The MSHP R&E Foundation continues to offer both our Resident Ground Rounds series and our Preceptor Development Series.
Information for the Resident Ground Rounds Series can be found here:
This series is expected to run routinely (approximately every other week) for the next several months. We are excited to bring this offering forward to provide a vehicle for residents within the state to continue to hone their presentations skills as well as share new information with other pharmacy practitioners (pharmacists, technicians, and students) throughout the state. These sessions are available for CE through the Missouri State Board of Pharmacy.
Our next session of our Preceptor Development Series will occur on February 24th and will be titled Enhancing Layered Learning Experiences for Preceptors and Learners. Registration and additional details will be shared in the near future.
R&E Foundation award nominations and poster submissions were due January 14th, 2022. We are busy evaluating these submissions and look forward to contacting the award winners and poster presenters over the next few weeks in preparation for our annual Spring Meeting.
Regarding the Spring Meeting if you, your organization, or other colleagues want to assist in the R&E Foundation fundraising efforts, we will once again be hosting a virtual auction. Of course, if you cannot sponsor a basket, we encourage you to bid on the baskets throughout the meeting later in the year!
Tony Huke, Pharm.D., BCPSMSHP R&E Executive Director
Farah Alhalabi, 2022, PharmD Candidate
Heather Erwin, PharmD, MHA, BCPS
Pneumococcal disease, caused by Streptococcus pneumoniae, can cause many types of illnesses. Most of these are mild, but some are considered invasive and can be fatal, such as meningitis, bacteremia, and pneumonia.1 While pneumococcal disease is very common in children, certain adults can also be at a very high risk. In fact, one in every four to five patients who are 65 years and older die after contracting pneumococcal disease.2 There are two types of vaccines that help prevent pneumococcal disease: pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23).3
PCV13 helps protect against thirteen types of pneumococcal bacteria and is recommended for both children and some adults.3 Regardless of age, patients with immunocompromising conditions or treatment, (such as human immunodeficiency virus, malignancy, or organ transplant), cochlear implant, anatomic or functional asplenia, and sickle cell disease should receive the PCV13 vaccine. In addition, patients with certain higher risk chronic medical conditions, such as chronic renal failure, nephropathy, or cerebral spinal fluid leak, are eligible for the PCV13 vaccine.4
The recommendations for PCV13 in patients without immunocompromising conditions are less specific. In 2014, the Advisory Committee on Immunization Practices (ACIP) recommended routine administration of PCV13 in addition to PPSV23 for all patients 65 years of age or older.5 However, in 2019, ACIP changed its recommendation for patient eligibility in the 65 years of age or older group for PCV13 to a shared decision-making process between patients and healthcare providers. This was largely due to increased pediatric uptake of PCV13 leading to decreased population-based burden and transmission. As a result, providers may be faced with a challenge in determining the best candidates for this vaccination among their patients without immunocompromising conditions.
Per ACIP, herd immunity protecting older individuals is likely impacted by decreasing childhood immunization rates, inadequate access to care in certain communities, or lack of a childhood PCV13 program. Thus, a shared clinical decision is based on individual rather than population level benefits.4 Risk of exposure to PCV13 serotypes and underlying disease(s) that a patient has are important factors to consider when determining the benefit of PCV13 for that individual. The vaccine is indicated for adults 65 years of age or older with medical conditions that can make PCV13 type disease burden higher in this age group. These include chronic medical conditions, such as heart disease, liver disease, and lung disease; diabetes mellitus; and inflammatory bowel disease. In addition, the vaccine is recommended for patients who smoke regularly and drink excessive amounts of alcohol. Moreover, patients who are homeless, those who have had a prior pneumonia, or people living in areas where the risk is much higher (e.g., nursing homes, shelters, and jails) should receive the PCV13 vaccine per ACIP.4 In addition, certain types of medications, such as proton pump inhibitors, antipsychotics, opioids, and sedatives may increase a patient’s risk of contracting pneumonia, so individuals on one or more of these medications may also be candidates to receive the PCV13 vaccine if deemed desirable after a discussion between the clinician and the patient. Lastly, groups at a higher risk of contracting pneumococcal infection, such as frail patients, African Americans, Alaska natives, and American Indians, could also benefit from PCV13 vaccine.4
The CDC recommends that PCV13 be administered first when a patient is eligible. The timing of PPSV23 administration following PCV13 vaccination is age- and indication-dependent and detailed in Table 1. If a patient has received a dose of PPSV23 before and is due for another PPSV23 immunization, they should wait five years until receiving that subsequent dose.2 More guidance on PPSV23 eligibility and administration is available on the CDC website.
Because the changes to eligibility and dosing schedules of PCV13 can be complicated and providers may not always find the time to effectively review the benefits of PCV13 with every patient, pharmacists play a vital role in educating patients and providers about pneumococcal vaccines. Pharmacists can help in identifying patients who are candidates for PCV13, especially patients who are immunocompromised or have chronic health conditions that put them at a greater risk of getting pneumococcal disease. The CDC offers excellent resources for patients and healthcare providers to help guide them toward safe and appropriate vaccination decision-making. Pharmacists and healthcare providers should also involve the patients in making this decision by explaining the benefits of PCV13 based on their conditions or risk factors while taking into consideration values, preferences, and views toward vaccinations.
Authors: Lauren Busch, Pharm.D. Candidate 2022, Michelle Tulchinskaya, Pharm.D. Candidate 2022, and Yvonne Burnett, Pharm.D., BCIDP
Sexually transmitted infections (STIs) or sexually transmitted diseases (STDs) in the U.S. are on the rise with an all-time high reached for the sixth consecutive year. According to the most recent STI surveillance report by the Center for Disease Control and Prevention (CDC), more than 2.5 million cases of chlamydia, gonorrhea, and syphilis were reported in 2019.1 Chlamydia and gonorrhea testing reached its lowest point in early April 2020, which is associated with the rise of the COVID-19 pandemic, with 27,659 chlamydia and 5,577 gonorrhea cases potentially missed.2 Stigma still remains as a major barrier to treatment as well. Knowledge and understanding of STIs help identify the issues and controversies contributing to the stigma created by STI diagnosis and treatment.3 The CDC’s STI treatment guidelines have been updated in July of 2021 with several new recommendations regarding gonorrhea, chlamydia, pelvic inflammatory disease, trichomoniasis, and Mycoplasma genitalium treatment.4 In addition, the CDC provides a thorough discussion of STIs that allow the healthcare team to gain the necessary understanding of the underlying factors surrounding STI stigma.3 As the guidelines had not been previously updated since 2015, it is important for clinicians to be aware of the several new recommendations in order to best serve their patients.
