By: Kacee Verhovec, PharmD; PGY1 Community-Based Pharmacy Resident
Mentor: Michelle Jeon, Pharm.D., BCACP, Walgreens/St. Louis College of Pharmacy
In August 2019, concerns about electronic cigarette use began to grow after the first death associated with the inhaled product was reported.1 Within several months, the death toll reached 68 in February 2020 with nearly 3,000 additional cases leading to hospitalization.2 Unfortunately, safety concerns continued to grow as electronic cigarettes gained popularity in the younger population. How did we get to this point?
The History of Smoking:
In 1492, Christopher Columbus “sailed the ocean blue,” bringing tobacco leaves back to Spain acquired from the Native Americans. Popularity quickly spread throughout Spain and all of Europe. During this time, many believed smoking had curative properties. As a result, tobacco was considered a protected crop and was rationed during times of war. It wasn’t until 1795 when tobacco smoking was linked to a negative health outcome: lip cancer.3 This was followed with a link to lung cancer in 1912. However, this was not reported by the United States (US) Surgeon General until 1964. Shortly after, secondhand smoke was also linked to cancer, leading to age limits on tobacco sales (age 18 beginning in 1992), required health warnings, public smoking bans, and smoking cessation assistance with the nicotine patch first released in 1992.4
In 2003, Chinese pharmacist Hon Lik invented the first electronic cigarette. He was inspired to create this product after witnessing his father die from lung cancer caused by long-term heavy cigarette smoking, in attempts to create a product to help others quit. Shortly after its release, countries around the world began implementing bans on these products, however regulation of these products by the Food and Drug Association (FDA) was implemented nearly 10 years after its release. Age limits for purchasing electronic cigarette products were not implemented until 2018, leading to younger people utilizing these products often due to ease of access.5 Bans of these products did not occur in the US until June 2019 in San Francisco. The first death linked to electronic cigarette use was reported in August 2019.6,7 At the present time, Federal tobacco sales increased to 21years old in December 2019, but questions remain surrounding the future of electronic cigarettes, their regulations, and if they have positive benefit.8
The Pathophysiology of Nicotine Addiction:
The most recent data from the Centers for Disease Control (CDC) indicates that 14% of the US population are smokers, which has been on a decline since 2005. It is estimated that 70% of this population would like to quit and many find the quitting process to be difficult.9
Nicotine is a sympathomimetic that activates the nicotinic receptors in our bodies and most notably, in our brain within the cerebral cortex and limbic system. With this activation, neurotransmitters such as dopamine are released, leading to the rewards pathway and effects of elevated mood and reduced tension, this pathway is shown in Figure 1 above. As nicotine levels decrease after metabolism, the body requires more to continue receptor activation and neurotransmitter release.10 Without more nicotine, the body will go through withdrawal leading to side effects such as cravings, anxiety, and irritability, most frequently leading to additional nicotine intake to relieve these effects. Symptoms typically occur within 1-2 days without nicotine. If nicotine is not replaced, these withdrawal symptoms typically last 2-4 weeks depending on the length of time a person has smoked and the amount a person typically smoked in order to achieve the positive nicotinic effects.11,12
The amount of nicotine required to achieve its desired effects depends on the length of time a person has smoked as nicotinic receptors eventually become desensitized. Desensitization of nicotine receptors requires more nicotine to achieve the positive effects. Utilizing this additional nicotine due to desensitized nicotinic receptors is not associated with the negative side effects typically associated with high amounts.13 Tolerance is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as having one or both of the following: 1. “absence of nausea, dizziness, or other characteristic symptoms despite using substantial amounts of nicotine” or 2. “diminished effect observed with continued use of the same amount of nicotine-containing products.”14 Because of this cycle, smokers tend to have a difficult time with quitting. The CDC estimates that 87% of adult smokers started smoking as adolescents.9 Increased length of smoking history may cause quit attempts to be even more difficult with resulting increased severity of withdrawal symptoms.13 Cigarette smokers have attempted to quit by utilizing electronic cigarettes as many of these products contain nicotine allowing smokers to continue obtaining nicotine without the additional harmful components of cigarettes such as tar.15
A survey of adult electronic cigarette (also known as e-cigarettes) users conducted in the Netherlands and Belgium identified the number one reason for e-cigarette use was to quit smoking. 94% of those surveyed believed electronic cigarettes were “healthier” than smoking cigarettes.15 A following CDC survey reported that the most popular reason for adolescent e-cigarette users initiating use was curiosity.16
Images of a Tanks and mods, rechargeable e-cigarette, and a disposable e-cigarette.
There are several different types of electronic cigarettes available in various designs, but each electronic cigarette has three key components to them: battery, atomizer, and inhaler. The battery allows for the electronic cigarettes to heat up the liquid. The atomizer contains coils attached to the battery that are soaked in the liquid to be vaporized. When these coils are heated, they subsequently heat the liquid atop the coil itself. Heating this liquid results in evaporation. The vapor is then contained within the atomizer allowing this to eventually be inhaled. The inhaler is the mouthpiece used to inhale the vapor contained within the atomizer.17
The liquid added to the device that is to be vaporized (also known as e-liquid) may contain a variety of ingredients.18 The majority of e-liquids contain a base, most frequently containing distilled water, propylene glycol, and vegetable glycerin, a flavoring, and at times nicotine or tetrahydrocannabinol (THC). Not all e-liquid contains nicotine or THC as some are designed to contain only flavoring to attract users.18,19
E-liquids containing nicotine typically equate to one pack of cigarettes per milliliter of liquid (although this may vary depending on the concentration purchased); most bottles of liquid contain around 30 milliliters. One bottle typically costs around $15, making this an attractive option for those attempting to quit for financial reasons.20
Potential Benefits of Electronic Cigarette Use:
At this time, numerous studies have been conducted that suggest the utility of e-cigarettes for smoking cessation. One study published in February 2019 in the United Kingdom, compared the safety and efficacy of e-cigarettes to traditional nicotine replacement therapy for smoking cessation. This study enrolled adult smokers willing to quit in an unblinded randomized controlled trial.21
At 4 weeks, both products led to abstention from cigarettes, but the e-cigarette group showed statistically significant rates of abstention compared to the traditional NRT group, data shown in Figure 3 below. At 52 weeks, both groups continued to show a decline in those continuing to abstain from cigarette smoking, however the e-cigarette group continued to have a higher percentage of patients abstaining from cigarette use. This study also showed improvements in side effects frequently caused by cigarette smoking in the e-cigarette group such as increased phlegm production, cough, wheezing, and dyspnea shown in Figure 4; this was hypothesized to be associated with the higher amount of patients abstaining from cigarette smoking in the e-cigarette group.21
This study also identified that 80% of those in the e-cigarette group who remained abstinent to cigarettes at 52 weeks were still continuing to use the e-cigarette device compared to roughly 9% in the traditional nicotine replacement product group shown in Figure 5. Leading the authors to question if e-cigarettes were a replacement to cigarette smoking rather than a tool for overall complete cessation.21
Risks of E-Cigarette Use:
In the previous study discussed, the e-cigarettes did not come without side effects. Figure 6 lists the most common side effects cited included nausea, throat/mouth irritation, and sleep disturbances; however, throat/mouth irritation was the only side effect cited to be more common in the e-cigarette group compared to the traditional nicotine replacement therapy group.21 Outside of this study, e-cigarettes have also been linked to endothelium changes in vessels, seizures, and physical injuries due to device malfunctions.22,23,24 The vapors produced by these products, including the second-hand smoke, contain harmful organic and inorganic chemicals such as formaldehyde and heavy metals.25 The deaths reported in August 2019 were associated with a peculiar lung injury only present in those with a recent history of e-cigarette use. Since then, the injury has been named “E-cigarette or vaping product use-associated lung injury” or “EVALI.”1,26
EVALI is diagnosed by the following: having symptoms consistent with EVALI, e-cigarette use within the last 90 days, and abnormal chest imaging (most frequently as bilateral ground glass opacities in the lower lobes). Symptoms of EVLAI are not nonspecific. The majority of patients diagnosed show respiratory symptoms such as dyspnea, hypoxemia, cough, chest pain, and hemoptysis. However, 77% of patients also have gastrointestinal complaints such as nausea, vomiting, and diarrhea as well as symptoms such as fatigue, headache, and weight loss. Patients may also show non-specific signs and symptoms such as fever, leukocytosis, and elevated liver function tests. Case reports led to questions of what would be causing such injuries. In the first case series addressing the issue, 89% of those studied reported THC product use within their devices.26,27
THC has become popular over the last few years with more states legalizing its use. A survey attempted to determine what attracted users of THC products within e-cigarettes to use these products instead of smoking cannabis products. The survey revealed using e-cigarettes (or vaping) THC tasted better or cleaner than other routes. Other reasons to vape THC products instead of smoking them included this was easier to conceal as the smell is not as strong, it is convenient, and it produces a stronger high than other routes.28
Some patients presenting with EVALI who reveale a history of vaping THC products underwent bronchi alveolar lavage (BAL) revealing a non-infectious disease, non-specific inflammation, and increased levels of lipid-laden alveolar macrophages.26 Alveolar macrophages act as the first line of defense for the lungs, clearing foreign bodies including external lipids. While it is normal to have a small amount of lipid-laden macrophages on the results of a BAL, these patients showed an excessive amount. This finding led to further testing of vaped THC products.29 It was identified that 94% of these products contained vitamin E acetate, a lipid containing additive.26 While the most popular THC-containing e-liquids did not report such additives, many did display warnings of fake products being sold.30,31 THC solutions have a naturally high viscosity, especially in comparison to nicotine solutions. Vitamin E acetate has a viscosity similar to THC and is often used as a thickening agent in fake products to deceive consumers.32
Vitamin E acetate is a problem in the lungs for two main reasons. First, vitamin E acetate has shown to penetrate lung surfactants, leading to a loss of surface tension. This eventually may result in damaged lung tissue, and increased risk of a collapsed lung. Another mechanism in which vitamin E acetate damages the lungs is when heated, vitamin E acetate breaks down into 30-ketene, a known lung irritant. This metabolite can cause inflammation in the lungs and eventual damage to the tissue.32 When mice were exposed to vitamin E acetate aerosols, the BAL performed showed very similar results to humans including this increase in lipid-laden alveolar macrophages.33
It is important to note that although there have been some potential benefits with utilizing these products, in particular for smoking cessation, there are risks that we currently know and risks we may not. Centuries passed before negative health effects were definitively associated with cigarette smoking, while e-cigarettes have only been around since 2006.5
