Potential Bacterial Co-infection with COVID-19 Pneumonia? Andrew Wang, Pharm.D.; BCPS, BCIDP

One of the questions often asked by providers is whether a patient should be Hughes et al., performed a retrospective cohort study investigating the incidence started on antibiotics to cover for potential co-bacterial infection in patients with of bacterial and fungal co-infection of hospitalized patients in a UK secondary care Matters confirmed COVID-19 pneumonia. This question stems ultimately from concerns setting. 836 laboratory-confirmed COVID-19 patients were evaluated, and it was November 2020 Pharmacy Medication Safety Alerts of co-bacterial and viral infections, as bacterial co-pathogens are commonly found that the overall incidence was 6.1% and only 3.2% for patients who were identified in viral respiratory tract infections such as influenza and are an important hospitalized 0-5 days. The most common pathogen identified was Pseudomonas cause of morbidity and mortality. In the most recent IDSA Community Acquired spp (9 patients) and S. aureus (4 patients). There was a 0% positivity rate for Pneumonia (CAP) guidelines, current literature supports that adults with clinical Legionella and streptococcal urinary antigen test. Lastly, surprisingly, Candida and radiographic evidence of CAP who test positive for influenza in the inpatient spp. was found in 21.4% of the samples; however, the authors postulated that LIFEBRIDGE HEALTH FORMULARY REVIEW COMMITTEE UPDATES and outpatient settings should be treated concurrently with antibiotics. This was this likely represented oropharyngeal thrush or normal flora rather than pulmonary LifeBridge Health Formulary Review Committee Updates based on evidence suggesting that bacterial coinfections as bacterial pneumonia candidiasis. The observational study concluded that they identified a low incidence can occur concurrently with influenza virus infection or present later as a worsening of bacterial coinfection in early COVID-19 hospitalized patients. ITEM FOR VOTE DECISION of symptoms in patients recovering from primary influenza infection, thus can be a In patients with mild-to-moderate respiratory disease consistent with COVID-19 Ravulizumab (Ultomiris) LFRC voted in favor of adding ravulizumab to formulary, making it a preferred common and serious complication of influenza. Bacterial co-infection in patients without obvious signs of bacterial infection, the likelihood of bacterial co-infection Monograph, LBH agent for adults and pediatric patients with atypical hemolytic uremic syndrome with severe influenza has been reported to be as high as 20-30% and is associated is low and antibiotics can be safely held off, even in the setting of gradual worsening with a greater severity of illness, greater use of healthcare resources, and increased and paroxysmal nocturnal hemoglobinuria, and restricting the use of of respiratory status, as this is likely from progression of COVID-19 rather than to adults with generalized myasthenia gravis and neuromyelitis optic spectrum risk of death. superimposed secondary bacterial co-infection. If a patient develops a new or It is important to note there is a significant knowledge gap as the prevalence, acutely worsening respiratory failure, sepsis or both after initial phase of consistent disorder. incidence and characteristics of bacterial infection in patients with COVID-19 improvement, then nosocomial acquisition of secondary bacterial co-infection is Capsaicin Cream LFRC voted in in favor of adding capsaicin 0.075% cream to formulary and pneumonia are not well understood. As such, most patients are started on reasonable and empiric antibiotic therapy may be appropriate. In patients who Monograph, LBH removing capsaicin 0.025% and 0.1% cream from formulary. antibiotics given the difficulty in ruling out bacterial co-infection on presentation as are critically ill with severe respiratory failure with COVID-19, empiric antibiotic Daptomycin Dosing for LFRC voted in favor of updating policies to reflect dosing of daptomycin by well as ruling in the possibility of secondary infection during the course of illness. treatment may be reasonable and should be targeted for community-acquired As a result, many guidelines recommend the use of empirical antibiotics in severe pneumonia unless patient has risk factors for resistant pathogens. Obese Patients, LBH adjusted body weight for obese patients (BMI > 30). COVID-19 disease; however, this ultimately raises the concern of antibiotic overuse While ruling out bacterial co-infection may be difficult, procalcitonin may be helpful. Sugammadex LFRC voted in in favor of maintaining current sugammadex restrictions and not and unintended consequences. Several reported series of COVID-19 have consistently reported low procalcitonin Medication Use allowing its use outside of the operating room. Langford et al., performed a systematic review and meta-analysis that included a levels in isolated COVID-19 infections, which can be helpful in ruling out bacterial Evaluation and total of 24 studies in which 3,506 laboratory-confirmed COVID-19 patients from co-infection4. Procalcitonin is detectable in 2-4 hours, peaks at 12-24 hours and United States, Spain, China, Thailand