CDC guidelines have previously recommended ceftriaxone 250 mg intramuscularly (IM) plus azithromycin 1 g orally for the treatment of uncomplicated gonococcal infections of the cervix, urethra, and rectum due to high rates of chlamydia co-infection and in order to delay resistance of Neisseria gonorrhoeae to cephalosporins.5 However, the new CDC guidelines recommend ceftriaxone monotherapy as a single 500 mg IM dose (1 g if patient ≥ 150 kg). If chlamydia coinfection has not been ruled out, then doxycycline 100 mg orally twice daily for 7 days should be added. The removal of azithromycin from the treatment regimen is due to increasing concern for growing rates of resistance to azithromycin by N. gonorrhoeae as well as M. genitalium, Shigella, and Campylobacter. Azithromycin is also no longer equally recommended as the preferred treatment for chlamydia alongside doxycycline as discussed below. The increased dose of ceftriaxone is thought to be necessary for N. gonorrhoeae isolates with elevated minimum inhibitory concentrations (MICs). Data shows that even though 250 mg of ceftriaxone is >99% effective in curing anogenital gonorrhea, a higher dose is needed for strains with a higher MIC.4 Ceftriaxone also needs to have a concentration above the MIC for a longer amount of time when treating pharyngeal gonorrhea compared to urogenital gonorrhea, and a 500 mg dose of ceftriaxone allows for about 50 hours above an MIC of >0.03 mcg/mL.6-8
Though other single-dose injectable cephalosporin regimens have been shown to be effective against uncomplicated urogenital and anorectal gonococcal infections in the past, the pharmacokinetics of these regimens have not been evaluated and are at a disadvantage when compared to ceftriaxone 500 mg. Cefixime is still a single oral dose alternative regimen in the new guidelines; however, it is now recommended without azithromycin and the recommended dose has increased to 800 mg.4 From 2006-2011, the minimum concentrations of cefixime needed to inhibit in vitro growth of the N. gonorrhoeae strains circulating increased, demonstrating that cefixime effectiveness may be decreasing.9 Therefore, cefixime should only be used as an alternative if ceftriaxone is not available. Additionally, an alternative regimen for patients allergic to cephalosporins is gentamicin 240 mg IM plus azithromycin 2 g orally as a single dose.4
The preferred treatment regimen for chlamydia among adolescents and adults is now doxycycline 100 mg orally twice daily for 7 days.4 Azithromycin 1 g orally in a single dose, previously a recommended regimen, is now only recommended as an alternative regimen for pregnant patients.4,5 This change is due to concern regarding the efficacy of azithromycin in treating rectal chlamydia infections.4 The presence of rectal chlamydia cannot be predicted based on sexual practices. Inadequately treated rectal Chlamydia trachomatis infection can increase the risk for transmission and put women at risk for repeat urogenital C. trachomatis infection through autoinoculation from the anorectal site. Treatment failure among men was higher for azithromycin than doxycycline, and other studies found that for rectal chlamydia infection among men who have sex with men (MSM) reported microbiologic cure of 100% with doxycycline vs. 74% with azithromycin.10-15 Azithromycin may be used when non-adherence to doxycycline is a concern, but might require post-treatment evaluation and testing due to lower effectiveness in treating rectal infection. Erythromycin is also no longer recommended as an alternative agent due to the frequency of gastrointestinal adverse effects that can result in non-adherence.4
Pelvic Inflammatory Disease
The recommended treatment of pelvic inflammatory disease (PID) was updated to include metronidazole, while previously it was optional.4,5 Metronidazole has been shown to more effectively eradicate anaerobic organisms in the upper genital tract, which helps prevent long-term side effects such as infertility and ectopic pregnancies.16 A new recommended parenteral regimen consists of ceftriaxone 1 g intravenously (IV) every 24 hours plus doxycycline 100 mg orally or IV every 12 hours plus metronidazole 500 mg orally or IV every 12 hours.4 Cefotetan plus doxycycline and cefoxitin plus doxycycline are still recommended parenteral regimens; however, clindamycin plus gentamicin is now only recommended as an alternative parenteral regimen along with ampicillin/sulbactam and doxycycline.4,5 The guidelines recommend transitioning to oral therapy, after 24-48 hours of clinical improvement with parenteral therapy, with a single dose of ceftriaxone 500 mg IM plus doxycycline 100 mg PO BID and metronidazole 500 mg PO BID for a total treatment duration of 14 days.4 The updated guidelines recommend doxycycline with the addition of metronidazole as these regimens have demonstrated improved prevention of long-term complications associated with PID.4,5
Recommendations for the treatment of trichomoniasis have also changed between the 2015 and 2021 guidelines. Previously, metronidazole 2 g orally or tinidazole 2 g orally as a single dose was preferred, with metronidazole 500 mg orally twice daily for 7 days as an alternative regimen.5 Now, the guidelines recommend metronidazole 500 mg PO BID for 7 days for women and metronidazole 2 g PO as a single dose only for men with tinidazole 2 g PO as a single dose as the alternative for both men and women.4 The change in recommendations comes from new data that demonstrates multi-dose metronidazole is more effective than the 2 g-single dose in women.17 There is currently no data comparing the different dosing regimens of metronidazole in men, so the 2 g-single dose is still preferred in this population.4
The treatment ofMycoplasma genitalium was only addressed in the setting of urethritis, cervicitis, and PID in the previous guidelines. The 2015 guidelines stated azithromycin 1 g PO was preferred over the 7-day PO doxycycline course; however, azithromycin resistance was identified to be on the rise. Moxifloxacin 400 mg daily PO for 7 days was also mentioned as a treatment with a few cases of success, but was not yet tested in clinical trials.5 The current CDC guidelines give the first official recommendations for the treatment of Mycoplasma genitalium. The guidelines recommend against the use of a single dose of 1 g azithromycin due to high rates of macrolide resistance with treatment failures. Treatment should use macrolide resistance-guided therapy. If macrolide sensitive, doxycycline 100 mg PO BID for 7 days, followed by a 1 g PO dose of azithromycin, then azithromycin 500 mg PO daily for 3 more days is recommended. If the strain is resistant to macrolides, doxycycline 100 mg PO BID for 7 days followed by moxifloxacin 400 mg PO daily for 7 days is recommended. If resistance testing is not available (currently not available in the U.S.), it is recommended to treat as if the M. genitalium is macrolide resistant. Doxycycline is included in treatment regimens because it is thought to reduce the organism load and help with clearance of the organism. The new guidelines state that PID treatment regimens are not effective against M. genitalium; therefore, after initial treatment of PID with doxycycline 100 mg PO BID for 14 days, if M. genitalium is detected, moxifloxacin 400 mg PO daily for 14 more days is recommended. The guidelines also updated to recommend a newly FDA-cleared nucleic acid amplification test (NAAT) to test for M. genitalium in men with recurrent non-gonococcal urethritis, women with recurrent cervicitis, and to be considered for women with PID.4
Overall, the 2021 CDC STI treatment guidelines contain several updates regarding not only treatment recommendations, but also diagnostic and screening recommendations.4 Clinicians must be aware of these new updates to best treat their patients due to evolving resistance patterns and new evidence since 2015. The updated guidelines also emphasize the importance of primary prevention of STIs through assessing behavior risk and biologic risk and routinely asking about sexual histories using effective counseling skills.4 With the COVID-19 pandemic potentially hindering patients’ access to screening and treatment, clinicians must be prepared with the knowledge of new treatment recommendations and with effective counseling strategies for when patients are able to seek care.
Authors: Kitana Caesar, PharmD Candidate 2022 and Gabrielle Gibson, PharmD, BCPS, BCCCP
Open fractures are injuries frequently seen in emergency departments or trauma centers. Typically, the skin barrier has been compromised, exposing the sterile bone to environmental debris and soft tissue damage. Exposure to the ambient environment places these wounds at an increased risk of infection.1 The Gustilo-Anderson classification system is utilized to grade the severity of open fractures, and to determine appropriate antibiotic prophylaxis (Table 1). The infection rates for grade I/II fractures range from 0 to 7% whereas the grade III fracture infection rate ranges from 5 to 50% without antibiotic prophylaxis.3 Ineffective prophylaxis may lead to complications such as nonunion of bones and osteomyelitis.2 In fact, 19% of osteomyelitis cases are secondary to traumatic injury. As such, the use of antibiotic prophylaxis to decrease the rate of infective complications after open fractures has been considered standard of care for over 30 years.
As with many historic practices, the justifications for the use of antibiotics have become obscured over time. Recent studies have been based on the standards established by a few key papers with no re-evaluation of the application of those principles in the setting of modern open fracture management nor today’s antibiotic and bacterial resistance patterns. As a result, open fracture antibiotic prophylaxis is currently defined and instituted variably, and evaluation of recommended approaches has been slowed by reluctance to challenge familiar practice patterns. Further complicating standardization is the lack of recommendations for a specific antibiotic and dose combination in open fracture guidelines.1,4 Therefore, this review will aim to analyze antibiotic prophylaxis regimens as well as suggested durations of therapy.
The most common pathogens involved in grade I/II fractures include Gram-positive bacteria (e.g.: Streptococcus spp. and Staphylococcus spp.).1 Patients presenting with grade III fractures and exposure to certain environmental factors are predisposed to infections involving Gram-negative bacteria (e.g.: Enterobacter cloacae and Pseudomonas aeruginosa).1 Increased presence of methicillin resistant Staphylococcus aureus (MRSA) occurs in patients with prior MRSA infection, prior MRSA nasal carriage, wounds present on admission, nursing home residents, recent prolonged health system exposure, and comorbidities, including diabetes or heart failure.5 Prophylactic antibiotic regimens should therefore be tailored to the severity of the fracture and the environment in which the fracture took place. The Eastern Association for the Surgery of Trauma (EAST) guidelines recommend that antibiotic coverage be directed at Gram-positive organisms and additional Gram-negative coverage be added for grade III fractures.1 The Surgical Infection Society (SIS) guidelines recommend first-generation cephalosporins be initiated as soon as possible but make no recommendations for gram-negative or clostridial coverage (Table 2).4
The aforementioned antibiotic recommendations largely originated from a study by Patzakis and colleagues published in 1974.6 This randomized, placebo-controlled trial was the first to examine infection rates in open fractures in relation to antibiotic use and as such, it continues to impact practice today. This study included 310 patients with open fractures (not graded for severity) over a one year period. Patients were randomized to three groups: no antibiotics, penicillin and streptomycin (aminoglycoside), or cephalothin (first-generation cephalosporin with a spectrum of activity similar to cefazolin) for 10–14 days. The study found that patients receiving cephalothin had a lower incidence of infection (2.4%) than the penicillin/streptomycin group (9.8%) and the control group (13.9%), with statistical significance between placebo and cephalothin groups only.6 These data provided strong evidence for the efficacy of first-generation cephalosporins in managing open fractures. In the same study, the investigators described the bacteria that caused the fractures to become infected. In the placebo group, the isolated organisms included Gram-positive, Gram-negative, and rarely Clostridium spp. The penicillin/streptomycin group developed infections with Staphylococcus aureus and Enterobacterales including Pseudomonas spp., whereas the cephalothin group demonstrated infections with gram-negative species.6 These findings led the authors to suggest that combination streptomycin and a cephalosporin would reduce infection rates further. However, this hypothesis was never tested and remains an extrapolation unsupported by the data. Nonetheless, conclusions from this study have been cited for over 30 years.
