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  • 21 May 2020 5:04 PM | Anonymous

    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.

  • 15 May 2020 1:56 PM | Anonymous

    By: Lauren Jacobsmeyer, PharmD

    Learning Objectives:

    1. Identify the Surviving Sepsis Campaign’s recommendation for the use of corticosteroids in sepsis.
    2. Discuss interventions that are proven to provide a mortality benefit in patients with sepsis.
    3. Describe the current literature regarding the use of corticosteroids in sepsis.
    4. Explain the pathophysiologic rational for the use of a vitamin C, hydrocortisone, and thiamine combination in the setting of septic shock.
    5. Evaluate the results of relevant clinical studies looking at the efficacy and safety of the vitamin C, hydrocortisone, and thiamine combination in patients with septic shock.

    Background:

    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.

    Conclusions:

    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.

    Click Here for CE Quiz

    References:

    1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guideline for management or sepsis and septic shock: 2016. Intensive Care Med. 2017; 43:304-77.
    2. Kumar G, Kumar N, Taneja A, et al. Nationwide trends of severe sepsis in the 21st century (2000 – 2007). Chest. 2011; 140:1223-31.
    3. Paoli CJ, Reynolds MA, Sinha M, et al. Epidemiology and costs of sepsis in the United States – an analysis based on timing of diagnosis and severity level. Crit Care Med. 2018; 46(12): 1889-97.
    4. Levy MN, Artigas A, Phillips GS, et al. Outcomes of surviving sepsis campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis. 2012; 12:919-24.
    5. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018; 378(9):797-808.
    6. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 378(9):809-18.
    7. Moskowitz A, Anderson LW, Huang DT, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. 2018; 22:283.
    8. Marik P. Hydrocortisone, ascorbic acid and thiamine (HAT therapy) for the treatment of sepsis, focus on ascorbic acid. Nutrients. 2018; 10(11):1762.
    9. Flower AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. Journal of Translational Medicine. 2014; 12:32.
    10. Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium. Biofactors. 2009; 35(1):5-13.
    11. Donnino MW, Andersen LW, Chase M, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016; 44(2):360-67.
    12. Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017; 151(6):1229-38.
    13. Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone on time alive and free of vasopressor support among patients with septic shock. JAMA. 2020; 323(5):423-31.
    14. Hager DN, Hooper MH, Bernard GR, Busse LW, Ely EW, Fowler AA, Gaieski DF, Hall A, Hinson JS, Jackson JC, Kelen GD, Levine M, Lindsell CJ, Malone RE, McGlothlin A, Rothman RE, Viele K, Wright DW, Sevransky JE, Martin GS. The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial. Trials. 2019 Apr 5; 20(1):197. doi: 10.1186/s13063-019-3254-2.
  • 15 May 2020 12:53 PM | Anonymous

    By: Brandon Reynolds, PharmD, BCPS

    Learning Objectives:

    1. Define the role of methicillin-resistant Staphylococcus aureus nasal swabs in preventing and de-escalating unnecessary antibiotic therapy for pneumonia, osteomyelitis, bacteremia, and skin and soft tissue infection
    2. Appropriately recommend the use of a methicillin-resistant Staphylococcus aureus nasal swab based on the patient’s presenting diagnosis
    3. Explain the targeted patient populations eligible to receive decolonization of nasal Staphylococcus aureus
    4. Determine if methicillin-resistant Staphylococcus aureus nasal swab results are viable if collected in patients with concurrent antistaphylococcal antibiotic therapy

    Introduction

    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.

    Pneumonia

    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

    Osteomyelitis

    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.

    Bacteremia


    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.