and Singapore were evaluated. The results has a half-life of about 25-30 hours. Keep in mind that procalcitonin can be elevated Monograph Addendum, showed that overall patients who were found to have COVID-19 with bacterial co- in patients with acute respiratory distress syndrome (ARDS), end-stage renal LBH infection was 6.9% (95% CI, 4.3-9.5%). When stratified to include only critically disease (ESRD), cardiogenic shock, multi-organ failure, surgery, malignancy and Anticoagulation Clinic LFRC voted in favor of adopting the Anticoagulation Clinic policy with ill patients, the rate increased to 8.1% (95% CI, 2.3-13.8%). It was also found congestive heart failure (CHF), therefore, having an elevated level (> 0.5 mcg/L) Policy, SH, NW recommended updates and addition of direct oral anticoagulation monitoring for that 71.9% received antibiotics overall. The most common organisms reported does not necessarily correlate to bacterial infection while having a low level (<0.5 Sinai and Northwest hospitals. were Mycoplasma species (11 patients), Haemophilus influenzae (5 patients), mcg/L) make bacterial infections less likely and can guide antibiotic discontinuation. and Pseudomonas aeruginosa (5 patients). Overall, the incidence of co-bacterial Hypertonic Saline Policy, LFRC voted in favor of adopting Hypertonic Saline policy changes as proposed by At the present time, current literature supports that the overall incidence of bacterial SH, NW, CH individual hospitals (Sinai, Carroll, Northwest). infection associated with COVID-19 patients appear to be much lower than co- coinfection remains low; therefore, antibiotic therapy should be considered for those bacterial infection associated with influenza patients at the present. with clinical high suspicion of bacterial pneumonia. Investigational Drug LFRC voted in favor of adopting updates to the Investigational Drug/Study Drug Service/ Study Drug policy for Sinai Hospital. Policy, SH USP 800- Hand Hygiene LFRC voted in favor of adopting the new USP 800 hand hygiene and PPE use Simple and Effective: Adenosine Single-Syringe Administration in Supraventricular Tachycardia and PPE Use Policy, LBH policy.

Xinyi Huang, Pharm.D. Candidate, University of Maryland Baltimore School of Pharmacy; Hellena Admassu, Pharm.D., BCPS, MPH - Clinical Pharmacy Specialist, Emergency Medicine, Northwest Hospital Radiopharmaceutical LFRC voted in favor of adopting/grandfathering the presented List, LBH radiopharmaceutical list to formulary for LBH. Adenosine, an endogenous purine nucleoside, decreases conduction saline in a single syringe. At the providers’ discretion, pharmacists prepared velocity in the atrioventricular node making it useful for management of adenosine and saline (2 mL + 18 mL) in a single syringe (SS arm) or in two narrow complex supraventricular tachycardias (SVT). It is metabolized by separate syringes (TS arm) (SS n = 26; TS n = 27). Patients in the SS group erythrocytes and vascular endothelial cells resulting in a very short half-life had a higher rate of successful conversion to normal sinus rhythm (NSR) at Sinai Hospital Anticoagulation Clinic: Official Center of Excellence Site (<10 seconds). To ensure adequate drug delivery to the myocardium, it must 73.1% versus 40.7% in the TS group (noninferiority, p = 0.0176). Conversion Leann Kwak, Pharm.D.,Si PGY-1mple Pharmacy and Effective:Resident Adenosine Single-Syringe Administration in be administered as a rapid intravenous bolus, followed by a 20 mL saline to NSR was 100% in the SS group after up to these doses (vs. 70.4% in TS Shari Fogelquist, Pharm.D.,Supraventricular BCACP, Clinical Pharmacist Tachycardia II flush. This administration method is logistically challenging; it requires two arm, p = 0.0043). Extravasation and phlebitis were noted in one patient in As the landscape of anticoagulation is advancing and evolving, the Anticoagulation Forum has built the first comprehensive set of standards for an anticoagulation separate syringes, a two-way stopcock and the coordinated action of staff the TS arm. service center that defines ideal practices by creating the Centers of Excellence certification program in 2012. Certification is granted through quality during administration. Xinyi Huang, PharmD Candidate Even though this study is under-powered and lacked randomization, improvement processes with priority in refining overall quality of patient care. According to these standards, an anticoagulation service center should be able University of Maryland Baltimore School of Pharmacy McDowell et al., conducted a prospective, observational study to compare it demonstrated the effectiveness of the simpler single-syringe method. to provide expertise and interdisciplinary support with anticoagulant management, provide high quality care to high risk or special patient populations, perform standard practice to an alternative method of combining adenosine and thorough patient education sessions and aid in transitions and coordination of care in collaboration with the patient’s healthcare team. An anticoagulation service center should also be ableHellena to utilize Admassu, a systematic PharmD, process BCP toS regularly, MPH - evaluateClinical andPharmacy review quality Specialist, metrics