Therefore, the current recommended antibiotic for all fracture grades is a cephalosporin (including first-, second-, and third-generation). Expanded Gram-negative coverage is recommended for grade III fractures if a first- or second-generation cephalosporin is selected, and additional anaerobic coverage is needed if the fracture is contaminated with soil or fecal matter. Guidelines do not recommend a specific Gram-negative agent, but aminoglycosides are widely used for prophylaxis in open fractures. Recently, the use of aminoglycosides has fallen out of favor due to nephrotoxicity and ototoxicity. A study by Bankhead-Kendall and colleagues evaluated 126 grade III fractures at their institution over a 5-year period.7 Antibiotic prophylaxis was based on the treating surgeon’s preferences, and roughly half (52%) were treated with a first-generation cephalosporin, while the other half (48%) were treated with the addition of an aminoglycoside. No difference was observed in surgical site infection, but there was a statistically significant increase in acute kidney injury in those treated with an aminoglycoside.7 Currently, there is insufficient evidence to support routine gram-negative coverage in prophylaxis for all open fractures.4 Additionally, in the event of a true allergy to cephalosporins, clindamycin and aztreonam may be considered for gram-positive and gram-negative coverage.1 Vancomycin is reasonable to add if patients have risk factors for a MRSA infection (Table 2).
A study by Rodriguez and colleagues evaluated a new protocol that was implemented at their institution. This pre- and post-protocol implementation analyzed 174 patients (101 pre-protocol and 73 post-protocol) with open fracture and stratified groups according to Gustilo-Anderson fracture grade, fracture site, and persistence of resistant organisms. Patients with grade I/II fractures received cefazolin while patients with grade III fractures received ceftriaxone for 48 hours. Aminoglycosides, penicillin, and vancomycin were removed from the post-protocol. There was no difference in skin or soft tissue infection rate per fracture before or after protocol implementation (20.8% vs 24.7%, p=0.58). The authors concluded that implementation of an evidence-based, narrow spectrum antimicrobial prophylaxis protocol resulted in similar infection rates.3 This was one of the first trials to challenge the use of broad-spectrum antibiotics and aminoglycosides when potentially less toxic and narrower agents could be considered.
The duration of antibiotic prophylaxis is a crucial aspect in the management of open fractures. The SIS and EAST guidelines recommend starting antibiotics immediately following injury in all fracture types.1,4 Antibiotics are continued for 24-72 hours depending on the severity of the open fracture and the time soft tissue coverage occurs. For grade III fractures, the EAST guidelines suggest continuing antibiotics for 72 hours after injury but not greater than 24 hours from the time soft tissue coverage is achieved.1 Chang et al demonstrated through a meta-analysis that infection rates between longer durations (3-5 days) and shorter duration (1 day) of antibiotics were no different. However, there was significant risk of bias present considering the included publications were largely provider-reported reviews of practice recommendations whose focus was not antibiotics.8 The SIS guidelines suggest that 48 hours of therapy may be appropriate in grade II fractures, but longer courses of antibiotics do not reduce the risk of infection and can lead to the development of drug resistant organisms and increased adverse effects.4,9 Accordingly, a duration of 24 hours for all fracture types is considered adequate prophylaxis, with special consideration for longer durations (up to 72 hours) in higher grade fractures.
Open fractures of all grades have a risk of infection, and patients benefit from antibiotic prophylaxis. Differences in the recommended antibiotic regimen and durations persist and understandably, optimal prophylactic antibiotic therapy may be dependent on the context of the injury. Although there are limited data supporting the efficacy of narrow-spectrum antibiotics for shorter durations of therapy, developing a unified approach regarding optimal therapy and duration for open fracture antibiotic prophylaxis will require a large, randomized trial.
Program Number: 2021-10-02Approved Dates: December 1, 2021-June 1, 2022Approved Contact Hours: One Hour(s) (1) CE(s) per session
Pharmacist Continuing Education: 2021 Rheumatoid Arthritis Guideline Update and Therapy Review Authors: Annie Ungerman, PharmD, BCPS, University Health - Kansas City, MO and Mary Beth Seipel, PharmD, BCACP, University Health - Kansas City, MO
What is Rheumatoid Arthritis?
Rheumatoid arthritis (RA) is an autoimmune disorder with unknown etiology that is commonly characterized by chronic inflammation, severe pain, joint stiffness, fatigue, and limited mobility.1,2 RA usually leads to destruction of joints due to erosion of cartilage and bone, which may cause joint deformities. Onset can occur at any time, but incidence increases with age. Women are more likely to be diagnosed than men are (by two-to-three times). Other characteristics that are more common in those developing rheumatoid arthritis are women who have never given birth, cigarette smoking, and obesity.1,2 Early evaluation, diagnosis, and management are imperative in achieving adequate control of disease and prevention of further progression.3
Early evaluation for suspected RA1
Diagnosis of RA often relies on a detailed past medical history, thorough physical examination, pertinent laboratory tests, and radiographic evidence consistent with joint damage. Radiographs of the hands, wrists, and feet are frequently used as a baseline for monitoring disease activity or progression.
Pertinent information to collect and examine may include, but is not limited to the following:
The following laboratory tests should be considered and may support a diagnosis of RA if positive and/or elevated:
Diagnosis of RA4
Based on the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification criteria for RA (as described below), classification of “definite RA” is outlined as:
Management of RA3
Pharmacological treatment of RA involves the following:
A treat-to-target approach is recommended for individuals who have not been previously treated with or have experienced an inadequate response to bDMARDs or tsDMARDs. This approach involves frequent monitoring of disease activity levels through the use of validated instruments. Modifications to an individual’s treatment are implemented based on response to prescribed therapy, which is determined by a reduction in disease activity. The overall goal of pharmacological treatment is to achieve a predefined target of low disease activity or remission. It is recommended to reevaluate treatment decisions within a minimum of 3 months based on efficacy and tolerability of prescribed DMARDs.3
Instruments to measure RA disease activity are recommended by the ACR for use to further define levels of disease activity (low, moderate, high) based on a variety of factors, including patient-reported symptoms, provider assessments, laboratory values, and/or imaging modalities.5 Table 2 shares details regarding thresholds of disease activity based on the tool used. The DAS28, CDAI, and SDAI all require a 28 count of specific joints, stating if they are tender and/or swollen joints. They vary in whether they incorporate an inflammatory marker or patient/provider rating of global health. Both the RAPID-3 and PAS II have similar questions on patient reported ability in being able to carry out 10 different tasks, a pain assessment, and/or a personal assessment.6-10
Moderate-to-high disease activity:
In patients that have moderate-to-high disease activity and are DMARD naive, methotrexate is strongly recommended over hydroxychloroquine or sulfasalazine and bDMARDs or tsDMARD monotherapy. In this same patient population, methotrexate is conditionally recommended over leflunomide, dual or triple csDMARD therapy, or combination of methotrexate plus a TNF inhibitor.Methotrexate is recommended in this patient population due to its established efficacy and low cost. When initiating methotrexate, the oral formulation is preferred over subcutaneous as bioavailability is comparable at initial dosing and ease of use. If patients have issues tolerating oral methotrexate, management strategies include dividing the weekly dose over 24 hours, switching to a subcutaneous route of administration, or increasing folic acid dosing. These are all recommended over switching to an alternative DMARD.3
The use of glucocorticoids for patients with moderate-to-high disease activity during initiation of csDMARD therapy for short-term (<3 months) or long-term (≥3 months) use is not recommended as the risks of toxicity outweigh the benefits. If a patient is unable to remain at target without glucocorticoids, it is conditionally recommended to add or switch DMARDs.3
Low disease activity:
In patients with low disease activity and are DMARD naive, hydroxychloroquine is conditionally recommended over any other csDMARDs, sulfasalazine is conditionally recommended over methotrexate, and methotrexate is conditionally recommended over leflunomide.3
DMARDs that were mentioned in the guidelines as treatment options for rheumatoid arthritis are listed in tables 3, 4 and 5. Typical dosing, adjustments and additional information are shared below.
