conditions, cardiomyopathy, type II diabetes mellitus, and cancer are established risk factors for severe COVID-19.32,33 SARS-CoV-2 has the highest rate of transmission compared to SARS-CoV and MERS-CoV.3,34
Common initial signs and symptoms of COVID-19 include cough, headache, fatigue, fever of >38oC, and diarrhea, like that of MERS and SARS.3 And, like MERS and SARS, it is thought that the symptoms vary at onset, with many COVID-19 patients presenting with mild symptoms, with severe cases following a progressive course.3,35 Severe or critical cases may present with hypoxia, shock, respiratory failure, and/or multi-organ dysfunction and failure. Furthermore, patients may be asymptomatic or pre-symptomatic, but may present with chest abnormalities upon imaging.35
Oral or nasopharyngeal swabs, sputum, and fluid from bronchoalveolar lavage are examined for presence of SARS-CoV-2 molecular PCR. Multiplex assays (RT-PCR tests) are available to detect both influenza and COVID-19.36,37 Sensitivity of SARS-CoV-2 PCR testing ranges from 57.9% to 94.6%.38-43 With such a wide range, depending on the test, there may be a chance of false negative results with lower sensitivity testes.38-43 The range could be due to different manufacturers, integrity of samples, rate of false negatives, etc. Serologic tests have also been developed for COVID-19 to detect prior exposure to SARS-CoV-2.44,45 Sensitivity for these tests have ranged from 66.0% to 97.8%.46 In people who have been infected 1 to 3 weeks previously, the serology test has a specificity of greater than 99% and a sensitivity of 96%.47 Antibodies are able to be detected approximately 1 to 3 weeks following onset of symptoms, but it is unknown for how long can antibodies to SARS-COV-2 may persist.48
Treatment guidelines for COVID-19 management are updated and published by the Infectious Diseases Society of America (IDSA) and the National Institutes of Health (NIH) as new data are made available. Currently, there is one FDA-approved drug for COVID-19 treatment: remdesivir, an antiviral nucleotide analog.49 Remdesivir is indicated for the treatment of COVID-19 in hospitalized adult and pediatric (>12 years and >40 kg) patients.50 From the multinational Adaptive COVID-19 Treatment Trial (ACTT-1), remdesivir reduced recovery time (10 vs. 15 days, 95% CI 13 to 18) and decreased mortality rates (11.4% vs. 15.2% on day 29, HR, 0.73; 95% CI, 0.52-1.03) compared to placebo.51 Based on available data, glucocorticoids, like dexamethasone 6 mg by mouth daily for up to 10 days, and/or remdesivir 200 mg intravenous (IV) on day one, then 100 mg IV once a day for 4 days are recommended for severe cases of COVID-19 (SpO2 < 94% on room air or requiring oxygen).52,53
The guidelines strongly recommend against initiation of hydroxychloroquine (HCQ) and/or azithromycin (AZI) in hospitalized COVID-19 patients, as HCQ was not associated with lower mortality rates, and the combination of HCQ and AZI was associated with increased mortality.52-54 There are agents still under investigation and are recommended for use only in the setting of a clinical trial, including lopinavir/ritonavir, famotidine, interleukin (IL)-6 inhibitors, IL-7 therapy, mesenchymal stem cells, convalescent plasma, etc. 52,53,55-57 Furthermore, many agents, i.e., convalescent plasma, remdesivir, etc., were initially approved for emergency use authorization to administer in COVID-19 patients; remdesivir has now received full FDA approval.58
Vaccines are also currently in development by several companies in the US. As of October 2020, none have been approved by the FDA, but initial reports are promising.59 They are being developed in record time with 11 already in Phase 3 clinical studies and 6 for limited or early use at the time of this writing (October 31st, 2020).60
MERS and SARS are examples of past deadly coronaviruses in the 21st century that became global threats. Since early 2020, the COVID-19 pandemic has spread worldwide. In response, many have looked back to previous, similar pandemics of viral diseases. Experience with past SARS and MERS outbreaks have changed the way we combat viral outbreaks today. COVID-19 treatment and vaccine discovery and development are advancing in record time, with emergency use authorization (EUA) agents being approved and remdesivir being the first FDA approved COVID-19 treatment.49,58-60 However, there is still much unknown about the current pandemic. We hope that by analyzing the previous clinical and epidemiological features of past-related viruses and applying them to current and future research, we will develop better insight into understanding and fighting COVID-19.