Rules and Regulations of Electronic Cigarettes:
FDA regulations on e-cigarette products did not occur until 2016, about ten years after its introduction to the United States. The federal minimum age limit for purchase was set in 2018 at 18 years old. 2016 FDA regulations cited that any product on the market prior to February 15, 2007 was exempt from FDA regulations and products on the market after that date was considered a new product. New products must be authorized by the FDA by September 9, 2020 to continue to be produced and sold.34 Therefore, there may still be products currently being sold that have not been approved by the FDA for sale.35 This approval process requires manufacturers to provide paperwork reporting product labeling, ingredients, advertisements, and warning label display.34
On December 20, 2019, the Federal Food, Drug, and Cosmetic Act was amended to increase the federal minimum age limit for purchase of tobacco products to 21, increasing the age from the previous limit of 18 years old.36 E-cigarettes and e-liquid are currently regulated as tobacco products, only if they contain nicotine.34 In 2019, 27% of high school students reported using e-cigarettes.37 To deter this age group from these products, several legislations at the federal and state level have been introduced, including a call for increased taxes on sale of these e-cigarettes and for banning of flavored e-liquids. Currently, Missouri has not implemented either of these.38
CDC Recommendations for E-Cigarette Use:
The CDC recognizes the potential risks and benefits associated with e-cigarette use and have recommended those not currently using combustible or non-combustible products such as e-cigarettes should not start using them. Pregnant women, adolescents, and young adults should never partake in vaping any products. However, those currently using e-cigarettes specifically for smoking cessation should not go back to using combustible products, should not utilize both e-cigarettes and combustible products at the same time, and should ensure e-liquids or devices come from a reputable source such as in-person e-cigarette or vape shops rather than online dealers, family, or friends. Other FDA-approved smoking cessation products would be preferred. The CDC also recommends against the use of THC products within e-cigarettes, especially those containing vitamin E acetate.39 The World Health Organization addresses these concerns similarly, however they address the lack of data behind e-cigarettes for smoking cessation and recommends currently known effective interventions for smoking cessation instead.40
The American Cancer Society agrees with the recommendations provided by the CDC however they also explicitly state being against the use of e-cigarettes for smoking cessation until a product is approved by the FDA to be used for this purpose alone.41 The American Lung Association states they do not support the use of e-cigarettes even for smoking cessation. They believe there should be increased regulations in regards to e-cigarettes.42 In addition, the American Medical Association agrees with these recommendations, calling for a total ban on e-cigarette products not meeting FDA approval as cessation tools and currently there are no such products available on the US market.43
The current recommendations for use from numerous health organizations all agree people should not start using e-cigarettes leisurely and agree there are still unknowns associated with the devices’ safety, however recommendations regarding cigarette smoking cessation is still widely controversial. It is important for pharmacists to provide as much education to patients regarding the use of e-cigarettes so users are fully informed of their widely unknown risks and possible benefits.
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By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain
Every time we turn on the TV or Twitter feed, we face a barrage of facts and opinions about rules. From masks to sports to school policy to social justice, it is impossible to ignore the fact that rules and rule-makers play a huge role in our everyday lives. It is also an interesting case study in the interplay among the rules at the federal, state, and local level, as well as how those rules play out in the real world of businesses and organizations and the family. When done well, rules level the playing field and keep us safe. While there are certainly huge differences in opinions about the definition of ‘good rules,’ everyone can agree that more input from more voices is the best way to create them. This is especially true when the data is conflicting and the basic understanding of the situation changes frequently. This type of scenario calls for leaders of bold vision who also ask questions and listen. Put simply, regulation in uncertain times requires participation. As MSHP members, we can participate by staying knowledgeable and getting involved.
Subscribe to newsletters, such as the Board of Pharmacy, MSHP, and ASHP. For example, our Missouri Board of Pharmacy has been very active as they have provided flexibility to Missouri pharmacies to deal with the pandemic response, and all of the information you need to know has been posted on the website and sent out via newsletters. You can subscribe to the ASHP Daily Briefing as well as Advocacy Updates and other options through your account NewsLink settings. You can also participate in the conversation on ASHP Connect. This MSHP newsletter is always informative, and MSHP is expanding our use of social media platforms to share information. Joint Commission, NABP, and USP also provide useful information. Read through the Pharmacy Practice Guide and the Department of Health hospital pharmacy rules. Schedule time on your work calendar or your personal calendar to catch up on current events in pharmacy and actually read those articles that are sitting in the “Read Me” folder. A small investment of time, consistently applied over weeks and months, will compound into a solid foundation of understanding.
Participate at your workplace as they work out the best plan for providing excellent pharmaceutical care in the ever-changing COVID landscape. Provide your input and your questions to the discussions about how to ensure that care, respect and opportunity is experienced by all patients and teammates, regardless of race. Join a committee or attend a live or virtual event to get involved with MSHP, with your regional chapter of MSHP, or with ASHP. Find out who your legislators are (link), and contact them. Let them know that pharmacists play an important role for our patients, and if we are given provider status we could do even more. It is an election year, so get educated and vote.
Uncertain times call for participation at all levels. As pharmacists, we have a responsibility to stay knowledgeable and get involved to ensure that our patients get the care that they need.
By: Nathan Hanson, PharmD, MS, BCPS
Have you ever wondered what the public policy committee does? As our previous article explained, you can learn about pharmacy by comparing it to sports, and in both settings, rules matter. (That has been taken to an extreme lately, because laws and rules have kept elite athletes on the sidelines!) The Public Policy Committee keeps an eye on 3 basic levels of pharmacy rules: Legislative, regulatory, and association. It has been a crazy couple months in healthcare rules, so we have put together just a few updates in all 3 spheres. Remember, MSHP matters. Collaboration is a priority. Things are changing. Stay engaged!
Legislative: Elected officials and votes
The Missouri legislative session wrapped up, after being significantly disrupted by COVID. Many of the legislative priorities were put on the backburner (think 2021), and a statewide Prescription Drug Monitoring Program was again voted down. However, a helpful proposal was passed that will make it safer for our patients to receive specialized compounded medications. When it has been signed by the governor MSHP will provide more information about how to implement this change. This is a patient safety improvement, and it was a wonderful example of MSHP working together with the Missouri Pharmacy Association and the Missouri Hospital Association to make a positive impact. We truly appreciate their leadership on this issue!
Regulatory: Government employees, inspectors, and boards
The Missouri Board of Pharmacy did an amazing job of responding to the public health emergency. They held multiple meetings and worked tirelessly over the past 3 months to ensure that they had done everything they could do to remove regulatory barriers that might get in the way of providing safe care to patients during the COVID emergency. Thankfully, many of the worst case scenarios did not materialize, but Missouri made a strong effort to be ready. The 2008 USP 797 standards will continue to be in effect, as the revisions go through the committee again. The FDA has finalized a document outlining clear regulatory cooperation with the state boards for interstate compounding. Each state board will review the document to determine if it meets the needs of their state.
Associations: Groups of thought leaders, providing best practices and direction for the profession
The 2020 ASHP House of Delegates has approved a slate of professional policies (link). These are designed to clearly explain the wishes and priorities of the 55,000 ASHP members. They are developed and approved with input from elected members from each state, including member of MSHP. MSHP Board of Directors approved guidance for safe implementation of a technician product verification program within the hospital setting. This guidance document was put to the membership for a vote and was passed. Stay tuned for more information.
By: Lauren Jacobsmeyer, PharmD
Sepsis is a life-threatening illness characterized by a dysregulation in host response to infection characterized by circulatory, cellular, and metabolic abnormalitites.1 Sepsis and septic shock affect millions around the world each year. Sepsis is a primary cause of mortality in Intensive Care Units (ICUs), and its incidence has doubled in the last 10 years.2 Greater than 50% of hospital deaths are due to sepsis with the mortality rate increasing as disease severity increases.3 Mortality rates are reported to range from 10 – 20% in patients diagnosed with sepsis and 40 – 80% in patients diagnosed with septic shock.3,4 In 2013, over $24 billion was spent in the United States on sepsis related hospital expenses, making sepsis the most costly inpatient disease state to manage.3 Based on the high rates of morbidity and mortality in combination with the large financial burden on the health care system, researchers are focused on identifying interventions that reduce sepsis related mortality. One of the most recent interventions of focus is the vitamin C, hydrocortisone, and thiamine three-drug combination.
Surviving Sepsis Campaign Guidelines1
In 2016, the Society of Critical Care Medicine released the Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock. The recommendations put forth in these guidelines were produced by a committee of 55 international experts representing 25 international organizations and serve as a current guideline for the provision of sepsis related care. These guidelines discuss interventions that have a proven mortality benefit in sepsis, including appropriate antimicrobial therapy and source control. They also explore various recommendations including interventions related to resuscitation techniques and adjunctive therapy for continued hemodynamic support including the use of corticosteroids. The guidelines recommend against the use of intravenous hydrocortisone if hemodynamic stability is restored with adequate fluid administration and vasopressor therapy. However, if adequate fluid resuscitation and vasopressor therapy are not able to restore hemodynamic stability, the guidelines suggest the use of intravenous hydrocortisone at a dose of 200 mg per day. This recommendation is classified as a weak recommendation based on a low quality of evidence. Currently, the guidelines make no recommendation regarding the use of the three-drug combination of vitamin C, hydrocortisone, and thiamine.
Steroids in Septic Shock
Steroid use in the setting of sepsis still remains controversial after the publication of the Surviving Sepsis Campaign Guidelines. It is important to note the weak recommendation with low quality evidence to use corticosteroids in the setting of refractory septic shock made by the Surviving Sepsis Campaign did not include evidence from two clinical trials due to the timing of publication. The two large clinical trials focusing on the use of corticosteroids in septic shock published following the publication of these guidelines include the ADRENAL5 and APROCCHSS6 trial.