TABLE 4: (download the PDF)
Recommendations for specific patient populations:
The 2021 RA guidelines address management of RA in individuals with specific comorbidities. Certain populations are discussed for the first time, including those with subcutaneous nodules, non-alcoholic fatty liver disease, and pulmonary disease.3
Methotrexate is conditionally recommended over alternative DMARDs if subcutaneous nodules are present in an individual with moderate-to-high disease activity. However, in the presence of progressive subcutaneous nodules, switching to an alternative DMARD is conditionally recommended because methotrexate may be associated with accelerated nodulosis.3, 27
If moderate-to-high disease activity is present, methotrexate is conditionally recommended over alternative DMARDs for individuals with clinically diagnosed mild and stable airway or parenchymal lung disease, or incidental disease detected on imaging.3 Preexisting lung disease is a risk factor for methotrexate-related pneumonitis.28,29 However, its use remains conditionally recommended due to its efficacy and lack of alternatives with similar benefits or superior long-term safety profiles. Those with preexisting lung disease should be educated on their increased risk of methotrexate-related pneumonitis before starting treatment.3
Heart failure (HF)
Risk of worsened HF was observed in trials of TNF inhibitors given to individuals with New York Heart Association class III or IV HF without RA.30,31 The low quality of evidence available resulted in the conditional recommendations to follow. If an individual with NYHA class III or IV HF has an inadequate response to csDMARDs, addition of a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended over addition of a TNF inhibitor. Additionally, if an individual develops HF while taking a TNF inhibitor, switching to a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended.3
For individuals with moderate-to-high disease activity and history of a previous lymphoproliferative disorder, rituximab is conditionally recommended over other DMARDs because it is not expected to increase risk of recurrence or worsening of these disorders.3
Hepatitis B infection
Those at risk for hepatitis B reactivation should be comanaged with a hepatologist. Prophylactic antiviral therapy is strongly recommended over frequent monitoring of viral load and liver enzymes alone for individuals starting rituximab who are hepatitis B core antibody positive, regardless of hepatitis B surface antigen status. If an individual is hepatitis B core antibody positive and hepatitis B surface antigen positive, prophylactic antiviral therapy is strongly recommended over frequent monitoring alone when initiating any bDMARD or tsDMARD. Due to uncertainty regarding benefit versus risk of prophylactic antiviral therapy and cost associated with use, frequent monitoring alone is conditionally recommended for individuals starting a bDMARD (other than rituximab) or a tsDMARD who are hepatitis B core antibody positive and hepatitis B surface antigen negative.3
Nonalcoholic fatty liver disease (NAFLD)
For DMARD-naive individuals with moderate-to-high disease activity and NAFLD with normal liver enzymes, liver function tests, and no evidence of advanced liver fibrosis, methotrexate is conditionally recommended over alternative DMARDs. Consultation with a gastroenterologist or hepatologist should be considered prior to initiating methotrexate in individuals with NAFLD.3
Persistent hypogammaglobulinemia without infection
The clinical significance of hypogammaglobulinemia in individuals without infection remains unknown. Continuation of rituximab for individuals at target is conditionally recommended over switching to an alternative bDMARD or tsDMARD in the setting of persistent hypogammaglobulinemia without infection. It is uncertain if switching to a different DMARD in those who are at target reduces infection risk to a larger degree while maintaining disease control versus continuation of rituximab.3
Previous serious infection
The 2021 guidelines define a serious infection as an infection requiring intravenous antibiotics or hospitalization. Addition of csDMARDs is conditionally recommended versus bDMARD or tsDMARD for individuals with moderate-to-high disease activity who have experienced a serious infection within the past 12 months.3 This conditional recommendation is based on observational data, which suggests a lower risk of infection associated with combination csDMARDs compared to bDMARDs or tsDMARDs.32
Nontuberculous mycobacterial (NTM) lung disease
Due to the variability of NTM lung disease severity and response to treatment, individuals should be closely comanaged with an infectious diseases or pulmonary specialist. Studies suggest an increased risk of NTM lung disease in individuals receiving inhaled or oral glucocorticoids.33,34 Therefore, discontinuation or use of the lowest possible dose of glucocorticoids is conditionally recommended for those with NTM lung disease.3 Due to lower expected risk of NTM lung disease, addition of csDMARDs is conditionally recommended versus bDMARD or tsDMARD for individuals with moderate-to-high disease activity.35 For individuals with NTM lung disease and moderate-to-high disease activity despite use of csDMARDs, abatacept is conditionally recommended over other bDMARDs and tsDMARDs.3
Key takeaways and future considerations:
Take the Quiz for CE
The MSHP R&E Foundation has successfully completed the first occurrence of both our Resident Ground Rounds series and our Preceptor Development Series.
Information for the Resident Ground Rounds Series can be found here: https://www.moshp.org/event-4540419
This series is expected to run routinely (approximately every other week) for the next several months. We are excited to bring this offering forward to provide a vehicle for residents within the state to continue to hone their presentations skills as well as share new information with other pharmacy practitioners (pharmacists, technicians, and students) throughout the state. These sessions are available for CE through the Missouri State Board of Pharmacy.
Our first session of our new Preceptor Development Series occurred on October 26th with MSHP President Christina Stafford as our first presenter. The event was a success and will be continued with new presenters, different topics, and various presentation methods. Our goal is to offer this series quarterly, please look for more information via e-blasts in the near future.
Lastly, it is time to start thinking about nominations for the R&E Foundation annual awards. Nominations for our three awards (Best Practice Award, Tonnies Preceptor Award, and The Garrison Award) are currently open. The nomination/submission deadline is January 14th, 2022.
Information about each award and the respective criteria can be found below:
MSHP R&E Best Practice Award
The Best Practice Award recognizes innovation and outstanding performance in health-system pharmacy. A poster of the program will be highlighted during the Spring Meeting Poster Session.
Applicants will be judged based on the following criteria:
Applicants must be active MSHP members in a health-system setting such as a large or small hospital, home health, ambulatory clinic, or other health care system.
Award recipient will receive a $250 honorarium.
Submission Instructions: A program summary not to exceed 400 words must be submitted with the application and include the following information.
Tonnies Preceptor of the Year Award
MSHP R&E Foundation is pleased to honor a health system pharmacist for outstanding service to the profession as a preceptor to pharmacy students and/or residents. Below are the Criteria and Procedures to nominate a preceptor for the award.
The award will be presented to a health system pharmacist that exemplifies the core values (Professionalism, Desire to educate and share knowledge with students, Willingness to mentor, Willingness to commit the time necessary for precepting, Respect for others, Willingness to work with a diverse student population) and the following characteristics:
The Garrison award was established in 1985, named after Thomas Garrison for his long-standing support of MSHP (past-president 1974-1976), ASHP (past-president 1984) and numerous professional and academic contributions to Pharmacy. The Garrison Award is presented each year in which a deserving candidate has been nominated in recognition of sustained contributions in multiple areas:
Each letter of nomination must include:
Tony Huke, Pharm.D., BCPS
MSHP R&E Executive Director
By: Sreemathi Palanisamy, PharmD Candidate 2022, Thara Kottoor, PharmD Candidate 2022, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Haley N. Johnson, PharmD, BCPS; Assistant Professor, Department of Pharmacy Practice, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
The general population is aging as 10,000, “Baby Boomers,” are turning 65 years old each day in the United States. It is predicted that older adults will comprise 20% of the population by the year 2030.1 With the increasing geriatric population, the number of patients with age-related chronic conditions is rising, as well. Elderly patients are prescribed multiple medications to control their chronic illnesses, which increases the risk for adverse events, poor adherence, and direct and indirect healthcare costs.
Polypharmacy, the use of at least five medications,is a growing peril as our healthcare system is heavily driven by evidence-based medicine.2 Specifically, antihypertensive medications are commonly prescribed in older populations to prevent strokes and cardiovascular diseases. Although efficacious, the agents can also increase the risk of falls, which could potentially be fatal, induce cognitive decline, and decrease overall quality of life. “Deprescribing,” is a method used to adjust medications to their minimum effective dosage or ceasing therapy if the harm outweighs the benefits of treatment. Although best practice recommendations such as the Beers, STOPP, and START criteria, highlight using clinical judgment and taking a patient-specific approach when prescribing antihypertensives in elderly patients, there has been a lack of data and literature noting the long term effects after antihypertensive medications have been deprescribed in the geriatric population.3,4
The Systolic Blood Pressure Trial (SPRINT) compared two strategies for treating systolic blood pressure (SBP) in reducing the incidence of several cardiovascular events and death, one that targeted a systolic blood pressure (SBP) of <140 mm Hg and another that targeted a more intensive SBP target of <120 mm Hg. Patients who were 50 years or older, had an average baseline SBP ≥ 130 mmHg, and at high cardiovascular risk were included in the study. Although higher rates of adverse events were observed in the intensive treatment group, the study supported an intensive treatment for a target SBP of 120 mm Hg for a significant 34% reduction in fatal and CVD events compared to patients who were treated with a SBP target of 140 mmHg.5 These results were consistent among all the age groups that participated in the study, including patients who are 75 year of age or older. However, the SPRINT trial did not include geriatric patients with multiple comorbidities including diabetes, dementia, stroke, and other conditions that would reduce participants’ life expectancy, so the study is limited by its lack of generalizability to patients who may experience more adverse events with intensive blood pressure goals.
Even though medication de-escalation is believed to attenuate efficacy, research has shown that adequate hypertension management can be achieved with fewer drug interventions. Specifically, the Hypertension in Very Elderly Trial (HYVET) found that the antihypertensive indapamide (a thiazide-like diuretic), with or without perindopril (an angiotensin-converting enzyme inhibitor), was beneficial in reducing the risk of fatal or nonfatal stroke, heart failure, and death from stroke or any cause in patients aged 80-89 years old treated to a target blood pressure of 150/80 mm Hg.6 However, the HYVET trial had extensive exclusion criteria, excluding patients with dementia, renal failure, and nursing home residents. 6 Thus, the narrowed participant pool does limit the external validity of the trial’s applicability to a wide range of elderly patients.
According to the Optimizing Treatment for Mild Systolic Hypertension in Elderly (OPTIMISE) randomized control trial, patients 80 years and older are able to maintain their blood pressure goal with antihypertensive de-escalation via removal of one drug. The randomized, non-inferiority, multicenter study included 569 patients who were aged 80 years and older, had a SBP lower than 150 mm Hg at baseline, and were prescribed at least two antihypertensive medications. Patients were allocated in a 1:1 ratio to the intervention group, or de-escalation group, by removing one antihypertension medication, or the control group, in which patients were continued on their current regimens. The OPTIMISE study highlighted that medication reduction is efficacious to standard therapy as the mean SBP in the intervention group and usual care group were 133.7 mmHg and 130.8 mmHg, respectively.7 The trial only evaluated the benefits of antihypertensive reduction over a 12 week period, so it is not conclusive of long-term clinical outcomes. Additionally, the study was conducted in an unblinded manner, with primary care providers allocating patients to medication de-escalation vs. the control group based on their clinical assessments, decreasing the study’s overall internal validity.The study also focused on a narrow spectrum of patients, 80 years and older, which is not representative of the overall geriatric population. 7 Despite the study’s methodology, the OPTIMISE trial was able to support a “less is more” approach in antihypertensive management in geriatric patients.