By: Jesse Smith, PharmD Candidate 2021, St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy in St. Louis
Mentor: Bryan Lizza, PharmD, MS, BCCCP, Barnes-Jewish Hospital – St. Louis
In the United States, more than 2.8 million antibiotic-resistant infections occur annually, leading to more than 35,000 deaths.1 Despite recent initiatives in infection prevention and antibiotic conservation, multi-drug resistant organisms (MDROs) continue to be a global health crisis as mortality and morbidity from MDROs continue to rise.2 As a result of this need for new antibiotic therapy, advancements in antimicrobial development have led to several recently approved antibiotics. Pharmacists will play a vital role in ensuring appropriate use of these new novel agents as well as understanding their mechanisms of action and their important clinical features. The purpose of this article is to describe new antibiotics with activity towards MDROs and summarize important studies that led to their FDA approval.
(Click on tables below to view full size image.)
The randomized double-blind phase 3 study Lefamulin Evaluation Against Pneumonia (LEAP 1) trial evaluated lefamulin’s ability to treat community-acquired bacterial pneumonia (CABP). The study compared the use of lefamulin at a dose of 150 mg intravenously every 12 hours to moxifloxacin at a dose of 400 mg intravenously every 24 hours for five to seven days. After taking six doses of intravenous therapy, patients in both groups could then be converted to oral formulations of their respective medication if improvement criteria were met. In addition, if methicillin-resistant Staphylococcus aureus (MRSA) was suspected, blinded linezolid was added to moxifloxacin and a placebo was added to lefamulin and the duration of treatment was extended to ten days. The study’s primary endpoint was early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug defined as improvement in ≥2 CABP signs/symptoms, had no worsening in any CABP sign/symptom, and had not received a concomitant, nonstudy antibiotic for CABP. Lefamulin was shown to be non-inferior to moxifloxacin for ECR at a rate of 87.3% for lefamulin and 90.2% for moxifloxacin in treating CABP in the intention-to-treat analysis (95% confidence interval (CI), -8.5 to 2.8). In the subsequent double-blind, double-dummy, parallel-group randomized LEAP 2 clinical trial, oral lefamulin at a duration of five days compared to moxifloxacin at a duration of seven days was evaluated in treating CABP. The study found that ECR at 96 hours ± 24 hours after the first dose of study drug was 90.8% in the lefamulin group and 90.8% in the moxifloxacin group, meeting the noninferiority margin of 10%. Like LEAP 1, LEAP 2 demonstrated lefamulin to be non-inferior to moxifloxacin in treating CABP and both agents were deemed safe and generally well tolerated.
One of the major phase 3 trials that led to delafloxacin’s FDA approval was A Phase 3 Study to Compare Delafloxacin With Moxifloxacin for the Treatment of Adults With Community-Acquired Bacterial Pneumonia (DEFINE-CABP). This randomized, double-blind, comparator-controlled, multicenter, global study compared delafloxacin 300 mg intravenously, with an option to switch to 450 mg orally every 12 hours, to moxifloxacin at 400 mg intravenously daily, with an option to switch to 400 mg orally daily, in patients with CABP. The study’s primary end point was ECR, defined as improvement at 96 ±24 hours after the first dose of study drug. The study found that patients receiving delafloxacin demonstrated an ECR rate of 88.9% compared with 89% in the moxifloxacin group (95% CI, -4.4% to 4.1%). Overall, the authors concluded that delafloxacin was a viable and well tolerated treatment option as monotherapy for CABP in adults where broad spectrum coverage, including MRSA, is indicated.