Adjunctive Glucocorticoid Therapy in Patients with Septic Shock, or the ADRENAL trial, was published in March of 2018. In this multicenter, double-blind, parallel group, randomized controlled trial, researchers sought to determine whether hydrocortisone resulted in lower mortality than placebo amongst patients with septic shock. A total of 3658 patients were included in this trial with 1832 patients randomized to the hydrocortisone group and 1826 patients randomized to the placebo group. Patients in the hydrocortisone group received hydrocortisone 200 mg intravenously (IV) daily by continuous intravenous infusion (CIVI) over a period of 24 hours for seven days or until ICU discharge or death, whichever occurred first. All other aspects of sepsis related care were conducted at the discretion of the treating clinician. Baseline characteristics were well matched between the hydrocortisone group and placebo group. Patients mean age (±SD) was 62.3±14.9 years in the hydrocortisone group and 62.7±15.2 in the placebo group; the median APACHE II scores (IQR) were 24 (19 – 29) in the hydrocortisone group and 23 (18 – 29) in the placebo group. Patients with an APACHE II score ≥25 in the hydrocortisone group versus the placebo group was 45.9% versus 43.1%. Examining sepsis therapy at baseline, 99.5% of patients in the hydrocortisone group and 99.7% of patients in the placebo group were receiving an inotrope and/or vasopressor at the time of randomization and 98.3% and 98.1% of patients, respectively, were receiving antimicrobial agents at the time of randomization. Time from ICU admission to randomization in hours for the hydrocortisone group was 26.1±70.7 and for the placebo group 28.9±72.8 and time of shock onset to randomization was 20.9±91.9 versus 21.2±83.4, respectively. No difference was found in the primary outcome, 90-day all-cause mortality, between the hydrocortisone group and the placebo group, 27.9% versus 28.8% (OR 0.95; 95% CI 0.82 – 1.10; p = 0.50). Additionally, a statistically significant difference was not found in 28-day all-cause mortality between the hydrocortisone group and the placebo group, 22.3% vs. 24.3% (OR 0.89; 95% CI 0.76 – 1.03). One of the secondary outcomes demonstrated patients who received hydrocortisone had a quicker time to shock reversal with the median days to shock reversal (IQR) in the hydrocortisone group being 3 days (2-5) versus 4 days (2-9) in the placebo group (HR 1.32; 95% CI 1.23 – 1.41; p <0.001). Patients in the hydrocortisone group also had a shorter median (IQR) time to ICU discharge than the placebo group, 10 days (5 – 30) versus 12 days (6 – 42) (HR 1.14; 95% CI 1.06 – 1.23; p <0.001). Adverse effects were reported based on clinical judgment and were not an outcome measure of this study. Authors’ concluded among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day all-cause mortality than placebo.5
Hydrocortisone plus Fludrocortisone for Adults with Septic Shock, or the APROCCHSS trial, was also published in March of 2018. This was a multicenter, double-blind, 2-by-2 factorial design, randomized trial. Researchers sought to determine in adult patients admitted to the ICU if low dose hydrocortisone plus fludrocortisone for 7 days affects 90-day all-cause mortality. In total, 1241 patients were included, 614 patients in the hydrocortisone-plus-fludrocortisone group and 627 patients in the placebo group. Patients in the hydrocortisone-plus-fludrocortisone group received hydrocortisone 50 mg IV every 6 hours and fludrocortisone 50 mcg per nasogastric tube daily for seven days without taper and patients in the placebo group received matched placebo. Baseline characteristics were well matched between groups. The mean age (±SD) in years was 66±14 in the hydrocortisone-plus-fludrocortisone group versus 66±15 in the placebo group, and the SOFA score (±SD) was 12±3 in the hydrocortisone-plus-fludrocortisone group and 11±3 in the placebo group. Looking at sepsis related care, 96.9% of patients in the hydrocortisone-plus-fludrocortisone group received appropriate antimicrobial therapy versus 96.2% in the placebo group, and 86.9% of patients in the hydrocortisone-plus-fludrocortisone group were receiving norepinephrine at the time of randomization compared to 88.0% of patients in the placebo group. A statistically significant difference was found in the primary outcome, 90-day all-cause mortality with a mortality rate of 43.0% in the hydrocortisone-plus-fludrocortisone group versus 49.1% in the placebo group (RR 0.88; 95% CI 0.78 – 0.99; p = 0.03). Difference was also seen in additional mortality outcomes with the mortality rate being significantly lower in the hydrocortisone-plus-fludrocortisone group than the placebo group at ICU discharge (35.4% vs. 41.0%; p = 0.04), hospital discharge (39.0% vs. 45.3%; p = 0.02), and day 180 (46.6% vs. 52.5%; p = 0.04). However, no significant difference was seen in 28-day mortality rate between the hydrocortisone-plus-fludrocortisone group versus the placebo group (33.7% vs. 38.9%; p = 0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than the placebo group (17 ±11 vs. 15 ±11 days; p <0.001). There were no statistically significant differences in serious adverse events, gastroduodenal bleeding, rate of superinfection, new sepsis, or new septic shock between groups. A statistically significant difference was seen between the hydrocortisone-plus-fludrocortisone group versus control group in ≥1 episode of blood glucose levels ≥150 mg/dL by day 7 (89.1% vs. 83.1%; p = 0.002). The mean (±SD) number of days with ≥1 episode of blood glucose levels ≥150 mg/dL by day 7 was 4.3±2.5 in the hydrocortisone-plus-fludrocortisone group versus 3.4±2.5 in the placebo group (p <0.001). Authors’ concluded that in patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo.6
The ADRENAL and APROCCHSS trials demonstrate different outcomes regarding the mortality benefit of corticosteroids in patients with refractory septic shock, but both demonstrate quicker time to shock resolution with corticosteroid use. The use of corticosteroids in the setting of refractory septic shock remains controversial, but it is a standard of care at many institutions due to the shorter resolution of shock symptoms and arguable mortality benefit. In an effort to develop an intervention to reduce sepsis related mortality, researchers have begun to investigate the administration of corticosteroids in combination with vitamin C and thiamine.
Vitamin C, Hydrocortisone, and Thiamine Combination Therapy
Vitamin C, hydrocortisone, and thiamine have been an interest of clinical research based on the pathophysiology supporting the three-drug combination, the minimal adverse effects associated with the medications, and the theoretical low-cost of the intervention. In the setting of sepsis, organ dysfunction can be attributed to a decrease in systemic vascular resistance resulting in decreased organ perfusion and thus decreased oxygen delivery. Organ dysfunction also occurs in sepsis in the absence of decreased organ perfusion. A variety of mechanisms have been proposed to cause organ dysfunction including mitochondrial dysfunction, a direct effect of the immune response to infection, microvascular abnormalities, and endothelial dysfunction. Traditional sepsis management including resuscitation with fluids and administration of vasopressors, focus on improving oxygen delivery to end organs. Vitamin C, hydrocortisone, and thiamine are theorized to provide overlapping and synergistic actions to target the non-oxygen delivery-dependent mechanisms of organ dysfunction.7,8
Hydrocortisone has long been theorized to benefit patients with septic shock because it decreases inflammation by suppression and migration of white blood cells and provides reversal of increased capillary permeability. Using stress dose steroids also supplements the adrenal dysfunction common in septic patients.7,8
In the setting of sepsis, reactive oxygen species (ROS) are produced in neutrophils. ROS invade and kill microorganisms but can also damage healthy host cells. Vitamin C serves as a potent antioxidant that decreases the damage caused to host cells due to ROS and protects many microvascular cellular functions that may be impaired during sepsis. Microvascular functions that vitamin C has been proven to protect in animal models include preserving tight junction, decreasing the microvascular permeability barrier, preserving capillary blood flow, and increasing arteriolar responsiveness to vasoconstrictors. Vitamin C has a relatively minimal side effect profile but most notably has been reported to cause hyperoxaluria, an excessive excretion of oxalate in the urine.7-10
The rationale for use of thiamine in the three-drug cocktail is two-fold. Thiamine works to prevent the formation of oxalate crystals in the kidneys, and it also treats a potential thiamine deficiency seen in septic patients. Thiamine plays an essential role in mitochondrial metabolism at the molecular level. Thiamine deficiency leads to impaired glucose metabolism, oxidative stress, glutamate excitotoxity, and inflammation. These metabolic derangements caused by thiamine deficiency can result in cell dysfunction and death. By providing thiamine, theoretically cell dysfunction and death can be prevented. Thiamine also provides a necessary cofactor for the metabolism of glyoxylate to oxalate, to prevent the development of hyperoxaluria in the setting of high-dose vitamin C administration. This prevents the development of renal impairment that is possible in the setting of hyperoxaluria.7,8,11
The three-drug combination together is theorized to work by hydrocortisone and vitamin C acting synergistically on multiple sites of the inflammatory cascade. Additionally, hydrocortisone facilitates the uptake of vitamin C into the cell by increasing the expression of sodium dependent transporters. Inside the cell, vitamin C is thought to restore the efficacy of glucocorticoid receptors providing the means for corticosteroids to work to prevent microvascular complications.7 Thiamine is used in the three-drug combination to prevent the development of hyperoxaluria by providing the necessary cofactor for the conversion of glyoxylate.8 The proposed synergy of these medications and the potential mortality benefit of this three-drug cocktail has been studied in limited clinical trials.
Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock12
The first study to examine the three-drug combination of vitamin C, hydrocortisone, and thiamine was published by Paul Marik and colleagues in 2017. This study was a single-center, retrospective, before-after clinical study that used historical controls to determine if intravenous vitamin C, hydrocortisone, and thiamine in addition to standard sepsis treatment, improve mortality in ICU patients with severe sepsis and septic shock, compared with standard treatment alone. In this before-after trial, the authors compared the outcomes and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a seven-month period. The control group was treated in the preceding seven months. Patients in the treatment group received vitamin C 1.5 g IV every 6 hours for four days or until ICU discharge, hydrocortisone 50 mg IV every 6 hours for 7 days or until ICU discharge followed by a taper over 3 days, and thiamine 200 mg IV every 12 hours for four days or until ICU discharge. All study medications were initiated within 24 hours of ICU admission. Sepsis related care was similar except for the administration of the vitamin C, hydrocortisone, and thiamine combination to the treatment group. Researchers noted there were no known significant changes to ICU protocols during the study period. Patients in the control group were allowed to receive hydrocortisone 50 mg IV every 6 hours at the discretion of the treating physician. Forty-seven patients were included in the treatment group as well as the control group. Baseline characteristics were well matched between groups. Mean (±SD) age in the treatment group was 58±14.1 years versus 62.2±14.3 years in the control group; both 46% of patients in the treatment and control group received vasopressor therapy; the day 1 SOFA score (mean ±SD) of patients in the treatment group was 8.3±2.8 versus 8.7±3.7 in the control group; and the APACHE II (mean ±SD) in the treatment group was 22.1±6.3 versus 22.6±5.7 in the control group.
A statistically significant difference was seen in the primary outcome, hospital mortality in the treatment group versus the control group (8.5% vs. 40.4%; p <0.001). Researchers also found statistically significant differences between the treatment group and control group for the secondary outcomes of duration of vasopressors and the change in SOFA score at 72 hours. The duration of vasopressors (mean ±SD) in hours in the treatment group was 18.3±9.8 versus 54.9±28.4 in the control group (p <0.001). The change in SOFA score at 72 hours was 4.8±2.4 in the treatment group versus 0.9±2.7 in the control group (p <0.001). Study researchers note 28/47 (59.6%) patients in the control group were treated with hydrocortisone since this was included in standard sepsis treatment.
The authors concluded the early use of intravenous vitamin C, moderate dose hydrocortisone, and thiamine may prove to be effective in preventing progressive organ dysfunction and reducing mortality in patients with severe sepsis and septic shock. However, authors discuss additional studies are required to confirm the preliminary findings of this study which was the first study to evaluate the vitamin C, hydrocortisone, and thiamine combination.
VITAMINS Randomized Clinical Trial13
Due to the study design and small sample size of the clinical trial conducted by Paul Marik and colleagues, it remained unclear whether vitamin C, hydrocortisone, and thiamine in combination provide a mortality benefit in septic shock patients. Investigators from the VITAMINS trial sought to determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.
This multicenter, open-label, randomized clinical trial was conducted in ten ICUs in Australia, New Zealand, and Brazil. Patients admitted to the ICU and with a primary diagnosis of septic shock based on the SEPSIS-3 definition were included in this trial. Patients in the trial were randomly assigned to the intervention group or the control group. The patients in the intervention group received vitamin C 1.5 g IV every 6 hours, hydrocortisone 50 mg IV every 6 hours and thiamine 200 mg IV every 12 hours, and patients in the control group received solely hydrocortisone 50 mg IV every 6 hours. The study intervention was continued until cessation of vasopressor administration or when any of the pre-defined stopping criteria were met. The predefined stopping criteria included shock resolution defined as when all vasopressors were discontinued for four consecutive hours in the presence of a mean arterial pressure (MAP) > 65 mmHg or achievement of MAP set by the treating clinician; 10 days of vitamin C and thiamine had been administered in the intervention group; 7 days of hydrocortisone had been delivered to the control group; death; discharge from the ICU; contraindications to any of the study drugs had arisen; or serious adverse events suspected to be related to a study medication developed. The primary outcome for this study was time alive and free of vasopressors at day 7 (168 hours) after randomization. This was defined as time, censored at 7 days, that a patient was both alive and had not received vasopressors for at least 4 hours. If a patient died while receiving vasopressor therapy following the initial episode of septic shock, the patient was assigned zero hours for the outcome. Additionally, if a patient was weaned from all vasopressors for 4 consecutive hours, then all of the remaining time through day 7 was treated as a success, even if the patient died or had vasopressors restarted after weaning within the 7-day period.
A total of 216 patients were included in this study, 109 patients in the intervention group and 107 in the control group. Baseline characteristics were similar between the two groups, however, baseline characteristics in this study were not compared to determine if there was a statistically significant difference at baseline between the intervention and control group. The mean (±SD) age of the intervention group was 61.9±15.9 years versus 61.6±13.9 years in the control group. The mean (±SD) APACHE III score in the intervention group was 77.4±29.7 versus 83.3±28.8 in the control group and the mean (±SD) SOFA score at admission was 8.6±2.7 in the intervention group and 8.4±2.7 in the control group. Patients could receive hydrocortisone prior to randomization with 42.1% of patients in the intervention group and 37.5% of patients in the control group receiving hydrocortisone prior to randomization. Vitamin C administration was not allowed in the control group since it was not a standard of care in study ICUs. Patients in the control group were allowed to receive thiamine at the discretion of the treating ICU clinician with 7.7% of patients in this group receiving thiamine. Median time from ICU admission to randomization in the intervention group was 13.7 hours (7.1 – 19.3) and in the control group 11.4 hours (5.5 – 17.8).
Researchers did not find a statistically significant difference in the primary outcome measurement of time alive and free of vasopressors up to day 7 between the intervention and control group. Median time alive and free of vasopressors up to day seven was 122.1 hours [76.3 – 145.4] in the intervention group versus 124.6 hours [82.1 – 147.0] in the control group (median of all paired differences between group, -0.6 hours (95% CI -8.3-7.2; p = 0.83). The only secondary outcome that demonstrated a statistically significance difference was the change in SOFA score at day three. Change in SOFA score at day 3 was significantly greater in the intervention group than the control group, with the median change in SOFA score -2 [-4-0] versus -1 (-3-0) (difference-1.0, 95% CI -1.9 to -0.1; p = 0.02). No significant between-group difference in 28-day all-cause mortality, 90-day all-cause mortality, ICU mortality, or hospital mortality were found. Additionally, no statistically significant between-group difference in 28-day cumulative vasopressor-free days, 28-day cumulative mechanical ventilation-free days, or 28-day cumulative renal replacement therapy-free days. Adverse events were reported based on clinician judgment and not a prespecified outcome. Two patients in the intervention group and one patient in the control group were noted to have adverse events.
Authors concluded in patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. They discuss these findings suggest treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to more rapid resolution of septic shock compared with intravenous hydrocortisone alone.
Comparing the Data12,13
Compared to the study conducted by Paul Marik and colleagues, the VITAMINS trial was the first randomized clinical trial examining the effect of the combination of vitamin C, thiamine, and hydrocortisone on sepsis. The VITAMINS trial included a larger number of patients than the study by Marik and colleagues and randomized patients to the intervention group or control group. However, in the VITAMINS trial researchers were not blinded to the study intervention. Even without investigator blinding, the design of the VITAMINS trial overcame many of the methodologic limitations of the single-center before-after study design used by Marik and colleagues.
Patients in the intervention group of the VITAMINS trial received the same dose of vitamin C, hydrocortisone, and thiamine that were administered to the patients in the study by Marik and colleagues. However, the treatment duration was longer in the VITAMINS trial providing a longer time period to see the effect of the intervention. Patients in the control group in the VITAMINS trial received hydrocortisone. The administration of hydrocortisone to patients in the control group in the trial by Marik and colleagues was not required, but 59.6% of patients in the control group received hydrocortisone based on discretion of the treating physician. Marik and colleagues did not conduct a subgroup analysis comparing the patients in the control group who received hydrocortisone to the patients in the intervention group.
A major limitation of both studies is the reporting of sepsis related cares. From previous data we know that appropriate antimicrobials and source control provide a mortality benefit in sepsis. The time to appropriate antimicrobials and the determination of appropriate antimicrobial administration was not reported in either of these studies. The amount of fluid resuscitation was also not quantified leading the reader to assume patients received appropriate resuscitation prior to the initiation of vitamin C, hydrocortisone, and thiamine. Without the knowledge regarding the provision of other sepsis related cares, it is hard to determine if the mortality benefit or lack of mortality benefit was due to the three-drug combination or other sepsis related cares.
Marik and colleagues found a statistically significant mortality benefit in the treatment group as well as quicker resolution in shock symptoms. These results were not repeated in the VITAMINS trial, where researchers found no significant difference in time alive and free of vasopressors at day 7. No difference was seen in any of the secondary mortality outcomes in the VITAMINS trial. Adverse effects were not a pre-specified outcome in either of these clinical trials. The results from these two trials are difficult to compare given the unknown sepsis related care provided to patients in each study. Based on current data, the mortality benefit from vitamin C, hydrocortisone, and thiamine remains questionable. The true adverse effects from this three-drug combination also remain unknown.
On the Horizon: VICTAS Clinical Trial14
To further examine the use of vitamin C, hydrocortisone, and thiamine in septic shock patients the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) trial is currently being conducted. This is a double-blind, placebo-controlled, adaptive randomized clinical trial designed to investigate the efficacy of the combined use of vitamin C, thiamine, and corticosteroids versus placebo in patients with sepsis. The objective of this study is to determine the efficacy of the vitamin C, hydrocortisone, and thiamine combination in reducing mortality and improving organ function in septic patients. A total of 501 patients have been included in this clinical trial with patients in the treatment group receiving vitamin C 1.5 g IV every 6 hours, hydrocortisone 50 mg IV every 6 hours, and thiamine 100 mg IV every 6 hours. The primary outcome looks at vasopressor and ventilator-free days at day 30 after randomization, calculated by recording all start and stop days for these measures. Secondary outcomes include 30-day all-cause mortality, ICU mortality, 180-day all-cause mortality, length of hospital stay and length of ICU stay. Per ClinicalTrials.gov, the VICTAS trial was completed in January 2020.
Even with new data regarding the use of a vitamin C, hydrocortisone, and thiamine three-drug combination in patients with septic shock, the actual mortality benefit of the intervention remains unknown. While the use of this combination is feasible in patients with septic shock, many questions regarding the three-drug combination remain unanswered including the optimal time of initiation, optimal medication doses, optimal treatment duration, and potential adverse effects. Additionally, questions remain if the benefit comes from the combination of vitamin C, hydrocortisone, and thiamine or if the benefit is due to a single agent. Further research is needed to determine the benefit of the vitamin C, hydrocortisone, and thiamine combination and answer the additional questions regarding the therapy. Based on limited data, the vitamin C, hydrocortisone, and thiamine combination has not shown negative clinical effects, but its place in sepsis care remains heavily debated causing inconsistency in clinical practice. To ensure the reduction of mortality in patients with sepsis, clinicians should first ensure all intervention proven to decrease mortality are implemented, including appropriate antimicrobial therapy and infection source control, prior to the initiation of the vitamin C, hydrocortisone, thiamine combination.