The SPRINT, HYVET, and OPTIMISE trials focused on patients with antihypertensive medications in outpatient settings. However, elderly patients are often prescribed intensified blood pressure regimens to manage their cardiovascular health upon discharge after hospitalizations. Anderson and colleagues conducted a study that looked at clinical outcomes after intensifying antihypertensive therapies upon discharge for geriatric patients who were hospitalized for pneumonia, urinary tract infection, and venous thromboembolism. The retrospective study included patients 65 years and older with hypertension admitted to Veterans Affairs (VA) health systems over a two-year period. Discharge with antihypertensive intensification was defined as receiving a prescription at discharge for a new or at least 20% higher-dose of antihypertensive medication than what was used prior to admission.8 The study found that in patients admitted to the hospital for non-cardiac causes, adding an additional antihypertensive was associated with increased risk of hospital readmissions and serious adverse events rather than improvements in blood pressure and fewer cardiac events following discharge.8 The trial primarily consisted of older male patients hospitalized for non-cardiac events, which is not applicable to all hospitalized elderly patients. Nevertheless, the study highlights the insignificance and potential harm in intensifying antihypertensives in elderly patients during hospital admissions.
Even though deprescribing antihypertensives is an area in geriatric medicine with lack of robust research, current studies suggest that de-escalating antihypertensive regimens has a positive impact on elderly patients’ quality of life. Geriatric patients are susceptible to medication-related adverse events due to their declining health, so it is rational to provide them with treatment regimens with adequate therapeutic benefits, minimal toxicities, and cost-effectiveness. Based on the current body of literature, it may be more beneficial to have patients on stable and consistent regimens and with close monitoring and follow-up rather than regularly intensifying antihypertensive therapy. Additionally, the inpatient data on antihypertensive escalation at discharge suggests that it is imperative not to modify chronic disease treatments in inpatient settings considering patients’ likelihood of benefit and the interplay of acute hospital conditions. Thus, clinicians should be cognizant of fluctuating blood pressure values which may be transient in the inpatient setting and should not always make medication adjustments accordingly.9
Pharmacists, specifically, can play a major role in optimizing elderly patients’ antihypertensive medication regimens. Specifically, pharmacists can aid in patients’ transitions of care between inpatient and outpatient settings by performing medication reconciliations to evaluate patients’ likelihood of benefiting from medication reduction. 10 Ambulatory care and community pharmacists can also be proactive in the deprescribing process by having conversations with elderly adults about their medications and consulting with patients’ primary care providers about possibly deprescribing antihypertensive medications.11 Overall, based on current data, pharmacists should feel empowered to have conversations about deprescribing with older patients and healthcare professionals to improve health outcomes in the geriatric population and combat polypharmacy.
The National Transitions of Care Coalition estimated that the United States wastes around 30 to 50 billion dollars in unnecessary medical expenditures to fix transitional care errors each year. Approximately 60% of which are medication related errors. With this in mind, the argument can be made that more emphasis should be placed on pharmacist-led transitions of care (TOC) programs to ensure patients are properly educated on their new medications. Furthermore, this would be a great area for pharmacists to make a positive impact, while expanding our scope of practice. The continuing trend of pharmacists expanding their scope of practice is becoming more and more relevant each year. For example, H.R. 2759/S. 136 is a bill currently in discussion that would add pharmacists to the providers list eligible for Medicare part B service reimbursement. While provider status may continue to elude our profession, pharmacists are the ideal choice to lead TOC programs-- and can successfully implement these programs now. Furthermore, these programs would likely pay for themselves by reducing emergency medical costs paid by health systems.
To begin, what is a transition of care program? A transition of care (TOC) program consists of a healthcare professional that follows up with a patient via phone call after they are discharged from the healthcare facility to return home. The goal of the program is to ensure the accurate communication of all pertinent healthcare information. This can include things such as discussing barriers, medication adherence, and any new developments in their conditions since discharge.
Below is an illustration of a standard TOC program timeline as an example:
The exact process of the TOC program can vary depending on the specific patient and hospital. Despite any difference in TOC follow up protocol, it remains unchanged that transitional follow up is effective for reducing readmission rates among high-risk patients, and reducing overall health care expenditure per patient. By understanding why TOC programs are beneficial, and furthermore, understanding why pharmacists are the ideal candidate to lead these programs, we can advocate for our profession and improve the health outcomes of patients along the way.
One noteworthy case published in the NCBI in 2016 is a great example of small details going unchecked causing big problems for our patients. The case report follows a geriatric patient who was discharged with the medication thiothixene (Navane) by mistake instead of amlodipine (Norvasc). The patient continued to take thiothixene for 3 months and suffered severe mental and behavioral side effects. The patient's untreated hypertension led to severe chest pain and readmission 3 months later. At that time, a different specialist prescribed the patient citalopram and alprazolam to treat these new mental and behavioral side effects that were labeled as depression and anxiety. A few weeks after this, the patient suffered a fall and was taken to the emergency department where the mistake was finally caught many months later. This case report serves as a great illustration as to why TOC programs are crucial for catching and fixing medication errors. Pharmacist-led TOC programs can cater specifically to the new medications that can be overwhelming for patients to sort out by themselves.
As stated previously, many problems during transitions of care arise from medication related problems. There are many notable studies that bolster data to suggest that TOC programs have a significant improvement for the outcome of the patient, while also saving the health system on overall expenditures. One study published in The American Journal of Accountable Care in 2018 contacted 90% of the patients enrolled in the intervention group at 72 hours post discharge. From this group, they found that 86.4% of the 185 patients contacted had a medication related issue. (Fig. 1) These medication related issues ranged from not taking their medication correctly, to discontinuing the medication due to the side effect profile. What’s more, the study found that the readmission rate for patients involved in the TOC program compared to routine care (no follow-up) was significantly lower for patients enrolled in the TOC program. These findings were further amplified by the patients all being categorized as high risk for readmission due to receiving more than 10 medications, having a diagnosis of pneumonia or congestive heart failure, or receiving anticoagulation therapy. The study concluded that a system wide TOC program would save the health system $582 per patient.
Furthermore, a budget impact analysis published in the Journal of Managed Care & Specialty Pharmacy in 2018 set out to determine the impact of regulated pharmacists-led TOC programs for all Medicaid patients. The authors found that pharmacist-led TOC programs could result in a savings of $25 million dollars to Medicaid over a two year time period. This was found by performing a decision tree analysis from the health system payer’s point of view for treatment of high risk patients. (Fig. 2) The main culprit for Medicaid waste was found to be mismanagement of medications leading to costly interventions that could potentially be avoided.
And finally, a study published in the American Journal of Health-System Pharmacy in 2020 found that the 30 and 90 day readmission rates for chronic heart failure patients were significantly lower when enrolled in a pharmacist-led TOC program. This was in comparison to having no follow-up, and had a difference of 13% of patients readmitted from the TOC group versus 28% from the control group. This highlights the ability of pharmacists to improve health outcomes in this setting.
With all of the presented data, and the high prevalence of medication related problems during transitional care, it is clear that medication specialists should lead such a crucial step in a patient's health care. Pharmacists are well equipped to be at the helm of this venture. With such a definitive way for pharmacists to make a dramatic impact on the health outcomes of patients, it is clear that pharmacists-led TOC programs are a great option for all pharmacists to pursue to benefit patient health outcomes, while saving the health system money as well.
References:Cua, Yvette M, and Sunil Kripalani. “Medication Use in the Transition from Hospital to Home.” Annals of the Academy of Medicine, Singapore, U.S. National Library of Medicine, Feb. 2008, www.ncbi.nlm.nih.gov/pmc/articles/PMC3575742/.
Da Silva, B., & Krishnamurthy, M. (2016, September 7). The alarming reality of medication error: A patient case and review of Pennsylvania and national data. Retrieved August 20, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016741/
Tully AP, et al. Evaluation of medication errors at the transition of care from an ICU to non-ICU location. Crit Care Med 2019;47:543-549.
Melody, Karleen T, et al. “Optimizing Care Transitions: The Role of the Community Pharmacist.” Integrated Pharmacy Research & Practice, Dove Medical Press, 22 Apr. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5741037/.
Ni, Weiyi & Colayco, Danielle & Hashimoto, Jonathan & Komoto, Kevin & Gowda, Chandrakala & Wearda, Bruce & McCombs, Jeffrey. (2018). Budget Impact Analysis of a Pharmacist-Provided Transition of Care Program. Journal of managed care & specialty pharmacy. 24. 90-96. 10.18553/jmcp.2018.24.2.90.