    Conclusions

    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

    Click Here for CE Quiz

    References

    1. Tilahun B, Faust A, McCorstin P, and Ortegon A. Nasal colonization and lower respiratory tract infections with methicillin-resistant Staphylococcus aureus. Am J Crit Care 2015; 24(1):8-12
    2. Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus (MRSA) Last reviewed Feb 28, 2019
    3. Honda H et al. Staphylococcus aureus nasal colonization and subsequent infection in intensive care units: does methicillin resistance matter? Infect Control Hosp Epidemiol. 2010 31(6):584-591
    4. Eiff C, Becker K, Machka K, Stammer H, and Peters G. Nasal carriage as a source of Staphylococcus aureus bacteremia. NEJM 344(1):11-16
    5. Infectious Diseases Society of America. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004; 39(9):1267-1284
    6. American Thoracic Society and Infectious Diseases Society of America. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Resp Crit Care Med. 2019; 200(7):e45-e67
    7. Infectious Diseases Society of America. Diabetic foot infections. Clin Infect Dis. 2012; 54(12):e132-e173
    8. Infectious Diseases Society of America. 2017 Infectious Diseases Society of America’s clinical practice guidelines for healthcare-associated ventriculitis and meningitis. Clin Infect Dis. 2017; 64(6):e34-e65
    9. Infectious Diseases Society of America. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013; 56(1):e1-e25
    10. Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014; 59(2):e10-e52
    11. Infectious Diseases Society of America. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis. 2015; 61(6):e26-e46
    12. Infectious Diseases Society of America, American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009; 49:325-327
    13. Pickens C and Wunderink R. Principles and practice of antibiotic stewardship in the ICU. CHEST 2019; 156(1):163-171
    14. Kalil A et al. Management of adults with hospital acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016; 63(5): e61-e111
    15. Parente D, Cunha C, Mylonakis E, and Timbrook T. The clinical utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening to rule out MRSA pneumonia: a diagnostic meta-analysis with antimicrobial stewardship implications. Clin Infect Dis. 2018; 67(1): 1-7
    16. Pharm S, Sturm A, Jacoby J, Egwuatu N, and Dumkow L. Impact of a pharmacist-driven MRSA nasal PCR protocol on pneumonia therapy. Hosp Pharm. 2019
    17. Baby N, et al. Nasal methicillin-resistant Staphylococcus aureus (MRSA) PCR testing reduce the duration of MRSA-targeted therapy in patients with suspected MRSA pneumonia. Antimicrob Agents Chemother 2017; 61(4): 1-8
    18. Lew D and Waldvogel F. Osteomyelitis. Lancet 2004; 364: 369-379
    19. Tice A, Hoaglund P, and Shoultz D. Outcomes of osteomyelitis among patients treated with outpatient parenteral antimicrobial therapy. Am J Med. 114: 723-724
    20. Robicsek A et al. Prediction of methicillin-resistant Staphylococcus aureus involvement in disease sites by concomitant nasal sampling. J Clin Microbiol 2008; 46(2): 588-592
    21. Pallin D et al. Clinical trial: comparative effectiveness of cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: a randomized controlled trial. Clin Infect Dis. 2013; 56(12):1754-1762
    22. Schleyer A, Jarman K, Chan J, and Dellit T. Role of nasal methicillin-resistant Staphylococcus aureus screening in the management of skin and soft tissue infections. Am J Infect Control 2010; 38:657-659
    23. Troeman D, Hout D, and Kluytmans J. Antimicrobial approaches in the prevention of Staphylococcus aureus infections: a review. J Antimicrob Chemother 2019; 74(2):281-294
    24. Mupirocin Study Group. Nasal mupirocin prevents Staphylococcus aureus exit-site infection during peritoneal dialysis. J Am Soc Nephrol 1996; 7:2403–2408.
    25. Sit D, Kadiroglu AK, Kayabasi H et al. Prophylactic intranasal mupirocin ointment in the treatment of peritonitis in continuous ambulatory peritoneal dialysis patients. Adv Ther 2007; 24: 387–93.
    26. Boelaert JR, De Smedt RA, De Baere YA et al. The influence of calcium mupirocin nasal ointment on the incidence of Staphylococcus aureus infections in haemodialysis patients. Nephrol Dial Transplant 1989; 4: 278–81.
    27. Perl TM, Cullen JJ,Wenzel RP et al. Intranasalmupirocin to prevent postoperative Staphylococcus aureus infections. NEJM 2002; 346: 1871–7.
    28. Kalmeijer MD, Coertjens H, van Nieuwland-Bollen PM et al. Surgical site infections in orthopedic surgery: the effect of mupirocin nasal ointment in a double-blind, randomized, placebo-controlled study. Clin Infect Dis 2002; 35:353–8.
    29. Konvalinka A, Errett L, Fong IW. Impact of treating Staphylococcus aureus nasal carriers on wound infections in cardiac surgery. J Hosp Infect 2006; 64:162–8.
    30. Suzuki Y, Kamigaki T, Fujino Y et al. Randomized clinical trial of preoperative intranasal mupirocin to reduce surgical-site infection after digestive surgery. Br J Surg 2003; 90: 1072–5.
    31. Wertheim HF, Vos MC, Ott A et al. Mupirocin prophylaxis against nosocomial Staphylococcus aureus infections in nonsurgical patients. Ann Intern Med 2004; 140: 419–25.
    32. Harbarth S, Dharan S, Liassine N et al. Randomized, placebo-controlled, double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1999; 43: 1412–16.
    33. Camus C, Sebille V, Legras A et al. Mupirocin/chlorhexidine to prevent methicillin-resistant Staphylococcus aureus infections: post hoc analysis of a placebo-controlled, randomized trial using mupirocin/chlorhexidine and polymyxin/tobramycin for the prevention of acquired infections in intubated patients. Infection 2014; 42: 493–502.
    34. Huang SS, Septimus E, Kleinman K et al. Targeted versus universal decolonization to prevent ICU infection. NEJM 2013; 368: 2255–65.
    35. Shenoy E et al. Concordance of PCR and culture from nasal swabs for detection of methicillin-resistant Staphylococcus aureus in a setting of concurrent antistaphylococcal antibiotics. J Clin Microbiol. 2014; 52(4):1235-1237
    36. Carr, Amy et al. Clinical utility of Methicillin-resistant Staphylococcus aureus nasal screening for antimicrobial stewardship: a review of the current literature. Pharmacotherapy 2018; 38(12): 1216-1228


  • 15 May 2020 11:40 AM | Anonymous

    By: Shannon Jones, PharmD

    Background1,2,3,4

    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.

    Treatment Strategies3,6


    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).


    References

    1. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: The Berlin Definition. JAMA. 2012;307(23):2526-33.
    2. Huppert LA, Matthay MA, Ware LB. Pathogenesis of Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med. 2019;40(1):31-39.
    3. Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl J Med. 2017;377(6):562-572.
    4. Bellani G, Laffey JG, Pham T, et al. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016;315(8):788-800.
    5. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967; 2(7511):319-323.
    6. Clar DT, Liu M. Non-depolarizing Neuromuscular Blockers. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK534828/. Published August 17, 2019. Accessed November 15, 2019.
    7. Papazian L, Aubron C, Brochard L, et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019;9(1):69.


  • 14 May 2020 6:26 PM | Anonymous

    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.