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By: Brandon Reynolds, PharmD, BCPS
Methicillin-resistant Staphylococcus aureus (MRSA) is found on the skin, axilla, groin, and nares, with the nares being the most common site of colonization.1 According to the Centers for Disease Control and Prevention (CDC) approximately 33% of patients have Staphylococcus aureus nasal colonization, while 2% harbor MRSA.2 Between methicillin-susceptible and MRSA strains, MRSA accounts for the majority of Staphylococcus aureus infections in intensive care units (ICUs).1 In one study published in 2010, patients with Staphylococcus aureus nasal colonization of either MRSA or methicillin-susceptible strains had between a two and four times higher risk of developing an ICU-acquired Staphylococcus aureus infection.3 In another study conducted by Eiff and colleagues, 85.7% of those nasally colonized with MRSA who later developed MRSA bacteremia had an identical strain of MRSA to that colonized in their nares.4 The association between Staphylococcus aureus nasal colonization and pathogenic infection provides a possible antimicrobial stewardship tool to improve the use of anti-infective drug therapy.
Medication therapy used in the treatment of MRSA infections typically includes vancomycin or linezolid based on the site of infection and patient-specific factors, with vancomycin being a commonly ordered first-line agent in several of the currently published guidelines by the Infectious Diseases Society of America (IDSA).5-11 Vancomycin therapy poses significant risks including nephrotoxicity, ototoxicity, and the development of antimicrobial resistance.12-13 Given these risks efforts to decrease the empiric use of vancomycin when it is not needed have become an important consideration for antimicrobial stewardship programs.13 Using MRSA nasal swabs to de-escalate antibiotics active against methicillin-resistant Staphylococcus aureus has gained traction with community acquired pneumonia,6 but the use of these swabs for other sites of infection with a risk of MRSA necessitates further evaluation. This review analyzes the evidence available for MRSA swabs in some of the disease states where anti-infective therapy active against MRSA is commonly used, including pneumonia, bacteremia, osteomyelitis, and skin and soft tissue infections.
In 2019, the community acquired pneumonia (CAP) guidelines published by the IDSA and the American Thoracic Society (ATS) were updated with a more pronounced stance on the use of MRSA nasal swabs than previous guideline iterations.6 The use of MRSA nasal swabs with polymerase chain reaction (PCR) evaluation is now recommended for some patients prior to starting antibiotics active against MRSA, and is also recommended as a tool to de-escalate MRSA coverage in patients already started on therapy.6 Regarding hospital-acquired and ventilator-associated pneumonia (HAP and VAP), the most recent guideline updates were published by IDSA and ATS in 2014.14 In this iteration, the use of MRSA nasal swabs to de-escalate or hold antibiotic therapy active against MRSA is limited, potentially due to a lack of available literature at the time of publication.
A meta-analysis of the current literature regarding the utility of MRSA nasal screens to rule out MRSA pneumonia was conducted in 2018 by Parente and colleagues.15 In this study, 22 trials were included for analysis, representing a total of 5163 patients. The results of this study are shown in table 1.
Table 1. MRSA nasal swab meta-analysis for pneumonia by Parente et al.
In this analysis by Parente and colleagues, MRSA nasal PCR tests were used in 12/22 studies. PCR-based methods had a sensitivity of 78% and a specificity of 92%. Culture-based methods had a sensitivity of 58% and a specificity of 88%. Negative predictive values were over 94% for all pneumonia types, including HAP and VAP. The high negative predictive values suggest a high likelihood that the infecting organism is not MRSA if none is detected in the nares, which allows the clinician to safely de-escalate therapy.
Findings such as these have prompted pharmacist-led antimicrobial stewardship initiatives such as pharmacist-ordered MRSA nasal swabs for patients receiving empiric antistaphylococcal antibiotic therapy for presumed pneumonia. One quasi-experimental study was performed by Pham and colleagues in their 350 community teaching hospital with a respiratory MRSA rate of 11% using PCR-based MRSA nasal swabs.16 In this institution, indications are required on any orders placed for antibiotic therapy. In patients receiving vancomycin or linezolid for any pneumonia indication without an extrapulmonary infection source, the pharmacist reviewing the antibiotic order could also order a STAT MRSA nasal swab per protocol without a physician order. The results of these nasal swabs were available 60 minutes after completion of the swab and when complete, the pharmacist would contact the provider regarding antibiotic de-escalation. In this study, 72 patients were included in the pre-implementation (physician required) group and 138 patients were included in the post-implementation (pharmacist-led) group. Notably, there were no patients with ventilator-associated pneumonia in either group. Compared with the pre-implementation group, the mean duration of intravenous vancomycin therapy decreased by 1.1 days (2.5 ± 1.3 days versus 1.4 ± 1.2 days, P <0.001) in all patients with pneumonia. In another community hospital study from Texas, Baby and colleagues published their findings supporting the implementation of nasal swab PCR testing as part of a pharmacist-led antimicrobial stewardship initiative.17 In this study, 27 patients were included in the pre-PCR testing group and 30 patients were included in the post-implementation cohort. Patients with healthcare-associated, community, and hospital-acquired pneumonia were enrolled. The use of nasal PCR testing decreased the mean duration of therapy active against MRSA by 46.6 hours (74.0 ± 48.9 hours versus 27.4 ± 18.7 hours, 95% confidence interval: 27.3 to 65.8 hours, P < 0.0001). There were no significant differences in days to clinical improvement, length of stay, or hospital mortality between groups.
Considering the relative challenge of obtaining high-quality respiratory specimens for culture in some patients, it would be prudent to consider the use of MRSA nasal swabs even in institutions where PCR testing is not available as a useful method of determining the need for MRSA therapy. A pharmacist-led approach may be an ideal method for promoting antimicrobial stewardship in this patient population without compromising clinical improvement.16,17
Staphylococcus aureus and coagulase-negative staphylococci are estimated to comprise ≥50% of osteomyelitis infections.18,19 For native vertebral osteomyelitis the IDSA guidelines note that blood cultures may be positive for Staphylococcus aureus in up to 50% of cases,11 and that it is recommended to collect blood cultures to assist in diagnosis and treatment. Considering that medical treatment for osteomyelitis often spans several weeks, proper identification of the infecting organism is strongly recommended by the IDSA,11 and bone biopsy is recommended as a standard of care. Likewise, there is a paucity of data available for the use of MRSA nasal swabs as a tool to prevent or de-escalate antibiotic regimens with activity against MRSA. Given this information, there is no recommendation that can be made for the use of MRSA nasal swabs in this disease state.
In 2008, Robicsek and colleagues published a retrospective cohort study analyzing the results of a universal MRSA nasal swab initiative at their 850-bed health system in Chicago, IL.20 In this study, the BD-GeneOhm real-time PCR test was used to analyze 57,089 nasal swabs. Of the total PCR tests obtained, 5,779 were performed within 24 hours of a positive culture. Culture sites included in the analysis are shown in Table 2. 1012 patients (18.5%) of patients received blood cultures. Of the confirmed cases of MRSA, 217 of 323 patients (67.2%) had a positive nasal PCR (confidence interval [CI]: 61.8, 72.3). Although two-thirds of patients with confirmed MRSA infections had positive MRSA nasal colonization, it could not be determined in this study if the infecting MRSA was identical to the colonizing MRSA strain. The nasal sampling results from this study are summarized in table 2.
From this study, the authors concluded that the negative predictive value derived in their patient population was high enough to consider using MRSA nasal swabs to rule out MRSA as an infecting organism in respiratory and bloodstream sources. They did, however, note that these results should be interpreted with caution due to the low prevalence of MRSA (5.6%) in their health system, and that the negative predictive value decreases as the disease prevalence increases. They also note the importance of the pre-test probability of MRSA infection as the MRSA nasal swab does have a relatively high false-negative risk. In conclusion, this study demonstrated that in an infection in any body site where MRSA accounts for ≤10% of isolates the negative predictive value is ≥96%, but decreases as the prevalence of MRSA infection increases. These findings stress the importance of institution-specific infection rates for correct interpretation of nasal swab testing campaigns.
Skin and Soft Tissue Infection
The 2014 IDSA guidelines for the diagnosis and management of skin and soft tissue infections do not recommend empiric anti-MRSA therapies for most patients with surgical site infections, simple cellulitis, erysipelas, or bite wounds.10 Despite these recommendations antibiotics active against MRSA are still frequently prescribed for common skin and soft tissue infections such as simple cellulitis without MRSA risk factors.21 The IDSA guidelines recognize the nares as an important predictor of MRSA skin and soft tissue infection. They recommend empiric anti-MRSA therapy in patients with a history of MRSA nasal colonization in both cellulitis and surgical site infections, and they also recommend nasal decolonization in patients with recurrent skin abscesses.10 In regards to simple cellulitis, a small retrospective study by Schleyer and colleagues22 assessed 52 patients with MRSA nasal swabs against cultures of their skin wounds. Superficial swabs were collected in cases of simple cellulitis without abscess (40% of cases) while 60% of cultures were collected from abscess fluid after incision and drainage. Staphylococcus species grew in 25 patients with 84% positive for MRSA. In this study, the nasal swab positive predictive value was 100% with a negative predictive value of 45% effectively ruling in MRSA, but failing to reliably rule-out disease. Superficial swabs are not recommended in simple cellulitis per the IDSA limiting the utility of this study, but these results may still support the use of an MRSA nasal swab as a tool to confirm the need for therapy active against MRSA in situations where these treatments are being considered. Of note, the IDSA does not currently have a stance on the use of MRSA nasal swabs to de-escalate therapy that has already started for these disease states.10
Decolonization of MRSA
Since MRSA nasal colonization has been associated with an increased risk of MRSA infection,3,4 decolonization of MRSA in known carriers is a strong consideration for improving infection rates. In a review by Troeman and colleagues in 2019,23 several potential ways to decrease MRSA colonization were highlighted including nasal mupirocin, chlorhexidine gluconate, povidone-iodine, trimethoprim/sulfamethoxazole, rifampicin, polyhexanide, and selective oropharyngeal decontamination. In this review, 54 trials were analyzed. There were very few high quality evidence trials that exclusively used one of the previously mentioned methods, however, mupirocin was found to have sufficient evidence to justify recommendations. The trials that analyzed mupirocin are summarized in Table 3.