By: Sarah Schriewer and Megan Smith, PharmD Candidates 2023; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Roxane Took, PharmD, BCACP; Assistant Professor, Department of Pharmacy Practice, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Gateway Apothecary
The increased prevalence of heart failure readmissions proves costly for both hospital health systems and patients. More than 20% of hospitalized heart failure patients will return for readmission within a 30-day period.1 Within the last ten years, the Centers for Medicare and Medicaid reduced reimbursement to health systems with excessive 30-day readmission rates in order to curb the climbing occurrence and associated costs of these readmissions.2 This was done to remove incentivizing procedures that may lessen the quality of patient care.3 Many hospitals have established transition of care (TOC) teams composed of various healthcare personnel following this reimbursement limitation.4 The inclusion of the pharmacy profession on the TOC team remains essential, as confirmed by numerous studies that examined the purpose, involvement, and outcomes related to pharmacy specifically. Through performance and accountability measures, the Joint Commission closely examines the efforts of hospitals to improve heart failure patient outcomes.5 Pharmacists play an integral role in improving standards for TOC in heart failure patients.
Clinical Trial Review
A single-center, retrospective, quasi-experimental study regarding the impact of pharmacy involvement in heart failure transitions of care found that 30-day readmission rates significantly decreased with the integration of a pharmacist-led TOC team. These TOC services included medication reconciliation performed by the pharmacist, pharmacy residents, or pharmacy interns upon admission and discharge; and patient education with verbal and written components. The majority of patients transitioned from the hospital setting to home, where the patient and caregivers would greatly benefit from written educational materials provided to patients in the intervention group. The study, conducted at Ascension St John Hospital in Detroit, Michigan, focused on 663 patients admitted to cardiac medical floors with a primary or new diagnosis of heart failure. The 333 patients in the intervention group received the pharmacy-led TOC services, whereas the 330 patients made up the control group received TOC services led by other professions. The most common interventions resulting from medication reconciliation involved addition of a medication, dose titration, treatment discontinuation, and duplication avoidance. A total of 17.3% of control group patients had a heart failure readmission within 30 days following discharge whereas only 10.5% of patients in the intervention group experienced a hospital admission within the 30-day window post-discharge.4
Cohort Study Review
A monocenter, retrospective, observational cohort study at the Veterans Administration Tennessee Valley Healthcare System determined the outcomes associated with heart failure patient follow-up interviews performed by a clinical pharmacy specialist (CPS). This study was performed to consider the value of a CPS, especially during a provider shortage. Cohorts were composed of Advanced Heart Failure Clinic (AHFC) patients within this VA health system. Researchers hypothesized that patients receiving care from a CPS would have similar results in comparison to patients following-up with a “familiar provider.” A novel clinical pharmacy telephone clinic was a valuable component in managing medications and reducing 30-day readmission rates. Patients who received the care provided by the CPS had a 10.9% readmission rate. In contrast, patients without the clinical pharmacy interventions had a 12.9% readmission rate within 30 days. Clinical pharmacy specialists in the Veterans Administration health setting are capable of performing more advanced practitioner care, such as limited prescribing and other patient care authorities. This study provides an interesting outlook on the expanding world of pharmacy practice and the impact pharmacists can make on patient outcomes.1
Management of Implementation
When implementing TOC teams, it is important to consider the additional time commitments that the pharmacy team will have to make and the best way to spread the added workload out amongst staff. Studies have shown positive results by utilizing pharmacy students in their 3rd and 4th year, PGY1 residents, and paid interns working together.4 Other studies emphasize the successfulness of community pharmacists assisting with heart failure TOC encounters via the Centers of Medicare and Medicaid Services Part D Medication Therapy Management programs. These programs allow pharmacists to bill for counseling patients with multiple high-cost medications for various chronic disease states.6 Some health systems found success with clinical pharmacists working directly with the patients during discharge.1 Although there are many ways to set up a pharmacy-led TOC team, it is important to arrange a team best suited to the staffing abilities of different organizations.
Heart failure remains one of the most prevalent disease states in the United States, and, in individuals over the age of 65 year, heart failure remains the most prevalent disease state that causes hospital admissions.7 Data predictions show that more than 8 million adults will be affected, and $69 billion will be spent by 2030 due to the overwhelming amount of hospitalizations.6 The benefits of providing pharmacist-led TOC can help improve these outcomes substantially, and this team can look different based on different preferences. Providing medication reconciliation to patients regarding their heart failure medications is one of the best ways to help improve overall quality of life and decrease the amount of money spent on heart failure readmission by catching discrepancies, titrating doses appropriately, and educating patients on proper use of their medications.7
Takeaways and Recommendations
Program Number: 2021-09-04
Approved Dates: October 1, 2021-April 1, 2022
Approved Contact Hours: One Hour(s) (1) CE(s) per session
Kids Survive: Evidence Based Management of Pediatric Sepsis
Author: Victoria H. Anderson, PharmD; PGY-1 Pharmacy Resident (2020-2021)
Mentor: Jordan E. Anderson, PharmD, BCPS, BCCPS; Pharmacy Clinical Coordinator/PGY-1 Residency Program Director
University of Missouri Women’s and Children’s Hospital – Columbia, MO
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The Surviving Sepsis Campaign published updated pediatric sepsis guidelines in February 2020. Prior to these guidelines, pediatric recommendations shared a guideline document with adult recommendations in 2004, 2008, and 2012, and the Surviving Sepsis Campaign only published adult guidelines in 2016.
Sepsis Considerations: Definitions and Pharmacokinetics
Early recognition of sepsis and evidence-based care of pediatric sepsis patients are of utmost importance to improve patient outcomes as a study in the UK found that over 50% of pediatric sepsis fatalities occurred in the first 24 hours and approximately half of those fatalities were prior to admission to pediatric intensive care units.1 Adherence to guidelines can improve outcomes and development of protocols including order sets and standardized education can reduce mortality.1 A study of emergency department teams found that only 45% correctly adhered to treatment metrics, so there is certainly room for improved implementation of guideline recommended care.1
Sepsis is defined as systemic inflammatory response syndrome (SIRS) plus suspected or known infection. SIRS criteria include hypo- or hyperthermia, leukopenia or leukocytosis, brady or tachycardia, and tachypnea (see Figure 1).2 At least two criteria must be met to diagnose SIRS and at least one of those criteria must be the patient’s temperature or leukocyte count.2 Of note, the SIRS criteria and sepsis definitions do not apply to premature infants.2 To qualify for severe sepsis, a patient must have cardiovascular or respiratory dysfunction or dysfunction of at least two other organ systems such as neurologic, hematologic, renal, and hepatic.2 Septic shock is defined as sepsis with cardiovascular organ dysfunction.2 At least 40mL/kg of fluids must be administered over an hour prior to assessing for cardiovascular dysfunction to meet the organ dysfunction criteria.2 It is important to recognize that hypotension may not be present with cardiovascular dysfunction until a patient is near collapse, as pediatric patients often have strong compensatory mechanisms.1 As a result, fluids are very important to management in even normotensive patients as delays can increase ICU and hospital length of stay and increase risk of acute kidney injury(AKI).1 Rather than titrating to blood pressure goals which is often practiced in adults, fluids should be titrated to increased urine output, improved mental status, and decreased capillary refill time as long as patients remain without hepatomegaly or rales.
Organ function changes are important to note not just for diagnosis of SIRS and subsequently sepsis, but because they also can change the pharmacokinetics of medications administered to these children. Critically ill children often have changes in both synthesis and binding affinity of albumin and alpha-1 acid glycoprotein which can impact unbound fraction of medications.3 Changes in pH whether acidosis or alkalosis can also impact drug levels by impacting ionization which can impact both effective concentration and elimination rates of medications.3 Fluid shifts impact volume of distribution which can lead to changes in concentration, particularly of hydrophilic medications such as vancomycin, so it is important when monitoring vancomycin to consider the impact of fluid resuscitation and maintenance fluids on serum concentrations.3 Renal dysfunction can impact enzyme activity, pH, total body water, and drug clearance, but conversely, sepsis can also lead to augmented renal clearance.3 Mild hepatic dysfunction can modify hepatic blood flow, enzyme activity, drug transport, protein binding, and total body water, impacting the disposition of medication.3 More severe hepatic dysfunction is marked by capillary leak, coagulopathy, renal dysfunction, and hypoglycemia.3 Additionally, inflammatory mediators can decrease P450 enzyme metabolism.3 Changes in blood flow to drug clearing organs may decrease elimination of many drugs.3 Cardiovascular changes can also lead to fluid overload and edema, changing volume of distribution, and increases in alpha-1 acid glycoprotein.3 Abdominal venous congestion can also lead to a decrease in enteral absorption of medication.3 Finally, therapies to compensate for dysfunctional organs such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) also can impact pharmacokinetics.3 The ECMO circuit tubing binds some medications requiring increased dosing initially until binding sites are saturated.3 ECMO also may increase volume of distribution of some medications secondary to added volume required for the circuit.3 The impact of CRRT varies primarily based on the level of protein binding of the medication with lower protein binding leading to increased removal.3
It is also important to consider comorbidities that may impact medication therapy. Forty-nine percent of children with sepsis have a comorbidity making them more vulnerable to infection.1 A common comorbidity is cancer which both the condition itself and the treatment can impact pharmacokinetics.3 For example, fluconazole trough concentrations have been found to be significantly lower in pediatric cancer patients.3 All of these changes make careful use and monitoring of medications in these patients of utmost importance.