Emergency in a timely manner.Medicine As of July 2020, Sinai NorthwestHospital’s outpatient Hospital anticoagulation clinic has become certified as an official Anticoagulation Forum Centers of Excellence site. The clinic has been recognized for its ability to provide the highest level of care and achieve the best possible outcomes for their patients. Amidst the COVID-19 pandemic, Sinai Hospital’s outpatient anticoagulation clinic will continue to care bravely and serve the Baltimore community by following the highest standards set forth by Medication Matters is a publication of the LifeBridge Health Pharmacy Departments. Its purpose is to educate and inform health care the Anticoagulation Forum. professionals about medication safety issues and best practices in medication use and monitoring. We welcome your thoughts on topics for future publications. Please contact Jacqueline Hartford, Pharm.D., at Sinai Hospital, [email protected], or Larry Siegel, Pharm.D., at Carroll Hospital, lsiegel@@lifebridgehealth.org. Use of Corticosteroids and UPDATED DOAC NOMOGRAM, Immunotoxicity Efficacy OCTOBER 2020 Morgan Njoku, Pharm.D.–Clinical Pharmacist, Pediatrics and Oncology–Sinai Hospital Elizabeth Shriver, RPh, BCOP, Carroll Hospital Catherine Roberts, Pharm.D., Pharmacy Resident; Shari Fogelquist, Pharm.D., BCACP, Clinical Pharmacist II – Anticoagulation Clinic Many years of research went into discovering In the United States, an estimated 44% of cancer patients are eligible to the role of the , or failure receive immune checkpoint inhibitors (ICI). thereof, in the proliferation of cancer cells ICIs have given durable responses and, in some cases, improved overall in the body. Many checkpoints have been survival in malignant cancers that are difficult to treat. ICI includes identified as targets for immune dysfunction, cytotoxic T-lymphocyte associated protein 4 (CTLA-4) such as , and thus avenues to stop the growth of cancer. programmed cell death ligand 1 (PD-1) such as , or Immunotherapy agents, including monoclonal programmed cell death ligand 1 (PD-L1) such as . antibodies and immune checkpoint inhibitors, ICIs help the body overcome tumor induced immune suppression are now being used to treat more cancers mechanisms by targeting PD-1, PD-L1 and CTLA-4 on the T cells. Blocking than ever. These have been these checkpoint proteins restores the body’s immune system’s ability observed to display a much different toxicity to recognize and defend itself against cancer. ICIs also in turn rev up profile than their traditional the body’s immune system causing side effects such as colitis, hepatitis, counterparts. Because these hypothyroidism and diabetes. Corticosteroids are immunosuppressive impact or manipulate the function of immune agents and are used frequently with ICIs. There is concern and controversy system, patients can consequently experience in what effect corticosteroids have on the efficacy of ICIs. immune-mediated side effects.

Corticosteroids are often used as a premedication in ICI combined with Immune-related toxicities of immunotherapies cytotoxic chemotherapy regimens to prevent adverse effects of the can be defined as discrete toxicities resulting cytotoxic agents, such as nausea. There have been multiple studies that The Direct Oral Anticoagulants (DOACs) have provided continuous from a non-specific activation of the immune have compared the baseline cytotoxic regimens to those that contain the challenges highlighted by complicated dosing based on indication. As system. These toxicities can affect many same cytotoxic regimen plus immunotherapy. All outcomes have been additional studies have been published, we have found the need to update organ systems, including GI, endocrine, statistically significant, and all show a benefit from immunotherapy, despite our dosing nomogram to include additional indications, renal dosing and pulmonary, renal and neuro, among others. premedication with steroids. obesity guidelines. The new nomogram is now multipage with each page Risk factors for immunotoxicity include: dedicated to a specific indication and then organized by choice of DOAC. underlying autoimmune disease, chronic organ After treatment, initiation with ICI patients who experience more severe dysfunction, chronic viral infection and prior immune-related adverse events (irAE) typically receive 0.5 to 1 mg/kg of It expands on the details of the previous nomogram and includes some prednisone, or the equivalent, to treat AE. In a retrospective review study, changes and additions. organ transplant. Horavat reviewed 254 patients who experienced irAE after immunotherapy For patients with atrial fibrillation and renal dysfunction, the dosing for There are several barriers to the appropriate initiation, and of these, 103 required systemic steroids. They found there was apixaban is 2.5 mg BID if serum creatinine is greater than 2.5 mg/dL or if diagnosis of immune-mediated toxicities. First, no difference in overall survival or time to treatment failure when patients creatinine clearance is less than 25 mL/min, but not on hemodialysis. In these effects could be mistaken for a myriad were given corticosteroids. patients receiving hemodialysis, 5 mg BID is appropriate