Based on the data by Troeman and colleagues, decolonization of nasal S. aureus using mupirocin has varying effects on the risk of S. aureus infection rates. In known carriers receiving dialysis or elective surgery it is reasonable to pursue decolonization. In ICU patients, universal decolonization of carriers, non-carriers, and patients with unknown carrier status using both mupirocin and daily bathing with chlorhexidine could be considered as an initiative to reduce MRSA infections in units with a significant disease burden.
Organism Detection After Anti-MRSA Therapy
In most infectious diseases, the initiation of antibiotic therapy before collection of culture risks decreasing yield resulting in continuation of broad-spectrum antibiotics when more narrow therapies would be appropriate.5-12 Given this paradigm, collection and interpretation of an MRSA nasal swab after initiation of antistaphylococcal antibiotics may be met with hesitation. In 2014, Shenoy and colleagues published a randomized controlled trial that enrolled 259 patients that were tested with both culture-based and PCR-based MRSA nasal swab methods.35 132 patients (51%) were tested within 48 hours of starting antistaphylococcal antibiotics and 127 (49%) patients were tested in the absence of antibiotics. There was strong concordance between the culture and PCR-based methods in the absence of antibiotics (93.7% concordance; 95% CI, 88.1%, 96.8%). There were also no differences in the proportion of positive results between methods without concurrent antibiotics (33.1% for culture, and 36.2% for PCR-based; P = 0.29). When tested in the presence of antibiotics, concordance remained strong (90.9%; 95% CI: 84.8%, 94.7%). There was a higher amount of positive results in the PCR method compared to the culture method when tested with concurrent antibiotics (41.7% and 34.1% respectively; P < 0.01). The authors of this study postulated that the decreased yield in the culture group may have been due to a decline in viable organisms, while the PCR method may have retained positive results due to the ability to detect DNA from non-viable organisms. Based on the results of this study, it may be reasonable to collect and analyze MRSA nasal swab results even in the presence of antistaphylococcal antibiotics if collected within the first 48 hours of therapy in institutions that use a PCR-based method.
In conclusion, MRSA nasal swabs can help detect patients that have a higher risk of MRSA infection based on their colonization status. MRSA nasal swabs can serve the clinician as an effective tool for antimicrobial stewardship, with more reliable results in those disease states with a low prevalence of MRSA. Pneumonia remains the disease state with the best evidence support for the use of MRSA nasal swabs. The 2019 community acquired pneumonia guideline recommendations strongly encourage the use of these swabs when deciding on empiric antibiotics and de-escalation prior to respiratory culture results.6 Likewise, in patients where a bloodstream infection is suspected, the high negative predictive value demonstrated by Robicsek and colleagues may allow the use of MRSA nasal swabs to de-escalate empiric anti-MRSA therapy.20 Cautious interpretation of the study results summarized is still encouraged including a local comparison of MRSA infection rates. It should also be noted that current evidence for the use of MRSA nasal swabs is fairly poor in osteomyelitis and skin and soft tissue infections, with weak recommendations that could be made to continue MRSA therapy in those patients with a positive nasal screen being treated for cellulitis and skin abscess.10,22 When MRSA is detected, decolonization regimens with mupirocin may be beneficial to reduce the risk of MRSA infection if the patient is on dialysis or scheduled for a surgical procedure.24-30 Even after starting antistaphyloccal antibiotics, an MRSA screen may still be useful when conducted within 48 hours from the start of therapy, and more reliable if a PCR method for organism detection is used.35
By: Shannon Jones, PharmD
Acute respiratory distress syndrome (ARDS) is a type of acute, diffuse inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight and loss of aerated lung tissue. The LUNG SAFE study in 2016 found that ARDS accounts for ~10% of ICU admissions and 23% of ventilated patients. The mortality rate has been reported as high as 25 – 40% in most studies. The main causes (~85% of cases) of ARDS include pneumonia (bacterial, viral, fungal, or opportunistic), aspiration of gastric contents, and sepsis from non-pulmonary sources. Pathophysiology of ARDS includes three distinct phases: exudative, proliferative, and fibrotic as follows:
Definition of ARDS1,3,5,6
The Berlin Definition, essentially a modification of the AECC Definition (1994), established ARDS severity categories (i.e. mild [PaO2/FiO2 ratio 200-300 mmHg], moderate [PaO2/FiO2 ratio 100-200 mmHg], and severe [PaO2/FiO2 ratio < 100 mmHg]) that are predictive of increased mortality and increased duration of mechanical ventilation. The Berlin defines ARDS as an acute onset of impaired oxygenation (PaO2/FiO2 ratio < 300 mmHg) with PEEP > 5 cm H2O + bilateral opacities – not fully explained by effusions, lobar/lung collapse, or nodules + respiratory failure not fully explained by cardiac failure or fluid overload.
Neuromuscular Blocking Agents3,6,7
Neuromuscular blocking agents (NMBAs) block neural transmission at the myoneural junction. Depolarizing NMBAs mimic acetylcholine and provide continuous depolarization of the action potential. Non-depolarizing NMBAs bind directly to cholinergic receptor sites and prevent the subsequent action potentials. The intended beneficial use in ARDS includes ensuring patient-ventilator synchrony and reducing the risk of ventilator-associated lung injury. Concerns that arise when using NMBAs include ICU-acquired weakness, thrombosis and thromboembolism, and patient awareness during paralysis. Some disease states have potential to increase or decrease efficacy of these agents such as burns, electrolyte abnormalities, and trauma. Monitoring of NMBAs is required to ensure adequate depth of neuromuscular blockade and is performed with the use of peripheral nerve stimulator AKA Train-of-Four (TOF) which stimulates specific muscles to assess the extent of the blockade.
Treatment Recommendations + Proposed Treatment Algorithm
When considering the use of NMBAs in ARDS, cisatracurium is the ideal paralytic based on pharmacokinetic and adverse effect profile for hemodynamically unstable patients; metabolism is by Hofmann elimination which avoids hepatic and renal dysfunction. Non-pharmacologic treatment strategies are centered around lung-protective ventilation and conservative fluid management (i.e. low tidal volume, high PEEP, monitoring of equal fluid input and output).
By: Marissa Chow, Michelle Tulchinskaya, and Lauren Busch; PharmD Candidates 2021
In 2018, 2 million people in the United States were diagnosed with an opioid use disorder, and 47,600 people died as a result of opioid overdoses.1 The rate of opioid overdoses has tripled since 2000 and continues to rapidly increase.2 Since the start of the opioid epidemic in the 1990s , there have been several programs and products developed to help combat this rapidly growing issue.3 The mainstay of treatment for opioid overdose is naloxone, which has seen dramatic increase in use within the past decade due to community education and initiatives to expand access. Currently, the FDA has approved the following routes of administration for naloxone: intravenous (IV) intramuscular (IM), subcutaneous (SubQ), and intranasal (IN).4 However, each of these routes has disadvantages such as difficulty of injection, potential for blood-borne pathogen exposure, and challenges with dose titration oftentimes resulting in overtreatment and agitation. Due to these challenges, nebulized naloxone has been suggested and used for opioid reversal as an off-label indication.
Prior to exploring this nontraditional route of administration of naloxone, approved routes of administration must be understood. A summary of the pharmacokinetic properties, along with the advantages and disadvantages for the current FDA approved routes of administration, is listed in the table below.
Key: Tmax = time to peak concentration T1/2 = half-life BA = bioavailability Cmax = peak concentration
Though these four traditional routes of administration have their advantages, they also all have limitations; thus, administration of nebulized naloxone has been explored. Nebulized naloxone poses significant benefits such as limiting potential exposure to blood-borne pathogens, quick accessibility and administration of naloxone due to not requiring IV access, and less withdrawal side effects associated with prolonged or bolus dose administration. During an opioid overdose, the primary life-threatening symptom is respiratory depression. In a single case study, serum concentrations of nebulized naloxone were compared with other routes of administration and found that 15 minutes post treatment, intranasal and nebulized naloxone had similar serum concentration levels of ~0.6ng/dL.11 In an observational study, nebulized naloxone (2mg in 3mL normal saline delivered via standard face mask) was given to 26 patients with suspected opioid intoxication who had a respiratory rate of ≥ 6 breaths per minute; this study showed a statistically significant decrease in the need for supplemental oxygen (81% to 50%, p = 0.03) and showed improved level of consciousness through the use of Glasgow Coma Score (GCS) and Richmond Agitation Sedation Scale (RASS) scores from baseline to 15 minutes post treatment.10 In a retrospective study of 105 patients, 22% had a complete response and 59% had a partial response to nebulized naloxone, and only 10% needed IV or IM rescue naloxone post treatment.12 Based upon these studies, nebulized naloxone is an acceptable alternative for patients with spontaneous respiration in suspected opioid overdose cases.
The primary benefit of the nebulized route of naloxone is to avoid the potential for overtreatment that is commonly seen with bolus dosing. Patients who are opioid dependent are more likely to have acute opioid withdrawal syndrome (OWS), which includes symptoms of aggressiveness, tachycardia, shivering, tremors, and sweating.13,14 With nebulized naloxone administration, gentle titration of naloxone to the patient’s response allows avoidance of significant overtreatment and potential OWS.13 Avoidance of overtreatment, particularly patient aggression, can improve safety for both patients and healthcare workers.