    References:

    1. The Opioid Epidemic by the Numbers. Health and Human Services. https://www.hhs.gov/opioids/sites/default/files/2019-11/Opioids Infographic_letterSizePDF_10-02-19.pdf. Published October 2019. Accessed April 24, 2020.
    2. Naloxone for Treatment of Opioid Overdose. October 2016. https://www.fda.gov/media/100429/download. Accessed April 24, 2020.
    3. Ostling PS, Davidson KS, Anyama BO, Helander EM, Wyche MQ, Kaye AD. America's opioid
    4. epidemic: a comprehensive review and look into the rising crisis. Curr Pain Headache Rep. 2018;22(5):32. Published 2018 Apr 4. doi:10.1007/s11916-018-0685-5.
    5. Naloxone Hydrochloride. Micromedex Solutions. Greenwood Village, CO: Truven Health Analytics. http://micromedex.com/. January 30, 2020. Accessed April 24, 2020.
    6. Loimer N, Hofmann P, Chaudhry HR: Nasal administration of naloxone is as effective as the intravenous route in opiate addicts. Int J Addict. 1994; 29: 819-827.
    7. Dowling J, Isbister GK, Kirkpatrick CMJ, et al.: Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers. Ther Drug Monit. 2008; 30:490-496.
    8. Fellows SE, Coppola AJ, Gandhi MA. Comparing methods of naloxone administration: A narrative review. J Opioid Manag. 2017; 13(4):253-260.
    9. Ryan SA, Dunne RB, Ryan SA. Pharmacokinetic properties of intranasal and injectable formulations of naloxone for community use: a systematic review. Pharmacokinetic properties of intranasal and injectable formulations of naloxone for community use: a systematic review | Pain Management. https://www.futuremedicine.com/doi/10.2217/pmt-2017-0060?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=www.ncbi.nlm.nih.gov&. Published April 23, 2018. Accessed April 24, 2020.
    10. Narcan [package insert]. Radnor, Pa: Adapt Pharma 2015.
    11. Baumann BM, Patterson RA, Parone DA, et al: Use and efficacy of nebulized naloxone in patients with suspected opioid intoxication. Am J Emerg Med. 2013; 31: 585-588
    12. Minhaj FS, Schult RF, Fields A, et al. A case of nebulized naloxone use with confirmatory serum naloxone concentrations. Annals of Pharmacotherapy, 2018; 52(5), 495–496. doi:10.1177/1060028017752428.
    13. Weber JM, Tatatis KL, Hoffman JD, Aks SE, Mycyk MB. Can nebulized naloxone be used safely and effectively by emergency medical services for suspected opioid overdose?. Prehosp Emerg care. 2012. 16(2):289-292.
    14. Kim HK, Nelson LS: Reducing the harm of opioid overdose with the safe use of naloxone. A pharmacological review. Expert Opin Drug Saf. 2015; 14:1137-1146.
    15. Buajordet I, Naess A-C, Jacobsen D. et al.: Adverse events after naloxone treatment of episodes of suspected acute opioid overdose. Eur J Emerg Med. 2004:1137-1146.


  • 14 May 2020 5:22 PM | Anonymous

    By: Eric Zhang, PharmD Candidate 2021

    Introduction

    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

    Table 1

    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.

    Epidemiologic features

    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

    Table 2

    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.

    Pathogenesis

    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

    Table 3

    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.

    Conclusions

    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.


    References:

    1. Dinardo P, Rome ES. Vaping: the new wave of nicotine addiction. Cleve Clin J Med. 2019;86(12):789-798.
    2. Cullen KA, Gentzke AS, Sawdey MD, et al. E-cigarette use among youth in the United States, 2019. JAMA. 2019;322(21):2095-2103.
    3. Villarroel MA, Cha AE, Vahratian A. Electronic cigarette use among U.S. adults, 2018. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/nchs/products/databriefs/db365.htm. Last updated April 30, 2020. Accessed May 2, 2020.
    4. Vaporizers, E-cigarettes, and other electronic nicotine delivery systems (ENDS). U.S. Food and Drug Administration Web site. https://www.fda.gov/tobacco-products/products-ingredients-components/vaporizers-e-cigarettes-and-other-electronic-nicotine-delivery-systems-ends. Last updated April 13, 2020. Accessed January 5, 2020.
    5. Vaping devices (electronic cigarettes). National Institute on Drug Abuse Web site. https://www.drugabuse.gov/publications/drugfacts/vaping-devices-electronic-cigarettes. Last updated January 2020. Accessed May 1, 2020.
    6. Is vaping better than smoking? American Heart Association Web site. https://www.heart.org/en/healthy-living/healthy-lifestyle/quit-smoking-tobacco/is-vaping-safer-than-smoking. Last updated October 30, 2018. Accessed January 5, 2020.
    7. Layden JE, Ghinai I, Pray I, et al. Pulmonary illness related to E-cigarette use in Illinois and Wisconsin – final report. N Engl J Med. 2020;382(10):903-916.
    8. Triantafyllou GA, Tiberio PJ, Zou RH, et al. Vaping-associated acute lung injury: a case series. Am J Respir Crit Care Med. 2019;200(11):1430-1431.
    9. National Academies of Sciences, Engineering, and Medicine (NASEM). 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press.
    10. Outbreak of lung injury associated with the use of E-cigarette, or vaping, products. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html. Last updated February 25, 2020. Accessed April 17, 2020.
    11. Smoking & tobacco use - for state, local, territorial, and tribal health departments. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease/health-departments/index.html#primary-case-def. Last updated April 17, 2020. Accessed November 1, 2019.
    12. Davidson K, Brancato A, Heetderks P, et al. Outbreak of electronic-cigarette-associated acute lipoid pneumonia – North Carolina, July-August 2019. MMWR Morb Mortal Wkly Rep. 2019;68(36):784-786.
    13. Maddock SD, Cirulis MM, Callahan SJ, et al. Pulmonary lipid-laden macrophages and vaping. N Engl J Med. 2019;381(15):1488-1489.
    14. Werner AK, Koumans EH, Chatham-Stephens K, et al. Hospitalizations and deaths associated with EVALI. N Engl J Med. 2020;382(17):1589-1598.
    15. Hartnett KP, Kite-Powell A, Patel MT, et al. Syndromic surveillance for E-cigarette, or vaping, product use-associated lung injury. N Engl J Med. 2020;382(8):766-772.
    16. Navon L, Jones CM, Ghinai I, et al. Risk factors for E-cigarette, or vaping, product use-associated lung injury (EVALI) among adults who use e-cigarette, or vaping, products – Illinois, July-October 2019. MMWR Morb Mortal Wkly Rep. 2019;68(45):1034-1039.
    17. Mikosz CA, Danielson M, Anderson KN, et al. Characteristics of patients experiencing rehospitalization or death after hospital discharge in a nationwide outbreak of E-cigarette, or vaping, product use-associated lung injury – United States, 2019. MMWR Morb Mortal Wkly Rep. 2020;68(5152):1183-1188.
    18. Taylor J, Wiens T, Peterson J, et al. Characteristics of E-cigarette, or vaping, products used by patients with associated lung injury and products seized by law enforcement – Minnesota, 2018 and 2019. MMWR Morb Mortal Wkly Rep. 2019;68(47):1096-1100.
    19. Blount BC, Karwowski MP, Shields PG, et al. Vitamin E acetate in bronchoalveolar-lavage fluid associated with EVALI. N Engl J Med. 2020;382(8):697-705.
    20. Zuo YY, Veldhuizen RA, Neumann AW, Petersen NO, Possmayer F. Current perspectives in pulmonary surfactant--inhibition, enhancement and evaluation. Biochim Biophys Acta. 2008;1778(10):1947-77.
    21. Wu D, O’Shea DF. Potential for release of pulmonary toxic ketene from vaping pyrolysis of vitamin E acetate. Proc Natl Acad Sci U S A. 2020;117(12):6349–6355.
    22. Bhat TA, Kalathil SG, Bogner PN, Blount BC, Goniewicz ML, Thanavala YM. An animal model of inhaled vitamin E acetate and EVALI-like lung injury. N Engl J Med. 2020;382(12):1175-1177.
    23. Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med. 2017;377:562-572.
    24. Evans ME, Twentyman E, Click ES, et al. Update: interim guidance for health care professionals evaluating and caring for patients with suspected E-cigarette, or vaping, product use associated lung injury and for reducing the risk of rehospitalization and death following hospital discharge – United States, December 2019. MMWR Morb Mortal Wkly Rep. 2020;68(5152):1189-1194.
    25. Smoking & tobacco use – for healthcare providers. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease/healthcare-providers/index.html. Last updated March 17, 2020. Accessed May 1, 2020.
    26. EVALI discharge readiness checklist. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease/healthcare-providers/index.html. Accessed May 1, 2020.
    27. Smoking & tobacco use – about electronic cigarettes (E-cigarettes). Centers for Disease Control and Prevention Web site. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/about-e-cigarettes.html. Last updated February 24, 2020. Accessed May 6, 2020.
  • 14 May 2020 4:59 PM | Anonymous

    By: Hannah Norris, PharmD

    Background

    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

    Patient Selection

    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

    Costs Considerations

    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

    Key Considerations

    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.




    References:

    1. Pirmohamed M. Pharmacogenetics and pharmacogenomics. Br J Clin Pharmacol. 2001;52:345–347. doi:10.1046/j.0306-5251.2001.01498.x.
    2. Pharmacogenomics, pharmacogenetics, and scientific research. Medical Laboratoy Observer. https://www.mlo-online.com/home/article/13006200/pharmacogenomics-pharmacogenetics-and-scientific-research. February 16, 2014. Accessed March 9, 2020.
    3. Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin Genet 1999; 56:247-258.
    4. Zhang H, Chen W, Sun K. Mendelism: New Insights from Gregor Mendel's Lectures in Brno. Genetics. 2017;207(1):1–8. doi:10.1534/genetics.117.201434.
    5. Carson PE, Flanagan CL, Ickes CE, et al. Enzymatic deficiency in primaquine sensitive erythrocytes. Science 1956;124: 484-485.
    6. Scott, S. Personalizing medicine with clinical pharmacogenetics. Genet Med 13, 987–995 (2011). https://doi.org/10.1097/GIM.0b013e318238b38c.
    7. Maraz D, Legrand M, Sabbagh N et al. Polymorphism of the cytochrome P450 CYP2D6 in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 1997; 7:197–202.
    8. Guidelines. Clinical Pharmacogenetics Implementation Consortium. https://cpicpgx.org/guidelines/. July 11, 2019. Accessed February 20, 2020.
    9. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature 2001;409:860-921.
    10. Feng J, Sun J Wand MZ, et al. Compilation of a comprehensive gene panel for systematic assessment of genes that govern an individual's drug responses. Pharmacogenomics 2010;11:1403-25. doi: 10.2217/pgs.10.99.
    11. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature. 2015;526(7573):343–350. doi:10.1038/nature15817
    12. Drug Label Annotations. PharmGKB. https://www.pharmgkb.org/labels. Accessed February 20, 2020.
    13. Tansey KE, Guipponi M, Hu X, Domenici E, Lewis G, Malafosse A, et al. Contribution of common genetic variants to antidepressant response. Biol Psychiatry 2013;73:679-682.
    14. Trivedi MH, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am. J. Psychiatry 2006;163:28–40. doi:10.1176/appi.ajp.163.1.28.
    15. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br. J. Psychiatry 2001;178:234–241. doi:10.1192/bjp.178.3.234.
    16. Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015;98:127–134. doi:10.1002/cpt.147.
    17. Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102:37–44. doi:10.1002/cpt.597.
    18. https://genesight.com/cost/
    19. UnitedHealthcare® Oxford. (2020). Pharmacogenetic Testing Policy. LABORATORY 023.6 T2.
    20. Maciel A, Cullors A, Lukowiak AA, Garces J. Estimating cost savings of pharmacogenetic testing for depression in real-world clinical settings. Neuropsychiatr Dis Treat. 2018;14:225–230. Published 2018 Jan 8. doi:10.2147/NDT.S145046.
    21. Winner JG, Carhart JM, Altar CA, et al. Combinatorial pharmacogenomic guidance for psychiatric medications reduces overall pharmacy costs in a 1 year prospective evaluation. Curr Med Res Opin 2015;31;1633-1643.
  • 14 May 2020 4:52 PM | Anonymous