The efficacy of cefiderocol was evaluated in the Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. The study compared cefiderocol 2 g over 1 hour intravenously every 8 hours or imipenem-cilastin 1 g/1g intravenously every 8 hours for 7-14 days in patients with complicated urinary tract infection, with or without pyelonephritis, or those with acute uncomplicated pyelonephritis. The primary efficacy endpoint for the study was the composite outcome of clinical response defined as the resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms and microbiological response defined as he bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less. The study showed that 73% of patients in the cefiderocol group versus 55% of patients in the imipenem-cilastin group achieved the primary efficacy (95% CI 8.23-28.92; p=0.0004). Thus, cefiderocol was deemed to be non-inferior to imipenem-cilastin in the treatment of complicated urinary tract infections.
The Future of Antibiotics
Although a steady number of novel antibiotics have received FDA approval over the past few years, providers continue to question if new medication approvals can keep up with evolving bacterial resistance. The World Health Organization (WHO) reports that as of September 1, 2019, there are 50 antibiotics and combinations (with a new therapeutic entity), and 10 biologicals in the clinical pipeline (Phase 1– 3) of which 32 target the WHO priority pathogens.2 A large barrier moving forward is whether pharmaceutical companies will allocate the necessary resources to develop new antibiotics as private investment funding continues to decrease.2 Regardless of the pace at which antibiotic therapy evolves, pharmacists will continue to play a key role in ensuring safe and effective use moving forward.
By: Rexhian Brisku, PharmD Candidate 2021, St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy in St. Louis; Elizabeth Neuner, PharmD, BCPS, BCIDP, Barnes-Jewish Hospital – St. Louis
In 2014, the Centers for Disease Control and Prevention (CDC) released the Core Elements of Hospital Antimicrobial Stewardship Programs (Core Elements) to provide guidance and structure for antimicrobial stewardship programs (ASPs). Regulatory bodies including Centers for Medicare and Medicaid Services and The Joint Commission have since incorporated the Core Elements into accreditation standards. Despite advancements in stewardship, antibiotic resistance is still increasing and remains a public health hazard. The updated 2019 Antibiotic Resistance Threats Report by the CDC estimates 2.8 million cases of resistant infections lead to 35,000 deaths each year.2
The CDC recently updated the original Core Elements to continue optimizing hospital ASPs. The new document provides more granularity and specificity related to ASP activities and identifies priority interventions based on new literature and learned experiences over the past six years. This newsletter provides a summary of the updated 2019 CDC ASP Core Elements.1
1. Hospital Leadership Commitment: The first Core Element discusses the critical role of hospital leadership support for implementing a successful ASP. Priority examples include providing the ASP with time, resources and routine communication with executive leadership. Literature is emerging with recommendations for minimal ASP fulltime equivalent (FTE)-to-bed staffing ratios. A 2018 cross-sectional survey of 208 hospitals examined the relationship between ASP staffing levels and ASP effectiveness which they defined as a positive survey response to at least one of the following: established cost saving, decreased antibiotic utilization and decreased multi-drug resistance rates of organisms within the last four years.3 Every 0.5 increase in combined physician and pharmacist FTE availability predicted a 1.48-fold increase in ASP effectiveness (95% confidence interval, 1.06-2.07).3
2. Accountability: This Core Element emphasizes the need for a designated leader responsible for management and outcomes and highlights the effectiveness of a co-leadership model between pharmacists and physicians. The 2019 National Healthcare Safety Network (NHSN) Hospital Survey report of all U.S hospitals with stewardship programs, 59% utilize the co-leadership model.1
3. Pharmacy Experience: The previous “Drug Experience” Core Element is now referred to as “Pharmacy Experience” to highlight the importance of pharmacy engagement for the success of a stewardship program.1 A 2016 commentary on behalf of the Society of Infectious Diseases Pharmacists (SIDP) and the American Society of Health-System Pharmacists (ASHP) emphasizes the role of pharmacists, especially those trained in infectious diseases or antimicrobial stewardship, as essential.4