Overall, administration of nebulized naloxone appears to be a promising route of administration in terms of both safety and efficacy. Nebulized naloxone has the advantages of preventing the transmission of blood-borne pathogens, avoiding the need for IV placement in patients with difficult IV access, and smoother titration of dosing to avoid withdrawal symptoms as compared to bolus dosing with IN, SubQ, IV, and IM routes. Of note, it is only an option for patients who have overdosed and still have spontaneous respirations. Much of the research on the safety and efficacy of nebulized naloxone is limited to case reports and observational studies with small samples sizes, but the results of these studies indicate that it is an effective route of administration with improvements in patients’ oxygenation and mental status.
By: Eric Zhang, PharmD Candidate 2021
Electronic cigarettes (E-cigarettes) and the subsequent act of using E-cigarettes, or vaping, were introduced in the US in 2007 and have become increasingly popular among youth and adults.1 In a 2019 survey, 27.5% of high school students and 10.5% of middle school students reported use of E-cigarettes in the last 30 days.2 A 2018 survey indicated 7.6% of adults aged 18-24, 4.3% aged 25-44, 2.1% aged 45-64, and 0.8% aged 65 and older reported using E-cigarettes every day or some days (defined as “current use”).3 Of adults, 3.7% of Caucasians, 2.5% of Hispanics, 1.6% of African Americans, and 2.2% of Asians were current E-cigarette users. 4.3% of men and 2.3% of women were current users.
Some vaping devices mirror combustible cigarettes, cigars, or pipes, but newer designs look like pens or flash drives.4 There are also larger devices known as tank systems or mods. Devices consist of four parts: a cartridge which holds a liquid solution, an atomizer which vaporizes the liquid, a battery, and a mouthpiece used to inhale vapor.5 Though vaping is perceived as less harmful than cigarette smoking, most E-cigarettes deliver nicotine.6 Liquid solutions also contain flavorings, propylene glycol, vegetable glycerin, and heavy metals.7,8 Users may also vape tetrahydrocannabinol (THC), cannabidiol, and butane hash oils (also known as dabs).
Long term effects of E-cigarettes are yet to be discovered, but there is evidence for short term harm such as increased asthma exacerbations in youth, acute endothelial cell dysfunction, DNA damage, and dependence.9 Also, batteries may explode and injure users, and exposure to liquid solution by ingestion or contact with the eyes can cause adverse effects.
Between June and September 2019, there was a marked increase in severe lung injury connected to vaping which the Centers for Disease Control and Prevention (CDC) considers to be an outbreak. As of February 18, 2020, there have been 2,807 hospitalized cases.10 The number of hospitalizations per day peaked in September 2019 and has steadily decreased through February 18, the last national data reported by the CDC. In February, the number of hospital admissions returned to pre-outbreak numbers.
Definition and pathological features
E-cigarette, or vaping, product use-associated lung injury (EVALI) has been defined by the CDC for the purpose of surveillance. There are definitions for confirmed and probable cases of EVALI (Table 1).11
Surveillance case definitions* of EVALI
*Note: these definitions are not meant for clinical diagnosis.
**Clinical team caring for the patient.
EVALI is a diagnosis of exclusion. It requires the use of an E-cigarette or dabbing in the 90 days before symptom onset, a pulmonary infiltrate seen on imaging, and no evidence in the patient’s medical record of alternative diagnoses, such as cardiac, rheumatologic, or neoplastic diseases. The difference is that while pulmonary infection is ruled out in a confirmed case, infection is either present or not ruled out in a probable case. In a probable case, infection is not seen as the sole cause of lung injury and vaping is likely to have a role.
Patients in Wisconsin, Illinois, Pennsylvania, and North Carolina presented with a variety of symptoms: respiratory (dyspnea, non-productive cough), gastrointestinal (abdominal pain, nausea, vomiting), and constitutional (fever, sweats, myalgias).7,8,12,13 There was a pattern of presenting signs as well. Patients were hypoxemic and had elevated inflammatory markers: white blood cell (WBC) count with neutrophilic predominance, C-reactive protein, and erythrocyte sedimentation rate. In patients presenting in Illinois and Wisconsin, hyponatremia (in 31%), hypokalemia (35%), and elevated AST/ALT (50%) were also seen. Pulmonary infiltrates were present, and chest CT scans showed ground glass opacities with various pathologies connected to vaping.
A national study examining all cases of EVALI as of January 7, 2020 found elevated WBC count (71%), neutrophilic predominance (64%), and elevated AST/ALT (73%) in patients with fatal cases with data for these parameters.14 They also found that 46% of fatal cases had tachycardia, 50% had tachypnea, and 53% had gastrointestinal symptoms. In contrast, 80% of nonfatal cases with data reported gastrointestinal symptoms. 98% of fatal cases and 96% of nonfatal cases reported respiratory symptoms.
In some cases, clinicians obtained bronchoalveolar lavage (BAL) samples from patients. Lipid laden macrophages were positive in 6 out of 6 samples from Utah and 7 out of 14 samples from Illinois and Wisconsin.13,7 Thus, lipid laden macrophages could be considered as a future diagnostic marker.
In Illinois, syndromic surveillance was used to determine that the mean monthly rate of emergency department (ED) visits for severe respiratory illness between June 1, 2019 to August 15, 2019 was double that of June 1, 2018 to August 15, 2018 (7.4 cases per 10,000 visits vs. 3.8 cases per 10,000 visits, p < 0.001).7 In December, the CDC also used surveillance data to find that ED visits pertaining to E-cigarette use gradually increased between January 2017 and August 2019, particularly among those 10 to 19 years old.15 They found ED visits among those 11 to 34 years of age where EVALI may have been part of discharge diagnosis increased starting from June 2019, peaked in September, and have decreased since then.
The Illinois Department of Public Health found that EVALI patients were more likely to be between 18 and 29 years old (OR 6.0, 95% CI 3.1-11.5; P < 0.0001) and to be non-white (OR 2.9, 95% CI 1.7-5.2; P = 0.0001).16 Also, EVALI patients were more likely to use only THC-containing products (OR 1.9, 95% CI 1.1-3.4; P = 0.03), use any THC-containing product more than 5 times a day (OR 2.7, 95% CI 1.5-51; P = 0.001), use Dank Vapes products (OR 10.1, 95% CI 4.6-22.0; P < 0.0001), and obtain THC-containing products informally (OR 12.1, 95% CI 2.9-50.8; P < 0.0001). Informal sources were defined as friends or dealers. It is important to have a nonjudgmental and confidential conversation about product use with the patient or their proxy because some may hide THC use out of fear or embarrassment.14
National characteristics of patients with fatal or non-fatal EVALI cases14
Patients with fatal cases had higher rates of chronic conditions than those with non-fatal cases (Table 2). When present, these factors might indicate patients at higher risk of dying from EVALI. Moreover, EVALI is unique in that most patients were under 35 (77%). In a similar study, the CDC compared characteristics of EVALI patients who were rehospitalized or died after hospital discharge to those who were neither rehospitalized nor died after discharge.17 In this cohort, those who were rehospitalized or died after discharge were more likely to have 1 or more chronic conditions (P < 0.001 for those rehospitalized, P = 0.006 for those who died), which included cardiac disease, respiratory disease, and diabetes mellitus. 25% of rehospitalizations and deaths occurred within 2 days after discharge. Because of this, they suggest intensive discharge planning and follow up within 48 hours after discharge.
The Minnesota Department of Health tested 10 THC-containing products seized by law enforcement in 2018 and 20 products seized in 2019.18 None seized in 2018, before the outbreak, contained vitamin E acetate, but all products seized in 2019 had vitamin E acetate. This indicates that vitamin E acetate may have been a new addition to E-cigarettes in 2019.
The CDC analyzed BAL samples from EVALI patients and a healthy comparator group which consisted of nonusers, exclusive E-cigarette users, and exclusive cigarette smokers.19 They considered a number of toxicants, including vitamin E acetate, plant oils, and medium-chain triglyceride oil. Vitamin E acetate was found in BAL samples of 48 out of 51 (94%) of EVALI patients and 0 out of 99 comparators. Coconut oil and limonene were found in BAL samples of one EVALI patient each. No other toxicants were identified. The study showed that vitamin E acetate was found in the respiratory epithelial-lining fluid of EVALI patients but not that of comparators.
While vitamin E is a common dietary supplement as well as an ingredient in skin creams, there are mechanisms by which it could cause lung injury when inhaled. One way is that vitamin E may cause phosphatidylcholines within lung surfactant to change from a gel to a liquid crystalline phase, which results in the surfactant losing its surface tension. Lung surfactant dysfunction may lead to severe respiratory disease.20 Also, at high temperatures, Vitamin E is converted to a ketene, a compound which irritates the lungs.21 One study found that the lungs of mice exposed to vitamin E acetate had increased albumin and leukocyte count compared to those of mice exposed to a mixture of propylene glycol and vegetable glycerin or air.22 Lipid laden macrophages were also present in the lungs of mice exposed to vitamin E acetate. It is possible, however, that vitamin E acetate is not a direct cause of EVALI. It may be a marker for exposure to other toxicants.
Treatment and prevention
Supportive care for acute lung injury (ALI) is the main treatment modality for patients with EVALI. Examples of supportive care are shown in Table 3.23 Hospitalized patients were also empirically treated for community acquired pneumonia, given IV steroids, and discharged on an oral prednisone taper.7,8,12,13
Examples of supportive care in ALI
Antimicrobials were stopped once infection was ruled out, and steroid use potentially helped improve respiratory status. One study found no significant difference in the percentage of discharged EVALI patients who received steroids while hospitalized whether they were later rehospitalized, died, or neither after discharge.24 This suggests that steroids were used consistently in hospitalized patients. However, the CDC notes that outpatient adherence to steroid tapers has been an issue with some EVALI patients. They recommend that discharge planning should include inpatient pharmacist counseling as it has been shown to decrease rehospitalization. Conversely, the use of steroids in patients treated solely as outpatients lacks data and should be considered with caution.25
The CDC has recommendations for discharge readiness as well as post-discharge follow-up.25,26 While also considering institutional guidelines, clinicians should ensure that the patient has stable oxygenation and exercise tolerance for 24-48 hours prior to discharge as well as stable vital signs, physical exam, resolution of symptoms, and laboratory parameters. Post-discharge, patients should follow up with their primary care provider or a pulmonologist within 48 hours. Additional follow-up with addiction medicine, physical therapy, or other providers may be warranted. At 2-4 weeks or at completion of the steroid taper, follow-up should assess pulmonary function and resolution of radiographic findings. Then, at 1-2 months, spirometry, diffusing capacity of the lung for carbon monoxide, and a chest X-ray might be assessed. Throughout this process, clinicians can also screen for substance use disorder and discuss smoking cessation with patients.