    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.

    • Original Research: Julia Wu, Rebecca Nolen, Davina Dell-Steinbeck for “Evaluation & Identification of Risk Factors Associated with Inappropriate Treatment of Asymptomatic Bacteruria”
    • Encore Research: Haley Bettlach for “Evaluation of Intravenous Immunoglobulin Use at an Academic Pediatric Hospital”
    • Student Research: Haley Rust & Kyle Roof for “A Retrospective Review of Glycemic Control of Patients on Parenteral Nutrition with Correctional Insulin Administered every 4 hours”

    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!

  • 31 Mar 2020 4:53 PM | Anonymous

    Author: Allison Hotop, PharmD Candidate; SIUE School of Pharmacy

    Mentor: Sarah Cook, PharmD, BCPS; SSM Health St. Joseph Hospital – St. Charles

    SARS-CoV-2, the virus that causes the disease known as COVID-19, is a betacoronavirus similar to MERS-CoV and SARS-CoV.1 Symptoms include fever (83-99%), cough (59-82%), fatigue (44-70%), anorexia (40-84%), shortness of breath (31-40%), sputum production (28-33%), and myalgias (11-35%); the illness tends to be more severe in older persons and those with underlying medical conditions of cardiovascular disease, diabetes, chronic lung disease, and cancer.2 A study examining publicly reported, confirmed cases of COVID-19 from 50 different provinces and countries outside of Wuhan, China estimated the incubation period of COVID-19 to be 5.1 days. Within 11.5 days, 97.5% of patients who became symptomatic showed symptoms, and 1.01% of cases developed symptoms after 14 days of exposure. This study was limited by the fact that the information came from publicly reported information, meaning severe cases may be overrepresented.3 According to the CDC on March 30, 2020, the US had 140,904 confirmed cases and 2405 deaths. Although early cases were mostly travel related, most cases in the US are currently from community transmission, and the US currently has the highest number of reported cases for any country worldwide.4

    There is currently controversy about what treatment options should be used and how to manage critically ill patients with COVID-19. The Surviving Sepsis Campaign created a preliminary guideline on the management of critically ill adults with COVID-19. In summary, these guidelines recommend healthcare workers wear fitted respirator masks in addition to gloves, eye protection, and gowns when performing procedures considered to be aerosol generating. This includes endotracheal intubation, open suctioning, nebulizing treatments, as well as others. In terms of supportive treatment, the guideline recommends crystalloid fluid over colloids when patients with COVID-19 are in shock and using norepinephrine as the first-line vasopressor. It is also recommended to start supplemental oxygen in COVID-19 patients if SPO2 is < 92%. If the patient also has concomitant acute hypoxemic respiratory failure on oxygen, the recommendation is to target an O2 saturation no greater than 96%. Empiric antimicrobial use is recommended over no antimicrobial agents in patients witch COVID-19 who are mechanically ventilated and in respiratory failure; however, this therapy should be de-escalated when appropriate and assessed daily. The Surviving Sepsis Campaign also recommends against lopinavir/ritonavir and states there is insufficient evidence for a recommendation regarding hydroxychloroquine or chloroquine in critically ill adults at the time of guideline publication. For the full text of this article and more information regarding the strength of these recommendations, please see: https://www.sccm.org/getattachment/Disaster/SSC-COVID19-Critical-Care-Guidelines.pdf

    Additional Pharmacist Resources:

    References:

    1. 2019 Novel Coronavirus (2019-nCoV) Situation Summary. (2020, March 9). Retrieved March 12, 2020, from https://www.cdc.gov/coronavirus/2019-nCoV/summary.html
    2. Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). (2020, March 30). Retrieved March 30, 2020 from https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html.
    3. Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich NG, Lessler J. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020 Mar 10. doi: 10.7326/M20-0504. [Epub ahead of print] PubMed PMID: 32150748.
    4. Cases in U.S. (2020, March 30). Retrieved March 30, 2020, from https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html


  • 27 Mar 2020 3:20 PM | Anonymous

    Authors: Julia Wu, PharmD; James Unverferth, PharmD, PGY-1 Pharmacy Practice Residents

    Mentor: Davina Dell-Steinbeck, PharmD, BCPS

    Learning Objectives

    • Identify the unique mechanism of SGLT2 inhibitors
    • Differentiate dosing and mechanisms of action between the different SGLT2 inhibitors
    • Identify specific concerns with the use of SGLT2 inhibitors in T1DM
    • Describe the proposed mechanism of action of SGLT2 inhibitor-mediated euglycemic DKA
    • Describe the results of relevant studies looking at the safety and efficacy of SGLT2-inhibitors in Type 1 Diabetes Mellitus
    Background