4. Action: This section was expanded to include evidence-based recommendations of effective ASP actions. The priority actions are prospective audit and feedback (PAF review of antibiotic therapy by an expert in antibiotic use), preauthorization (PA approval required prior to use of certain antibiotics) and facility-specific treatment guidelines.1 Several recent studies provide rationale for prioritizing PAF and PA by demonstrating the effectiveness in reducing overall antimicrobial use and improving appropriateness. A 2017 quasi-experimental, crossover trial comparing PAF and PA concluded that the incorporation of PAF had a more profound effect on reducing antimicrobial days of therapy.5 However, guideline adherence was found to be higher on day one in the PA group. The CDC considers both actions “foundational” for ASPs as they are complementary; PA optimizes initial empiric therapy and PAF reassesses continued therapy.1 Facility specific treatment guidelines can augment the effectiveness of both PAF and PA through optimizing antibiotic selection and therapy duration. ASPs should focus on the most common infections (e.g. lower respiratory tract, urinary tract, skin and soft tissue, etc.) and consider other infection-based interventions for sepsis, S. aureus and C. difficile infections.1
The usefulness of antibiotic timeouts, designated reassessment of antibiotic therapy by providers, is reframed as a supplemental strategy.1 Limited data suggests timeouts may improve appropriateness, but not reduce overall antimicrobial use. Therefore, this strategy should not replace PAF.6
Other supplemental actions organized around different ASP key stakeholders (pharmacy, microbiology and nursing) may help improve antibiotic prescribing, duration and safety. Pharmacy focused interventions include requiring indications, IV to PO switches, dose optimizations, alerts for duplicate therapy or drug interactions, and automatic stop orders. Microbiology-based interventions involve selective and cascading susceptibility reporting and “nudge” based interpretive comments.7 ASP actions for nursing discuss optimizing culture acquisition.
5. Tracking: The CDC recommends that ASPs track a variety of different measures to identify intervention opportunities and assess the impact of their efforts. It is highly recommended to submit antimicrobial use data to the NHSN Antimicrobial Use module to allow benchmarking with the use of the standardized antimicrobial administration ratio.8 Tracking of both outcomes (including C. difficile infections, resistance and financial impact) and process metrics is also recommended. Priority process measures include intervention types and acceptance rates, ensuring PA does not delay therapy and adherence to institution specific treatment guidelines.
6. Reporting: The CDC continues to recommend ASPs report antimicrobial use and resistance to hospital staff and leaders on a regular basis. Provider-level feedback is an effective outpatient ASP strategy; however, limited data exists for hospital ASPs given the complexity of inpatient prescribing.
7. Education: Antimicrobial stewardship education is important for many disciplines including prescribers, nurses and pharmacists. A variety of ways to provide education exist including a case-based approach through PAF or PA. For pharmacists specifically, SIDP, ASHP and CDC developed a campaign on the 5 Ways Hospital Pharmacists Can Be Antibiotic Aware. Hospital pharmacists should (1) verify penicillin allergies, (2) avoid duplicative anaerobic coverage, (3) reassess antibiotic therapy, (4) avoid treatment of asymptomatic bacteriuria and (5) use the shortest effective duration possible. Additional campaign material can be found at www.sidp.org/AMRchallenge.
In conclusion, as antimicrobial resistance continues to evolve, so too must antimicrobial stewardship practices. Hospital ASPs should work to incorporate the updated Core Elements to combat current and developing antibiotic resistance threats.
By: Gadison Quick, PharmD; PGY1 Pharmacy Resident
Mentor: Kerry Yamada, PharmD, BCPS; PGY-1 Pharmacy Residency Coordinator, Truman Medical Center – Kansas City, Mo
Program Number: 2020-11-01
Approval Dates: December 1, 2020 to May 1, 2021
TAKE CE QUIZ
Electrolyte disorders like hyponatremia or hypernatremia are not diseases, but rather a pathophysiologic process indicating a disturbance in water homeostasis.1 Sodium is abundantly used throughout every major body system to maintain homeostasis. One of sodium’s many vital roles is to help maintain normal fluid volumes throughout various intracellular and extracellular compartments.2 Sodium and blood osmolarity are highly dependent upon each other, hence the phrase “where goes water, goes salt”. Physiologically, we see if the serum sodium concentrations (SNa) are elevated (>145mEq/L), fluid will move into plasma to dilute the high sodium concentration. Likewise, if SNa is low (<135mEq/L) fluid will move out of the plasma to concentrate and correct the sodium concentration. Understanding the pathophysiology related to changes in sodium concentrations, as well as serum osmolarity (SOsm) will help identify the underlying causes of sodium disorders and allow for a proper treatment course in clinical practice. This review will not be highlighting gaps in therapy, or new treatments, but rather review the complexity of sodium disorders in practice. It is necessary to periodically review the foundations of physiology to appreciate treating the patient rather than the number.