Initial Care: Antibiotic and Hemodynamic Management
Once we have made the presumptive diagnosis of sepsis, rapid protocol-driven treatment is the next important step. Per the Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children, in patients presenting without shock, antimicrobial therapy should be started within three hours of recognition.4 While blood cultures should be obtained prior to initiation of antibiotics if this will not cause delay, it is important to start treatment with antimicrobials as soon as possible, so timing of antibiotics is not dependent upon availability of blood cultures.4 The guidelines do not address obtaining multiple blood cultures, however, it is common practice to obtain two blood cultures to enhance our ability to detect causative organisms, and to help determine if bacteria found are pathogenic versus a contaminant. If patients have pre-existing intravenous access devices it is prudent to obtain a set of cultures both from the device and from a peripheral site. In addition to blood cultures, cultures should also be obtained from any suspected non-blood site of infection such as urine, cerebrospinal fluid, or wound drainage.4 If a patient presents with shock, guidelines recommend treatment with antimicrobials within one hour of recognition, but for patients without shock, treatment within the first hour has not been found to have a significant impact on mortality as compared to treatment by the end of the third hour.4 This is in contrast to the 2016 adult and 2012 pediatric guidelines which recommended antimicrobials within the first hour for all patients with sepsis regardless of the presence of shock, and the 2008 pediatric guidelines which recommended antibiotics within one hour of recognizing severe sepsis, but after inidicated cultures have been taken without the caveat in more recent guidelines not to delay evidence-based treatment while waiting for cultures.5,6,7 Giving antibiotics sooner than required will clearly not cause harm as long as this is not done at the expense of fully evaluating the patient, so following the older practice of administration within the first hour is not an inappropriate practice when practical.
These initial antimicrobial agents should be broad spectrum to cover all likely pathogens without excess coverage.4 A previously health child presenting from home should receive a third-generation cephalosporin such as ceftriaxone.4 A child at risk for methicillin-resistant Staphylococcus aureus (MRSA) or presenting from a community with high prevalence of ceftriaxone-resistant pneumococci should additionally receive vancomycin.4 In communities where ceftriaxone-resistant gram negative rods are prevalent, addition of aminoglycosides or substitution of a carbapenem in place of the third generation cephalosporin is recommended.4 If patients have influenza-like illness and influenza is unable to be ruled out, an anti-viral should additionally be given.4 Immunocompromised patients or those with hospital acquired sepsis should receive a beta-lactam covering Pseudomonas aeruginosa.4 Patients with suspected intra-abdominal source of sepsis should receive an antibiotic covering anaerobes, and those with toxic shock syndrome or necrotizing fasciitis should receive clindamycin or lincomycin.4 Neonates should receive ampicillin and if HSV is suspected should additionally receive acyclovir.4 Synergy may be required for device-associated infections, Enterococcal or Staphylococcal endocarditis, group B Streptococcus infections, and carbapenem-resistant Enterobacteriaceaea, but the only patients who should receive double coverage are cancer and transplant patients who are unstable and come from a community with a gram-negative resistance rate of greater than ten percent.4 These patents should receive a second agent covering gram-negatives.4 This is in contrast to the 2016 adult guidelines which recommended empiric combination therapy for patients in shock with de-escalation within the first few days if the patient is clinically improving regardless of results of cultures, but recommended against routinely double covering any particular pathogen in neutropenic patients unless they were presenting with shock.5
The antimicrobials selected should be dosed based on published pharmacokinetic and pharmacodynamic information to ensure safe and effective use.4 It is important to note that because vancomycin and beta-lactams have time dependent antimicrobial activity, extended infusion times may enhance therapeutic effect in patients with augmented renal clearance in early sepsis.4 Once this initial treatment is selected, it should be re-assessed daily for opportunities to optimize coverage.4 Narrowing of therapy should occur based on culture and sensitivity results, or if unavailable, on site of infection and other patient specific factors.4 Source control, which is physical removal of infection such as draining an abscess, and site and etiology of infection, as well as the patient’s response to treatment should guide duration of treatment for pediatric sepsis, although the 2016 adult guidelines suggest a duration of 7-10 days unless clinical evidence suggests that a longer or shorter course could be indicated.4,5
Sepsis can cause an array of physiologic changes which may lead to hemodynamic instability and poor organ perfusion. Fluids are therefore another important component of the initial management of a septic patient. Although caution is required in patients presenting with or developing signs of fluid overload, generally in a health care setting with access to intensive care resources, patients should receive up to 40-60mL/kg in 10-20mL/kg doses over the first hour of treatment.4 In settings where intensive care is unavailable, the maximum volume of bolus fluid a child should receive is 40mL/kg in the first hour if hypotension is present, and if hypotension is not present, fluids should be given at a maintenance rate rather than administered as boluses.4 Signs to assess for hydration status include blood pressure, capillary refill and heart rate.4 Caution is required to avoid fluid overload which may present as pulmonary edema or worsening hepatomegaly.4
While most recommendations on selection of fluids for resuscitation are weak, generally balanced buffered crystalloids such as Lactated Ringer’s or PlasmaLyte solutions are recommended over albumin, normal saline, starches, or gelatin-derived fluids.4 These recommendations balance both cost and safety with cost being the driving factor in recommending against albumin, and safety being the driver of the only strong recommendation to avoid starches as adult data has shown significant risk of both AKI and mortality with the use of hydroxyethyl starch. The adult guidelines, however, give the option of normal saline in place of balanced crystalloids, and recommend use of albumin if patients are requiring significant crystalloids.5 The recommendation to use balanced crystalloids such as Lactated Ringer’s over normal saline in the pediatric guidelines is based on risk of hyperchloremic acidosis, AKI, and coagulopathy with the increased chloride content of normal saline.4,8 Interestingly, the American Academy of Pediatrics clinical practice guideline for maintenance intravenous fluid in children recommends isotonic fluids for maintenance and specifically mentions normal saline and PlasmaLyte, while excluding Lactated Ringer’s solution from their discussion.9 Further studies have evaluated the risks of the supraphysiologic chloride concentrations in normal saline and found that the risk is more significant in bolus fluid administration than slower administration rates, so outside of the bolus phase of treatment switching to normal saline is a reasonable choice although the selection of this fluid for boluses is less clear.8 PlasmaLyte is similar though not identical to Lactated Ringer’s, but is used less often secondary to cost. Per the guidelines, albumin is not a preferred fluid in children secondary to evidence that there is not a mortality benefit and there is a significant cost difference between albumin and crystalloids.4
For septic shock resistant to fluids or in children who are already at risk of or showing signs of fluid overload, epinephrine and norepinephrine are good first line options recommended over dopamine for blood pressure support.4 This is a change from 2008 and 2012 pediatric guidelines when dopamine and inodilators were recommended prior to initiation of norepinephrine or epinephrine.6,7 While central access is preferred for vasoactive medications, peripheral administration is reasonable during stabilization if central access is not available, and the 2008 and 2012 pediatric guidelines further recommend intra-osseous access if central access is not readily available.4,6,7 If children are on high doses of catecholamines and still in shock, vasopressin may be added, and if hypoperfusion is still present, addition of an inodilator such as milrinone or dobutamine may be a reasonable option.4 This is similar though not identical to the 2016 adult guidelines which recommended norepinephrine first line followed by epinephrine or vasopressin then inodilators.5
Some patients may also require hydrocortisone. Hydrocortisone is a corticosteroid that decreases inflammation and reverses capillary permeability. In both the 2016 adult guidelines and the 2020 pediatric guidelines, hydrocortisone is recommended in patients who are still hemodynamically unstable after administration of fluids and vasoactive agents, but not those who are stable on those medications.4,5 While hydrocortisone can enhance the activity of norepinephrine by decreasing reuptake, steroids have numerous adverse effects including immunosuppression, hyperglycemia, and neuromuscular weakness, so routine use is clearly not benign.4 Additionally, while hydrocortisone is an evidence-based treatment for primary adrenal insufficiency, stimulation testing or random cortisol levels in the setting of sepsis are not recommended unless there is evidence to enhance concern for adrenal insufficiency such as significant unexplained hyponatremia and hypoglycemia.4
Continued Care: Drugs with and without Routine Indications
Patients with sepsis may also require intubation. In these patients, etomidate is not a recommended induction agent secondary to risk of adrenal insufficiency following etomidate exposure.4 The 2008 pediatric guidelines were a bit more specific discouraging etomidate only in meningococcal sepsis.7 This recommendation was broadened to address all pediatric sepsis patients in the 2012 guidelines in which a mortality benefit to avoiding etomidate in meningococcal sepsis was mentioned, and avoiding both etomidate and dexmedetomidine in all sepsis patients was recommended secondary to risk of adrenal suppression.6 The recommendation to avoid dexmedetomidine was not carried forward into the 2020 pediatric sepsis guidelines.4 Future evidence seeks to strengthen recommendations regarding length of neuromuscular blockade for intubated patients which is currently a grey area. Life-threatening Acute Respiratory Failure in Children: to Breathe or Not to Breathe Spontaneously, That’s the Question, is a current study in the Netherlands which started in December 2019 to evaluate rocuronium versus placebo in mechanically ventilated children.10 This study is expected to be completed in mid-2024.10