    Type 1 diabetes (T1DM) is a chronic condition in which the pancreas produces little or no insulin. The exact cause of type 1 diabetes is unknown. Most commonly, the body's own immune system mistakenly destroys pancreatic islet β-cells, thereby disabling the body’s ability to produce insulin in response to elevated blood sugars. Other possible causes include genetics, exposure to viruses, and other environmental factors. Approximately 1.25 million Americans have Type 1 diabetes and an estimated 40,000 people are diagnosed with Type 1 diabetes each year. By 2050, 5 million people are expected to be diagnosed with Type 1 diabetes. This disease state is also costly for the patients: there are $14 billion in Type 1 diabetes-associated healthcare expenditures and lost income each year, mostly through medication cost and complications associated with the disease state. Preliminary data from T1 International’s 2018 access and supply survey reported 1 of every 4 US respondents have rationed insulin due to cost, and less than a third of patients consistently achieve target blood glucose levels.17

    Because the hallmark of type 1 diabetes is absent or near-absent β-cell function, insulin treatment is essential for individuals with type 1 diabetes9. Over the past three decades, evidence has accumulated supporting multiple daily injections of insulin or continuous subcutaneous administration through an insulin pump as providing the best combination of efficacy and safety for people with type 1 diabetes9. However, other treatment options have been studied and proposed as adjunct therapy for patients unable to reach their A1c and blood glucose goals on insulin alone. This is partially due to unfavorable adverse effects associated with insulin therapy, which include blood glucose variability, hypoglycemic events, and weight gain. These agents, listed in Table 1, all provide their own unique benefits and disadvantages in this particular patient population. SGLT2 inhibitors specifically were identified as a possible adjunct therapy due to their added A1c benefit and increased glycemic control through minimizing glycemic variability.


    SGLT2 Inhibitors

    There is an interest in SGLT2 inhibitors as adjunct therapy to insulin due to their unique mechanism of action. These agents work by lowering the renal threshold for glucose and increasing urinary glucose excretion by interfering with the reabsorption of renally-filtered glucose across the tubular lumen of the proximal renal tubules. Through this mechanism, glucose excretion is continuous and proportional to serum glucose levels, thus minimizing risk of hypoglycemia. This would help to lower A1c without introducing additional risk for hypoglycemia that is associated with insulin, thus partially negating this adverse effect. Table 2 illustrates the different agents available and their dosing schemes, currently only approved for Type 2 Diabetes by the US FDA.


    Concerns with SGLT2 Inhibitor Use

    There have been several common adverse effects associated with SGLT2 inhibitors including genital and urinary tract infections, hypotension and hypovolemia, acute kidney injury, intestinal side effects, diabetic ketoacidosis, foot amputations, bone fractures, and cancer.10 Though the incidence and actual risk of some of these may be debated, the adverse effect of primary concern in patients with T1DM is diabetic ketoacidosis (DKA). In traditional DKA, an excessive rise in glucagon levels during states of relative insulin deficiency stimulates hepatic glycogenolysis despite presence of excessive blood glucose levels. This fuels lipolysis, which provides a source of free fatty acids that are shunted through the ketosis pathway and converted into different ketone bodies. The overwhelming build-up of glucose and ketone bodies in the presence of insulin deficiency culminates in elevated anion gap metabolic acidosis with potentially fatal outcomes if DKA is not diagnosed and treated in a timely fashion.18

    Timely diagnosis of DKA in patients with T1D taking SGLT2 inhibitors may be difficult as they can develop a phenomenon known as euglycemic DKA. This occurs when the ultimate manifestations of traditional DKA arise in the absence of elevated blood glucose, one of the hallmark and easily identifiable symptoms of traditional DKA, making early recognition and treatment more difficult. SGLT-2 inhibition lowers the renal threshold for glucose excretion, reducing blood glucose levels and thereby reducing insulin secretion from pancreatic β-cells.20 This decline in circulating insulin levels results in a reduction of the anti-lipolytic effects of insulin. Following this, substrate utilization shifts from carbohydrates to fat oxidation and production of ketone bodies, which in turn poses a theoretical risk for euglycemic ketoacidosis. Evidence also suggests that SGLT2 inhibitors stimulate glucagon secretion, either directly through effects on pancreatic α-cells or indirectly through decreasing insulin secretion. Finally, another mechanism of euglycemic DKA is thought to occur through renal effects on ketone excretion: during starvation, renal re-absorption of ketones increases in proportion with serum ketone levels, but renal utilization of ketone bodies is reduced. It is thought that SGLT2 inhibitors mimic starvation conditions and cause an increase in ketone renal reabsorption, thereby continuing to produce glycosuria and render the body susceptible to acidemia through ketogenesis. Factors associated with increased risk of DKA while taking an SGLT2 inhibitor include:

    • Inappropriate insulin dose reduction or omission
    • Diminished food and fluid consumption
    • Low carbohydrate diets
    • Alcohol abuse
    • Infection
    • Abdominal crisis
    • Thyrotoxicosis
    • Myocardial infarction
    • Surgery
    • Trauma

    Literature Review

    Due to increased interest in use of SGLT2 inhibitors in Type 1 Diabetes, several efficacy and safety outcome trials have been performed to investigate these agents as adjunct therapy to insulin. Most of the trials had similar designs; however, differences between inclusion and exclusion criteria, primary endpoints, risk mitigation strategies, and definitions of hypoglycemia and DKA are of particular importance as they may misrepresent the results of one study compared to another. Because of this, these differences will be highlighted in each trial.


    Most DEPICT-1 participants were white and all were from Europe. The mean age was 43 years and the mean time since type 1 diabetes diagnosis was 20 years. Mean baseline HbA1c was 8.53% and mean baseline bodyweight was 82.4 kg.