Symptomatic vs Asymptomatic Hyponatremia
Hyponatremia defined as a SNa <135mEq/L is a common electrolyte disorder that possess a therapeutic challenge when treating in clinical practice. Hyponatremia can be categorized based on sodium concentration, timing of onset, presence of symptoms, serum osmolarity, and fluid status. The vast categorization of hyponatremia can easily confuse practitioners and make identifying and treating the underlying cause difficult. Currently there are two sets of guidelines developed discussing the management of hyponatremia. One by professional organizations within the United States (“American guideline”) and one from within Europe (“European guideline”).3
Recognizing symptomatic hyponatremia is vital for patient outcomes, as severe symptomatic hyponatremia is life threatening and requires emergent intervention. Key symptoms to monitor for when assessing symptomatic hyponatremia can be divided into either moderately severe or severe symptoms. Moderately severe symptoms include nausea, vomiting, altered mental status, and headache. Severe symptoms can include cardiac arrest, deep somnolence, seizures, or coma. Both the European and American guidelines recommend aggressive therapy with infusion of hypertonic saline in the presence of symptoms. However, dosing differs between guidelines. The American guidelines recommend a 10 minute infusion of 100ml of 3% saline repeated 3 times as needed versus the European guideline recommendations of 2 150ml boluses of 3% saline each over 20 minutes. Although both guidelines recommend a rapid, intermittent treatment using hypertonic saline, there is also literature to support an alternative dosing strategy with a slow continuous infusion of hypertonic saline to minimize the risk of overcorrection. The SALSA trial is one trial currently being conducted comparing rapid intermittent infusion of hypertonic saline versus slow continuous infusion of hypertonic saline. Additionally, Garrahy et al5 compared rapid, intermittent infusion vs slow, continuous infusion of hypertonic saline in symptomatic hyponatremia patients with syndrome of inappropriate antidiuretic hormone (SIADH). This study concluded intermittent bolus dosing of hypertonic saline resolved serum sodium levels quicker, and had a positive effect on patient’s Glasgow-Coma Scale (GCS) score. Additionally, this study did not have any cases of osmotic demyelination syndrome (ODS) in either group, therefore this study reinforces guideline recommendations to use rapid, intermittent doses of hypertonic saline in symptomatic hyponatremic cases.
Asymptomatic hyponatremia is much more common in practice, but requires careful evaluation in order to identify the underlying cause. A stepwise approach is key when determining the correct underlying factor. The first step in this stepwise approach is to determine if your patient is truly hyponatremic without other confounding factors like hyperglycemia. Second, check the serum osmolarity. Various institutions may have different absolute cutoffs for osmolarity, but a standard serum osmolarity (SOsm) ranges from 275-290mOsm/kg. Identifying the serum osmolarity will help you determine whether this is a hypotonic, isotonic, or hypertonic disorder. Third, evaluate the fluid status. Does your patient have signs of dehydration or excess fluid? For example, signs of dehydration or low fluid volume can include hypotension, tachycardia, polydipsia, weight loss, dry mucous membranes, sunken eyes, decreased skin turgor, and increased capillary refill time. On the other hand, signs of excessive fluid status can included hypertension, shortness of breath, weight gain, peripheral edema, ascites, and a positive jugular venous distension (JVD). Lastly, ordering a urinalysis to assess urine sodium and urine osmolarity will allow you to assess for salt wasting syndromes, or dilution of sodium.