EVALI can be prevented by avoiding use of E-cigarettes. The CDC states E-cigarettes should never be used by adolescents or pregnant women.27 This is because nicotine is harmful to developing brains and to the fetus. The CDC further recommends avoiding THC-containing E-cigarettes and products obtained from informal sources.10 Clinicians should report possible causes of EVALI to their local or state health department.
As more is being learned about how vaping induces lung injury, individuals should avoid E-cigarette use. There are currently no diagnostic markers identified and EVALI is a diagnosis of exclusion, primarily by ruling out infectious causes. Patients may present with severe respiratory symptoms that can result in ALI, as well as other signs and symptoms.
EVALI should be considered whenever someone using E-cigarettes experiences severe respiratory symptoms; some had symptoms for weeks to months prior to an acute event. The use of THC-containing, informally obtained, or Dank Vape products was associated with EVALI.
EVALI patients with a chronic condition were more likely to be rehospitalized or die after discharge. Other factors such as age > 35, being white and non-Hispanic, and former combustible tobacco use were also more prevalent in patients with fatal cases. The CDC provides guidance for clinicians which includes discharge planning and follow-up. Patient adherence to their outpatient medication regimen is essential as nonadherence may contribute to mortality.
Though vitamin E is strongly linked to EVALI, further research is needed to identify its role and to elucidate whether other toxicants are also responsible. The decline in EVALI cases can be attributed to multiple factors8: increased public awareness of the risk of E-cigarettes, removal of vitamin E from some products, and law enforcement actions related to illicit products.
By: Hannah Norris, PharmD
Pharmacogenomics and pharmacogenetics are misconceived to be synonymous terms, but there is a recognized difference between the two.1-2 Pharmacogenomics encompasses all genes in the genome that may determine response to a drug. This field of study evaluates differences in drug receptor activity, uptake, and breakdown of medications based on differences in genetic profiles. Pharmacogenomics can also be used to aid in targeted drug development. Pharmacogenetics is the study of variability in drug response due to an individual’s specific gene or genes and clinically used primarily in relation to genes determining drug metabolism.
Although the idea of personalized medicine may seem novel, pharmacogenetics has a long history. The first documentation of the study of pharmacogenetics dates back to 510 BC by Pythagoras, who observed that a potentially fatal reaction after ingesting fava beans affected only certain individuals while leaving others unscathed.3 In 1866, Mendel discovered inherited traits through his study of the flowering colors of pea plants that resulted in his recognition of dominant and recessive genes.4 In 1956, Carson and colleagues uncovered a genetically determined enzymatic deficiency of glucose-6-phosphate-dehydrogenase (G6PD) in primaquine-sensitive erythrocytes.5 The term “pharmacogenetics” was first mentioned by Vogel in 1957.6 The enzyme, cytochrome P2D6 (CYP2D6) was found to be responsible for the metabolism of approximately 60 drugs in 1997 and is one of the major enzymes involved in the metabolism of psychiatric medications. 7-8 One of the major breakthroughs in the study of genetics was the completion of the human genome in 2000, 9 which has resulted in identification of almost 2000 genes that affect drug pharmacokinetics and pharmacodynamics.10 These revelations propelled the rapidly expanding study of pharmacogenomics, a termed introduced in the 1990s.11 With the understanding of pharmacogenomics, clinicians can better utilize the pharmacogenetic information currently included in more than 250 drug labels.12
Pharmacogenomics has the potential to provide clinicians information to simultaneously maximize efficacy and minimize toxicity of medication regimens. Therefore, any patient can be a candidate for pharmacogenetic testing. There are many unknowns in the field of mental illness, and pharmacogenetic testing is one tool clinicians can use in their practice to guide medication therapy.
The most compelling pharmacogenetic data are for patients with depression. Currently, genetics impact 26 antidepressants, and up to 42% of variance in therapy response for major depressive disorders (MDD) can be explained by genetic variation.8,13 With efficacy of first-line agents for depression ranging from 30-50%, the use of pharmacogenomics to better define drug selection is expected to greatly enhance patient outcomes in the near future.14,15 Of note, only about 50% of people have normal CYP2D6 enzyme levels, which affect many psychotropic and pain management medications.14 However, the clinical utility of this is not yet established.
Currently, consensus guidelines are not available for patient selection; however, an understanding of the current literature on specific genes and medications can aid in determining those that would have the most benefit. The current multi-gene panels promoting results that determine a specific drug for a specific patient can be misleading. There are four genes recommended by the International Society of Psychiatric Genetics as clinically valuable in pharmacogenetic testing, human leukocyte antigen (HLA)-A, HLA-B, CYP2D6, CYP2C19.8 The recommendations of the Clinical Pharmacogenetics Implementation Consortium (CPIC) provides levels of evidence strong, moderate, optional, and no recommendation for dosing based on pharmacogenetic testing with specifics included for several antidepressants including 5 selective serotonin reuptake inhibitors, amitriptyline, and nortriptyline (table).16,17 Additional information is available on the CPIC website for other tricyclic antidepressants, voriconazole, and HLA testing for carbamazepine and oxcarbazepine.8
One of the major considerations is the cost of testing. Private insurance coverage is variable, and more likely to occur in the following situations: adverse drug reactions or lack of response to medication, pain management, cancer management, and management of many co-morbid conditions. One company estimates a cost ranging from $0 for qualifying Medicaid or Medicare patients, and “typically” $330 or less for employer or other insurance.18 Medicare covers CYP2D6 testing for patients with depression taking amitriptyline, nortriptyline, or tetrabenazine doses greater than 50 mg/day.
One example of requirements for coverage of genetic testing for psychiatric disorders from a major insurance company is that the individual has a diagnosis of MDD or generalized anxiety disorder and has failed at least one prior medication to treat their condition.19 This coverage is only for a multi-gene panel with no more than 15 relevant genes. For patients without insurance, many pharmacogenetic testing companies offer financial assistance programs. The pharmacogenetic test can be cheek swab or blood draw, with results usually returning in 1-2 weeks.
As discussed above only a few genes have shown significant clinical utility for antidepressants, but pharmacoeconomic data with a multi-gene panel has shown cost-effectiveness. A database review of patients with MDD predicted a savings of $3,962 annually per patient with pharmacogenetic-guided medication management based on a test costing $2000. While Winner and colleagues reported an annual pharmacy cost savings of $2774 per patient on psychiatric medications.20,21
Clinical context for pharmacogenomics and pharmacogenetic testing is essential. Although presently limited in utility for patients with mental illness, data is rapidly becoming available and pharmacists should keep informed regarding this expanding area of knowledge. As information becomes increasingly established, pharmacists need to be prepared for greater patient demand for genetic testing. However, patient aversion (ethical and genetic privacy, e.g.) should not be discredited and pharmacists may need to offer reassurance. Understanding which tests are available, what the costs to health care and patients are, and how the results can potentially influence therapy are key. Assisting the patient and other healthcare providers in understanding these key points is the responsibility of any pharmacist working with patients with mental illness. A paradigm shift from which patient may qualify for genetic testing to how pharmacists incorporate genetic testing into daily practice is fast approaching.
By: Jacklyn Harris, PharmD, BCPS
Although our Spring Meeting this year was virtual, we were still able to celebrate together and recognize all the great work Missouri’s pharmacists and student pharmacists have been doing. I was super impressed by the virtual posters. Each presenter put in a lot of hard work to both create a poster and then create a 5-minute video reviewing their work. I really enjoyed learning about each project, and most of the questions that I had from reviewing the abstract were answered in the presentation. If you have not reviewed the virtual posters, I highly recommend that you go straight to the MSHP website and check them out now- you won’t be disappointed!!! Our poster winners this year are listed below.
The MSHP R&E Foundation Best Practice theme this year was ‘Innovative Stewardship Roles’. We had many great submissions. This year’s Best Practice award was presented to Rebecca Nolen for her project entitled “A Pharmacist-Drive Penicillin Allergy Overhaul”. Watch out for a review of her project in the next newsletter!
This year’s Best Residency Project award was presented to Joseph Walter for his project entitled “Impact of Pharmacist-led Education on Providers’ Prescribing Rates and Perceptions of Naloxone in High-Risk Opioid Patients”. Watch out for a review of his project in our next newsletter!
The first Tonnies Preceptor Award was given out at this year’s meeting. The Tonnies award was established in honor of Fred Tonnies, Jr for his longstanding support of MSHP, MMSHP, and numerous professional and academic contributions to Pharmacy, including over 35 years of dedicated service to precepting student learners. The award recognizes a pharmacist for their sustained contribution to precepting learners in health-system pharmacy, mentoring students/residents in the research process, activity with pharmacy students throughout the state, and service to the profession through ASHP, MSHP, and/or local affiliates. This year’s recipient of the Tonnies Preceptor Award was Davina Dell-Steinbeck. Her passion and commitment to precepting the next generation of pharmacists was evident in her Presidential address during the meeting.
Our final award presented was the Garrison Award. The Garrison award recognizes an individual who demonstrates outstanding accomplishments in health-system pharmacy practice, demonstrates teaching through involvement with pharmacy students and contributions to the profession of pharmacy through involvement with MSHP, ASHP, or local affiliates. This year’s award winner is Karrie Derenski. Karrie is the Clinical Pharmacy Services Supervisor and PGY-2 Critical Care Residency Program Director at Cox Health. She embodies the spirit of the Garrison award, not just in her everyday practice, but in her continuous efforts in precepting students and residents, research and publications, and leadership. She has expand service lines and programs within her department strategically placing pharmacy at the forefront of patient care. In addition, she has served many leadership roles in MSHP. Congratulations Karrie!! We look forward to presenting the award to her in person later this year.
Please congratulate each of our award winners!!! Thank you again for another great year and thanks for continually to push pharmacy practice in Missouri to the next level!