    DEPICT-2 was performed in an effort to include a more diverse population. Most participants were white and from Europe, except a small contingent from Japan that made up ~20% of the study population. The mean age of the study population was 43 years, with a mean time since diagnosis of type 1 diabetes of 19 years. The mean baseline HbA1c was 8.4% and mean baseline body weight was 79.2 kg.

    Both trials concluded that dapagliflozin was a promising adjunct treatment to insulin to improve glycemic control, promote weight loss, and decrease daily dose of insulin requirements for patients with T1DM. Results were statistically significant for both strengths of dapagliflozin compared to placebo. In DEPICT-1 there was no difference realized in hypoglycemia or DKA events in the dapagliflozin group compared to placebo. However, this could be due to the fact that almost every participant in all treatment groups experienced a hypoglycemic event. Additionally there were very few DKA events, likely due to the lack of definition to use for diagnosis of the disease state. DEPICT-2 found an increase in DKA events associated with dapagliflozin treatment independent of the dose that patients received compared to placebo. Dapagliflozin was approved for treatment of T1DM by the European Commission in March 2019 and was also approved as an adjunct to insulin for T1DM in Japan but was rejected by the FDA for this indication in July 2019.

    EASE (2015, 2018)12,13

    The EASE trials were all multinational, randomized, double-blinded, placebo-controlled trials that investigated the efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes. Two of these trials utilized a unique strength of empagliflozin, 2.5mg, which was specifically made for the indication of T1DM.

    EASE-1 had a notably smaller sample size of 75 patients, randomized patients to empagliflozin 2.5 mg, 10 mg, 25 mg, or placebo as adjunct to insulin, and followed their patients for 28 days. In addition, patients underwent a 2-week run-in period during which they received diet and exercise counseling. Notably, 100% of patients enrolled were white, and a majority were male. The primary outcome was the change in 24-hour urine glucose excretion on day 7, and the trial found that empagliflozin as adjunct to insulin increased UGE, improved HbA1c, and reduced weight with lower insulin doses compared to placebo without increasing episodes of hypoglycemia.


    EASE-2 had a much larger sample size of 730 patients and studied empagliflozin 10 mg and 25 mg only compared to placebo, and only looked at change in HbA1c after 26 weeks. Patients were required to have a C-peptide level <0.7 ng/mL and underwent a 6-week insulin intensification period prior to randomization.

    EASE-3 studied 977 patients, added empagliflozin 2.5 mg back in as a study group, and continued to look at the change in HbA1c after 26 weeks. Both EASE-2 and 3 slightly improved the diversity of the population studied over EASE-1, with about 3% black and Asian patients, but still had a high percentage of white patients at about 94%.

    The EASE-2 and EASE-3 trials found that empagliflozin improved glycemic control and weight without increasing episodes of hypoglycemia. Results were consistent and statistically significant among all strengths of empagliflozin. Between EASE-1 and 2, it was found that ketoacidosis rates were increased in the 10 mg and 25 mg groups, but not the 2.5 mg group.


    The EASE trials corroborated the results from DEPICT-1 and 2: empagliflozin improved glycemic control and decreased weight in T1DM without increasing episodes of hypoglycemia, but there was an increased risk of ketoacidosis associated with the higher doses. Similar to dapagliflozin, in November 2019 an FDA advisory committee declined to recommend approving use of empagliflozin T1DM, citing insufficient data for efficacy with increased risk of DKA.

    inTandem (2018,2018,2017)14-16

    The inTandem trials investigated the efficacy and safety of sotagliflozin as adjunct to optimized insulin in patients with type 1 diabetes. All three trials were multinational, double-blind, randomized placebo-controlled studies. inTandem 1 occurred in North America, inTandem 2 occurred in Europe, and inTandem 3 occurred across multiple continents in 19 different countries.

    Both inTandem 1 and 2 randomized patients to sotagliflozin 200 mg, 400 mg, or placebo, and the primary outcome was the change in HbA1c after 24 weeks and 52 weeks. Patients were required to undergo insulin optimization in the 6 weeks before randomization, which was continued throughout the trial, and were excluded if they had elevated beta-hydroxybutyrate (BHB) levels, which is the primary ketone body found in patients who develop DKA. Patients were provided with urine ketone strips and monitors, blood BHB meters, and extensively educated on signs and symptoms of ketoacidosis. Patients in both studies were primarily white (92% and 96% respectively) and around 45 years old on average. Both inTandem 1 and 2 found that sotagliflozin was associated with sustained HbA1c reduction, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo. Results were statistically significant for both doses of sotagliflozin.

    inTandem 3, which randomized patients to only sotagliflozin 400 mg or placebo, looked at HbA1c <7.0% without episodes of severe hypoglycemia or DKA as their primary outcomes. Patients were similarly provided with urine ketone strips, blood BHB meters and strips, and extensive education. The majority of patients were also white (88%) and had similar average age of about 42 years old. They found that the proportion of patients who achieved HbA1c < 7.0% without severe hypoglycemia or DKA was larger in the group that received sotagliflozin than in the placebo group. However, rates of DKA were also higher in the sotagliflozin group, similar to both the DEPICT and EASE trials, despite more robust attempts to screen out patients at higher risk of DKA and providing monitoring supplies and education.