Approaching hyponatremia in a stepwise process can help the practitioner approach each case in a more simplified manner. The next step to treating hyponatremia is to recognize the various categories, that being hypotonic hyponatremia, isotonic hyponatremia, and finally hypertonic hyponatremia. The latter two are less complex, and easier to recognize; therefore will be discussed first before moving onto hypotonic hyponatremia. First, isotonic hyponatremia, also known as “pseudo-hyponatremia” is classified as a falsely low SNa. The falsely low SNa is due to excess substances in the plasma. These excessive substances can include triglycerides, cholesterol, and plasma protein. Mathematical equations can be utilized to predict the true SNa but the treatment of this process is to treat the underlying cause.
Plasma triglycerides (g/L)x 0.002=mEq/L decrease in Na
Plasma Protein- 8(g/L)x 0.025=mEq/L decrease in Na
Second is hypertonic hyponatremia. The etiology of hypertonic hyponatremia is similar to isotonic hyponatremia in that SNa is falsely low due to an excess of serum substances, specifically in this case glucose. Hypertonic hyponatremia is commonly seen in hyperglycemic states like diabetic ketoacidosis (DKA) or hyperosmotic hyperglycemic state (HHS). Similar to isotonic hyponatremia, there is a mathematical equation used to predict the true SNa, as well as the treatment goal to treat the underlying cause.
Corrected Sodium=measured sodium+1.6 ((serum glucose-100))/100
Moving onto the third and last, but easily the most complex hyponatremic disorder is hypotonic hyponatremia. This category of hyponatremia can be more complex because this disorder is further categorized based on patient fluid status. Because of the vast sub-categorization within this disorder, it is worth mentioning again the importance to use the previously mentioned stepwise approach to identify the underlying disorder. First using the stepwise approach, hypotonic hypovolemic hyponatremia, can be identified by recognizing SNa <135mEq/L, SOsm <275mOsm/kg, and finally incorporating patient specific symptoms of dehydration. The next step is to identify urine sodium (UrNa) and urine osmolarity (UrOsm). Measurement of UrNa and UrOsm can help distinguish between disorders like SIADH and hypervolemic hyponatremia.6 Increased concentrations of UrNa and UrOsm in this case can be due from renal losses of sodium, including an excess of diuresis, or a deficiency in aldosterone. Diuretics work by blocking the reabsorption of electrolytes, and subsequently water, and therefore in states where diuretics are used in excess, a higher ratio of sodium, and other electrolytes can be found in the urine. Secondly, aldosterone is an endogenous mineralocorticoid secreted by the adrenal glands, and regulated by the renin-angiotensin-aldosterone system. Aldosterone is secreted in response to low systemic blood pressure, or increased serum potassium. It works by regulating the nephrons to retain a higher amount of sodium and water, while also secreting more potassium into the filtrate to increase blood pressure and decrease potassium. In states with a deficiency of aldosterone, the nephron fails to retain sodium and a higher concentration of sodium is eliminated in the urine. On the other hand, if the urine study shows a diluted sodium and osmolarity, the loss of sodium is from a non-renal source, whether that be gastrointestinal in the form of emesis or diarrhea, blood loss or skin loss, in the form of burns, open wounds, or excessive diaphoresis. Regardless of the source of non-renal loss, treating the underlying cause will correct the low SNa.