While nutrition is important in recovery from any illness, enteral nutrition, particularly gastric nutrition, is preferred over parenteral nutrition for both adult and pediatric sepsis patients.4 The 2008 pediatric guidelines did not address nutrition, but the 2012 pediatric guidelines agree that enteral is preferred if tolerated and additionally address that if not tolerated parenteral feeding with dextrose 10% in a sodium containing solution is recommended.6 If patients are not tolerating full enteral feeds, prokinetic agents such as erythromycin or metoclopramide may be tempting options, however this is a practice that is not evidence-based, not risk-free, and not guideline recommended for pediatric patients despite being recommended in the 2016 adult guidelines.4,5 Even if patients are not tolerating full enteral feeds, total parenteral nutrition (TPN) is not recommended during the first seven days in the PICU.4 Delaying initiation of TPN may improve neurocognitive development without negative impacts on survival or health status.4 The guidelines are not designed to fully address neonatal sepsis, so neonates expected to be unable to tolerate enteral feeding should be an exception to this seven-day delay in TPN. While the benefit of focusing on enteral nutrition seems clear, blood glucose and calcium goals are less well-defined. A blood glucose goal of less than 140mg/dL is not recommended in order to avoid hypoglycemic events, however the pediatric sepsis guidelines do not define a specific blood glucose target.4 American Diabetes Association guidelines for care of hospitalized diabetic patients recommend a blood glucose target of 140-180mg/dL in most critically ill and non-critically ill patients, so this range is a reasonable target.11 This is corroborated with the 2016 adult guidelines which suggest initiating insulin if the blood glucose is greater than 180mg/dL as opposed to more stringent blood glucose targets and the 2012 pediatric guidelines recommending a blood glucose goal less than 180mg/dL.5,6 Calcium goals are even more poorly defined. The prevalence of hypocalcemia in pediatric sepsis may be as high as 75%, yet calcium supplementation has not been evaluated nor is there consensus in the pediatric healthcare community on the management of hypocalcemia in these patients.4 This is further muddied as in the adult critical care population, calcium supplementation has been associated with worsening organ dysfunction, yet in the pediatric population it is known that calcium is associated with improved hemodynamics, particularly in infants with immature cardiomyocytes.4,12
The pediatric sepsis guidelines specifically recommend against certain nutritional supplements. These include enteral lipid emulsions such as fish oil supplements, selenium, glutamine, arginine, zinc, vitamin C, and thiamine.4 Studies have not found benefit to using these supplements, and some studies have even found harm with arginine.4 Additionally, acute vitamin D replacement is not recommended despite vitamin D deficiency being associated with organ dysfunction.4 While this seems counter-intuitive, vitamin D levels appear falsely low post-resuscitation, and hypervitaminosis D can cause complications leading to death.4 If patients are known to be vitamin D deficient prior to onset of sepsis it is recommended to provide supplementation as recommended outside of sepsis, but measuring of levels during sepsis to guide treatment would not be an acceptable standard of care.4 The 2016 adult guidelines do not comment on as many supplements, but do agree in recommending against selenium, arginine, and glutamine.5 The adult guidelines were unable to make a recommendation for or against carnitine, which is in agreement with pediatric guidelines as carnitine is not mentioned.5
There is also limited evidence on temperature management in pediatric sepsis patients. The guidelines discuss use of antipyretics or a permissive strategy for fevers.4 Elevated temperature dose have some positive effects on the immune system which are lost if temperature is reduced with antipyretics, however it is not benign, which is most obvious in terms of patient comfort.4 Additionally, comparing antipyretics to physical cooling strategies favors antipyretics for early mortality, so it is clear that cooling is generally not a recommended approach in a pediatric sepsis patient.4 Acetaminophen and ibuprofen are commonly used antipyretics, but acetaminophen is not recommended in patients less than 3 months of age and ibuprofen in patients less than 6 months of age as the difference between effective and toxic doses is much smaller in these patients leading to heightened risk of adverse events. These are not absolute contraindications, and in fact a study in 2018 found that ibuprofen use in patients less than 6 months of age was not associated with greater adverse events than use in patients over 6 months.13 Risk of gastrointestinal and renal adverse events was heightened modestly in patients receiving ibuprofen versus those receiving only acetaminophen, but this risk difference was the same in both age groups.13 However, it is still prudent to use these medications cautiously in our youngest patients.
In sepsis patients, T3 and T4 level turnover increases and de-iodination of T4 to T3 decreases.4 Additionally, TSH may not be elevated, however, levothyroxine is not recommended for routine use in children with sick euthyroid.4 Although theoretically there may be a role for levothyroxine, studies in critically ill children have found no difference in patients treated with levothyroxine as compared to those who did not receive levothyroxine.4
Pediatric stress ulcer prophylaxis is a grey area as little research has been published in this area. Hospitals have published protocols, but there are no recent guidelines. A recent observational study found that age, mechanical ventilation, and not receiving enteral nutrition were all independently associated with increased likelihood of the patient receiving stress ulcer prophylaxis.14 These authors also acknowledged that use of vasopressors, corticosteroids, and NSAIDs, presence of coagulopathy, and higher PRISM III score on admission may also be factors in determining need for stress ulcer prophylaxis, but there was not a uniform prescribing practice.14 As stress ulcer prophylaxis is not benign, potentially leading to increased risk of pneumonia and Clostridium difficile infections as well as decreased bone mineral density with longer durations of treatment, it is important to consider risks and benefits of stress ulcer prophylaxis in determining which patients require these medications. It is clear that simply being diagnosed with sepsis or even septic shock is not enough to warrant use of stress ulcer prophylaxis.4 While there is better data in the adult population, the adult guidelines agree that stress ulcer prophylaxis is only indicated if patients have risk factors that would indicate requiring stress ulcer prophylaxis outside of sepsis.5 The 2008 and 2012 pediatric guidelines had no graded recommendations for or against stress ulcer prophylaxis.6,7 As histamine 2 receptor antagonists are more studied in the pediatric population than proton pump inhibitors and have lower rates of adverse events, choosing histamine 2 receptor antagonists over proton pump inhibitors is a good choice though drug selection is not addressed in the sepsis guidelines.
Venous thromboembolism (VTE) prophylaxis is not routinely indicated in pediatric sepsis patients as VTE is much less common in pediatric patients than it is in adults, but some patients may benefit from VTE prophylaxis.4 This is in contrast to the adult guidelines which recommend both mechanical and pharmacologic VTE prophylaxis in sepsis patients.5 Pediatric sepsis patients most at risk for VTE and therefore most likely to benefit from VTE prophylaxis are those who are post-pubertal and have a central venous catheter.4 As much data on pediatric VTE has been extrapolated from adult data, other risk factors are similar in the two populations including obesity, cancer, use of exogenous estrogens, and renal and cardiac comorbidities.15 Previous pediatric guidelines had similar grey areas in terms of VTE prophylaxis with the 2008 guidelines stating to use VTE prophylaxis in post-pubertal children and primarily addressing heparin bonded central venous catheters rather than administration of LMWH or UFH, but there was no mention of management of children who have not yet reached puberty.7 The 2012 update simply stated no graded recommendations for VTE prophylaxis in pre-pubertal children, again discussed heparin bonded catheters, and did not mention post-pubertal children.6 The medication most often used for VTE prophylaxis in pediatric patients is enoxaparin.
Intravenous immune globulin (IVIG) may also be indicated in select patients because it enhances passive immunity but evidence has not supported routine use of IVIG in patients with sepsis.4 While IVIG is not routinely recommended for sepsis in pediatric patients, there are a subset of patients for whom IVIG may be a reasonable treatment option.4 Patients with streptococcal toxic shock syndrome are likely to benefit from IVIG.4 Additionally, it may be beneficial to consider IVIG in immunodeficient or immunocompromised patients with low immunoglobulin levels and patients with necrotizing fasciitis.4 While the adult guidelines recommend against IVIG without this caveat of potentially appropriate use, they also suggest that further research may be needed to evaluate the efficacy of IVIG, so with four additional years of research these two guideline statements are essentially in agreement.5 The 2012 pediatric guidelines stated that use of IVIG in toxic shock was unclear, which is a bit incongruent with 2008 pediatric guidelines which suggested IVIG in patients with severe sepsis, not just those with toxic shock.6,7
Medications that no longer appear in the pediatric sepsis guidelines but have previously been recommended against include recombinant human activated protein C in the 2008 guidelines secondary to findings in clinical trials of no difference between patients receiving activated protein C versus placebo.7 Based on these findings it would be reasonable to assume that despite not being mentioned, continuing to not utilize activated protein C would be appropriate. The 2012 guidelines recommended against long-term propofol for sedation in patients under three years of age secondary to concerns for metabolic acidosis.6 This is another recommendation that while not being mentioned in other iterations of the guidelines continues to seem prudent to follow as it is known that propofol related infusion syndrome is a risk for patients of all ages with extended use of propofol, making propofol a less than ideal agent for patients requiring long-term sedation.
Organ dysfunction is useful not only in differentiating sepsis from severe sepsis, but also in considering changes to medication pharmacokinetics. When shock is present antibiotics should be given within one hour. Fluids are an important component of care even in normotensive patients and balanced buffered crystalloids are recommended. Unless patients require hydrocortisone at baseline, it should only be given if fluids and vasoactive medications are insufficient to maintain hemodynamic stability. Nutrition should be provided enterally if possible, and many supplements including zinc, thiamine, and vitamin C are not routinely indicated. Finally, it is important to carefully consider indications for IVIG, stress ulcer prophylaxis, and VTE prophylaxis.