    Sotagliflozin has a unique mechanism of action, inhibiting both SGLT1 and 2. SGLT1 receptors are located in the intestine, and inhibition results in delayed glucose absorption and reduced post-prandial blood glucose levels.21 The combination of these mechanisms is thought to have a greater impact on efficacy in treatment of diabetes. There are also hypotheses involving SGLT1 receptors in the myocardium and the effect of sotagliflozin on cardiovascular outcomes: the SOLOIST-WHF Trial is currently ongoing and seeks to demonstrate superiority of sotagliflozin in reducing cardiovascular mortality and morbidity in patients with T2DM. It is currently approved for use in Europe but was denied by the FDA via split decision in January 2019 due to concern for increased risk of DKA. Based on clinical trial data, use of sotagliflozin in patients with T1DM would be expected to cause an additional 5000 cases of DKA and 20 deaths each year, assuming around 10% of patients would be using it. At this present time, sotagliflozin is not available in the US and will likely require further efficacy and safety investigation before it is approved for use.

    Conclusions

    Based off of the studies described above, SGLT2 inhibitors as a class have demonstrated increased efficacy in improving glycemic control in patients with type 1 diabetes. Additionally, certain agents showed decreased insulin requirements with limited hypoglycemia events, but an increased risk of diabetic ketoacidosis among all agents. Therefore, these agents are a viable option as adjunct to insulin in select patients with Type 1 Diabetes (see Figure 2 for characteristics of ideal candidates). Some final considerations when deciding to initiate therapy: as mentioned previously, none of these agents are approved yet in the US for the treatment of T1DM due to a mixture of efficacy and safety concerns. At this time, the cardiovascular benefits demonstrated by SGLT2 inhibitors in patients with T2DM may not be extrapolated to patients with T1DM, which negates that potential added benefit. Additionally, these agents are expensive and can run close to $20 per tablet without insurance. Lastly, in several of the studies discussed, patients were provided with a means to monitor blood ketones as a way of minimizing the risk of DKA. These machines are not widely available in the US, are not likely covered by insurance, and purchasing outright could increase out-of-pocket costs to unmanageable levels. Urine ketone strips were also provided in several studies; however, separate studies have shown that urine ketone strips are not effective at detecting development of DKA, and these tests still pose an expense barrier. In addition, the studies that provided these monitoring devices still found a statistically significant difference in DKA risk, which may indicate that their use does not actually help to mitigate DKA occurrence. If a patient is interested in initiating therapy, it should be a provider-patient decision that weighs these risks and benefits, especially knowing that this is not a currently FDA-approved indication in the US.

    Take CE Quiz

    References

    1. Ratner RE, Dickey R, Fineman M, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med 2004; 21: 1204–1212.
    2. Edelman S, Garg S, Frias J, et al. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care 2006; 29: 2189–2195.
    3. Meng H, Zhang A, Liang Y, Hao J, Zhang X, Lu J. Effect of metformin on glycaemic control in patients with type 1 diabetes: a meta-analysis of randomized controlled trials. Diabetes Metab Res Rev 2018; 34: e2983.
    4. Petrie JR, Chaturvedi N, Ford I, et al.; REMOVAL Study Group. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2017; 5: 597–609.
    5. Wang W, Liu H, Xiao S, Liu S, Li X, Yu P. Effects of insulin plus glucagon-like peptide-1 receptor agonists (GLP-1RAs) in treating type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetes Ther 2017; 8: 727–738.
    6. Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care 2015; 38: 2258–2265.
    7. Dandona P, Mathieu C, Phillip M, et al.; DEPICT-1 Investigators. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5: 864–876.
    8. Patoulias D, Imprialos K, Stavropoulos K, Athyros V, Doumas M. SGLT-2 inhibitors in type 1 diabetes mellitus: a comprehensive review of the literature. Curr Clin Pharmacol. 7 August 2018 [Epub ahead of print].
    9. Standards of Medical Care in Diabetes – 2019.
    10. Dellepiane S, Nasr M, Assi E, et al. Sodium Glucose Cotransporters Inhibitors in Type 1 Diabetes. Pharmacological Research 2018; 133: 1-8.
    11. Mathieu C, Dandona P, Gillard P, et al. Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial. Diabetes Care 2018; 41 (9): 1938-1946.
    12. Pieber TR, Famulla S, Eilbracht J, et al. Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes Metab. 2015; 17: 928-935.
    13. Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care 2018; 41: 2560-2569.
    14. Buse JB, Garg SK, Rosenstock J, et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American inTandem1 study. Diabetes Care 2018; 41: 1970-1980.
    15. Danne T, Cariou B, Banks P, et al. HbA1C and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes: the European inTandem2 study. Diabetes Care 2018; 41: 1981-1990.
    16. Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med 2017; 377: 2337-2348.
    17. CENTERS FOR DISEASE CONTROL AND PREVENTION. NATIONAL DIABETES STATISTICS REPORT, 2017. ATLANTA, GA: CENTERS FOR DISEASE CONTROL AND PREVENTION, U.S. DEPT OF HEALTH AND HUMAN SERVICES; 2017.
    18. Goldenberg R, Gilbert J, Hramiak I, Woo V, Zinman B. Sodium-glucose co-transporter inhibitors, their role in type 1 diabetes treatment and a risk mitigation strategy for preventing diabetic ketoacidosis: The STOP DKA Protocol. Diabetes Obes Metab 2019: 1-11.
    19. Rawla P, Vellipuram A, Bandaru S, Raj J. Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma. Endocrinol Diabetes Metab Case Rep 2017: 17-0081.
    20. Gajjar K, Luthra P. Euglycemic Diabetic Ketoacidosis in the Setting of SGLT2 Inhibitor Use and Hypertriglyceridemia: A Case Report and Review of Literature. Cureus 2019: e4384.
    21. Cefalo CMA, Cinti F et al. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovascular Diabetology 2019, https://doi.org/10.1186/s12933-019-0828-y.
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