Taking the same stepwise approach to hypotonic euvolemic hyponatremia, objectively will show a low SNa <135mEq/L, low SOsm <275mOsm/kg, but with an absence of patient symptoms for both dehydration, and edema. Examining the urine study, a diluted urine osmolarity can be due from beer potomania, or psychogenic polydipsia. Beer potomania is a unique syndrome of hyponatremia,7 as alcohol, in this case, beer combined with a poor diet causes a dilution hyponatremia. Remembering water reabsorption in the nephrons of the kidney is dependent on the reabsorption of solutes and electrolytes, if a patient were to have poor intake of solutes and electrolytes, the kidney would not be able to reabsorb water in normal homeostasis, leading to more free water in the urine, and thus a diluted UrOsm. Secondly, in psychogenic polydipsia (PPD), there is a disruption in the thirst control mechanism related to the endocrine system. Although PPD is most commonly seen in chronic schizophrenia, other mental illnesses including psychotic depression and bipolar disorder can portray polydipsia behavior.8 The pathogenesis of the polydipsia may be related to a hypersensitivity to vasopressin, an increase in dopamine activity, or a defect in osmoregulation.8 The mainstay of treatment for PPD is fluid restriction, as excessive fluid intake can lead to life-threatening water intoxication, manifesting as symptomatic hyponatremia. On the other hand, when examining the urine study, and UrOsm is concentrated, the underlying disorder can include hypothyroidism, glucocorticoid deficiency, or most commonly SIADH. Hypothyroidism is a common disease affecting millions of Americans, and countless others across the globe every year. Patients with moderate to severe hypothyroidism and mainly patients with myxedema may exhibit reduced sodium levels.10 The main mechanism related to hypothyroidism-associated hyponatremia is due to a decreased capacity of free water excretion secondary to elevated antidiuretic hormone (ADH) levels. The hypothyroidism-induced decrease in cardiac output (CO) stimulates carotid baroreceptors to release more ADH to retain fluid, and increase CO. This overtime causes a buildup of ADH, and subsequently a dilution of SNa. Next, relating hyponatremia to glucocorticoid deficiency, the mechanism of hyponatremia seen in glucocorticoid deficiency is similar to what was previously discussed with hypothyroidism-induced hyponatremia. A lack in the principle glucocorticoid cortisol may cause a reduction in systemic blood pressure and CO, stimulating a release of ADH. However, a second mechanism may be related to glucocorticoid deficiency-induced hyponatremia in that cortisol deficiency results in increased hypothalamic secretion of corticotropin releasing hormone (CRH), an ADH secretagogue.10 Lastly, and most commonly observed in practice in euvolemic hyponatremia is SIADH, which is a condition defined by the unsuppressed release of ADH. ADH is a hormone that stimulates water reabsorption in the kidney, primarily through stimulating the insertion of aquaporins to help the nephron reabsorb more water. When left unsuppressed, copious amounts of water gets reabsorbed back into the serum, causing SNa to be diluted. SIADH is most commonly treated non-pharmacologically through fluid restricting, however pharmacologic options are available including loop diuretics, vasopressin receptor antagonists (aka “vaptans”), and demeclocycline. Conivaptan (Vaprisol®) and tolvaptan (Samsca®) are examples of vaptans. Conivaptan is only available IV, while tolvaptan is available PO. These medications should be used cautiously as they can unpredictably change SNa and in some instances overcorrect. Secondly, these medications are hepatotoxic, and should be avoided in hepatic dysfunction. Demeclocycline (Declomycin®) is a tetracycline antibiotic that blocks ADH. It is only orally available, has a long onset of action, and is not recommended in patents with renal or hepatic dysfunction. One last point is as pharmacists, it is important to monitor for medication-induced disorders. Although there is a plethora of medications that have been linked to SIADH, the five most common drug classes related to medication-induced SIADH include antidepressants, anticonvulsants, antipsychotics, cytotoxic agents, and pain medications, and more specifically selective serotonin reuptake inhibitors (SSRIs), and carbamazepine are among the most common agents.
Lastly, in hypotonic, hypervolemic hyponatremia, patient’s objectively will have a SNa <135mEq/L, SOsm <275mOsm/kg, but ultimately are fluid overloaded. Signs and symptoms of fluid overload have been previously mentioned in the content and should be applied here. This category of hyponatremia may be the most straightforward as it can be theorized the excessive fluid dilutes sodium, causing SNa to drop below normal limits. Disease states that can cause a buildup of fluid in this scenario can include liver cirrhosis, heart failure, and kidney failure. Treating the underlying disease state, in combination with fluid diuresis can help raise the SNa back within to normal limits.
As previously discussed, some hyponatremic disorders are treated with fluids, while others are treated with fluid restriction. When the underlying condition warrants the need for fluids. It is imperative to know how much sodium the body is deficient in, and how much fluid is theoretically necessary to correct the problem. There is a mathematical equation that can be used to figure out the total body deficit of sodium. Once calculating the total body deficit of sodium, a practitioner can translate that amount to a volume of fluid needed to correct the electrolyte imbalance.