if the patient is less of other common health issues or underlying Patients with more advanced disease frequently are already on than 80 years old and weighs greater than 60 kg. All other DOACs should comorbidities of the average oncology patient, corticosteroids for palliative reasons. These palliative indications for steroids be avoided in patients with atrial fibrillation who are receiving hemodialysis. and thereby go misdiagnosed and mistreated. In addition, delayed onset and prolonged duration could be brain metastasis, anorexia or pain from bone metastasis. Others For the indications of venous thromboembolism (VTE) treatment and VTE of immunotherapy toxicities when compared to may be on steroids for non-cancer reasons such as for chronic obstructive prophylaxis (including post-op), all of the DOACs, including apixaban, the adverse events of traditional chemotherapy pulmonary disease (COPD) or autoimmune diseases. Studies are ongoing should be avoided in patients receiving hemodialysis. Apixaban should also make diagnosis even more difficult to attribute to determine what impact corticosteroids when given prior to the start of be avoided in patients with serum creatinine greater than 2.5 mg/dL or if to the immunotherapy. When patients finish immunotherapy have on the efficacy. creatinine clearance is less than 25 mL/min in these indications. Of note, with their limited immunotherapy cycles and Arbour and colleagues looked at the impact of baseline steroids on the edoxaban is not FDA approved for the prophylaxis of VTE. enter routine post surveillance, they are not efficacy of PD and PD-L1 blockage in non-small cell lung cancer. They The only DOAC with approval for the reduction of cardiovascular events in seen by oncologists as frequently, and these found a decrease in the overall survival rate but were unable to determine patients with chronic coronary artery disease or peripheral artery disease is effects can be missed by providers of other correlation versus causation with baseline corticosteroid use. Ricciuti and rivaroxaban. The dosing is 2.5 mg BID along with aspirin 81 mg daily, as long specialties of care. colleagues looked at checkpoint inhibitor outcomes for patients with non- as creatinine clearance is at least 15 mL/min. small cell lung cancer receiving corticosteroids for palliative versus non- Treatment of the symptoms with which patients present depends largely on making an appropriate initial diagnosis. Systemic corticosteroids and cancer related indications. These studies revealed that patients with a poor Rivaroxaban can also be used off-label for the reduction of cardiovascular immunotherapy dose reduction or discontinuation remain mainstays of treatment of these inflammatory adverse events, as opposed to symptom prognosis and receiving corticosteroids for palliative reasons had significant events in patients with acute coronary syndrome, after initial stabilization. management, antibiotics and other modalities. This dichotomy in diagnosis and treatment could greatly affect the patient’s prognosis and quality of life, decreases in efficacy. However, patients who were taking corticosteroids The dosing for this off-label indication is 2.5 mg BID along with both aspirin and a multidisciplinary approach is crucial to properly identifying and treating immune-mediated adverse events. for non-cancer reasons had no significant difference in progression-free 81 mg and clopidogrel, as long as creatinine clearance is at least 30 mL/ Although much of the proper treatment of these toxicities hinges upon appropriate diagnosis by providers, there are some ways pharmacists can survival or median overall survival. min. intervene. Medication reconciliation is of utmost importance, as providers need to be aware that patients are on immunotherapies and that their Summary of the impact of corticosteroid use with immunotherapy include: The new nomogram also highlights that in patients weighing more than 120 presentation is a result of associated toxicities. Technology can be developed to flag patients with cancer diagnoses, which would prompt a further kg, or with a BMI of more than 40, warfarin is the anticoagulant of choice • Minimize the use of corticosteroids, if possible look into their past and current medications. Finally, pharmacists can conduct sessions and/or construct materials to educate emergency room staff, as due to a lack of evidence with the use of DOACs in this population. • Treating irAE with steroids is likely ineffective they are typically the first to receive patients experiencing these toxicities. The overarching goal is to encourage all healthcare providers to make the • Premedication use of corticosteroids shows benefit Lastly, it is important to remember to watch for duplicate active connection between these symptoms of unclear etiology and cancer therapy with immunotherapy drugs. • Corticosteroids when given prior to starting ICI may have little impact on anticoagulation orders and that when treating a patient with multiple efficacy, more studies are needed to understand the reason indications for anticoagulation, to choose the treatment that is associated with the higher dosing.

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