Total Body Na Deficit (mEq)=(desired Na-serum Na) x TBW
TBW=weight (kg) x correction factor
Each liter of crystalloid fluid contains a different amount of sodium. As previously mentioned, once the total body sodium deficit is calculated, one can theoretically predict how much volume of fluid is needed to correct the electrolyte.
Although less commonly seen in clinical practice, hypernatremia on the other hand can also present in practice. It is seen as the opposite of hyponatremia by having an excess of solute, and a deficit of water. Hypernatremia can be categorized by volume status just like hyponatremia. The same causes of hypovolemic hyponatremia can further progress and lead to hypovolemic hypernatremia. As a reminder, these causes can include emesis, diarrhea, skin loss through open wounds, or burns, as well as excessive diaphoresis. Other causes that have not been previously mentioned include water loss from hyperventilation, and nasogastric sanctioning. In euvolemic hypernatremia, a condition known as diabetes insipidus can cause a lack of ADH, leading to excessive water wasting in the urine and a more concentrated serum. Diabetes insipidus (DI) is commonly known to be the exact opposite to SIADH and can be divided into either central DI or nephrogenic DI. In central DI, there is a disruption in normal ADH production, storage, and release. On the other hand, in nephrogenic DI, the aquaporins responsible for water reabsorption are not able to insert themselves into the nephron, failing to reabsorb water. Lastly, hypervolemic hypernatremia is usually the result of a large amount of fluid, overcorrecting hyponatremia with hypertonic saline, sodium bicarbonate, or even hormonally via Cushing syndrome, or primary hyperaldosteronism. Cushing syndrome is an excess of glucocorticoids, which can impair the hypothalamic-pituitary axis (HPA) and cause a lack of osmoregulation through ADH. The mechanism of aldosterone has been previously discussed, but reiterating it to hypervolemic hypernatremia, an excess of aldosterone causes sodium and water reabsorption, leading to increase volume, and increase SNa. Regardless of volume status as it relates to hypernatremia, it is always key to calculate the water deficit to correct the problem.
Water deficit (liters)=TBW x [((serum Na)/140)-1]
Using the mathematical equation provided above will help practitioners know how much fluid to theoretically give to allow the SNa to retreat to within normal limits. However, it is vital to closely monitor as in clinical practice, this water deficit calculation can often over-predict, putting patients at risk for rapid changes in SNa. When replacing the deficit, replace half of the deficit over the first 24 hours, and the remaining over the next 24-72 hours, always keeping into account never to decrease SNa >10-12mEq/L per 24 hours.
Rate of Correction
The rate of correcting SNa should be closely monitored, as the consequences of a rapid increase in SNa can lead to osmotic demyelination syndrome, while a rapid decrease in SNa can lead to cerebral edema. Regardless, both are deadly and difficult to reverse once a patient begins to exhibit symptoms. Both the European and American guidelines agree the correction of SNa should not exceed 10mEq per 24 hours. Additionally the American guidelines elaborate on this recommendation, and further recommend an even more conservative approach of 8mEq/24 hours correction in patients at high risk for ODS. Patients who are at high risk for ODS include hyperkalemia, alcoholism, liver disease, and malnutrition.4 The more conservative approach in these patients come from case reports of post-therapeutic neurologic complications after correction with once thought to be safe conservative therapy.
In summary, sodium is one of the most abundant solutes disturbed throughout the body and human cells rely on osmoregulation to maintain homeostasis. When there is a breakdown in this osmoregulation, an uneven distribution of solute and water causes a shift in normal cell physiology, which can manifest into life-threatening complications. Early recognition of symptomatic hyponatremia is vital to provide positive patient outcomes. As noted, sodium imbalances can be vastly sub-categorized based on the underlying cause and can easily confuse practitioners. Therefore by taking a stepwise approach when investigating the objective data available can help the provider identify the most pertinent underlying cause of the electrolyte imbalance. Practitioners can then easily calculate a theoretical amount of either solute or fluid needed to correct the imbalance. Remembering to correct the imbalance slowly over hours to days will help ensure life-threatening complications of overcorrection are avoided.