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There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 1
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PROVISIONAL GUIDANCE: COVID-19 TREATMENT OPTIONS
Most recent version: http://intranet.bhssf.org/en/departments-and-directories/ebcc/pages/coronavirus.aspx
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There are no FDA-approved antiviral medications for SARS-CoV-2. Remdesivir has been granted temporary Emergency Use Authorization (EUA) by FDA (details below). The FDA EUA issued in March 2020 for
chloroquine phosphate and hydroxychloroquine was revoked in June 2020. New data are emerging daily as the pandemic progresses and research is completed. This guidance document reflects recommendations
from local experts regarding therapies that have in vitro activity against coronaviruses, have reported human data in clinical practice, or have been used to treat similar infectious diseases. Risks versus benefits for each unique patient case should be carefully considered. This document is designed using theoretical
principles to help assess possible risk and does not guarantee reduced harm potential. This is not meant to replace sound clinical judgement and BHSF does not mandate the use of any listed therapy.
CONTENTS
Page 2……………………………………………COVID-19 Key Points
Page 3-4…………………………………………WHO Classification of Clinical Syndromes Associated with COVID-19
Page 5……………………………………………COVID-19 Investigational Therapies: General Information
Page 6-7…………………………………………Convalescent Plasma Contact Information
Page 7.…………………………………………..Hydroxychloroquine (Plaquenil®) & Chloroquine
Page 7.………………………………………….Lopinavir/ritonavir (Kaletra®)
Page 8-10.………………………………………..Remdesivir (Veklury®, GS-5734, RDV)
Page 11-13……………………………………..BHSF Remdesivir Scarcity Prioritization & Criteria For Use
Page 14-16……………………………………..Tocilizumab (Actemra®)
Page 17-21....…………………………………References & Readings
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 2
COVID-19 KEY POINTS
Infection control should be notified of any suspected or confirmed COVID-19 patients, as per institutional protocols
Patients with suspected or proven COVID-19 infection should be counseled on quarantine and infection prevention practices
Proper droplet and contact precautions should be practiced when managing proven or suspected COVID-19 patients
Not all patients (especially those with mild disease) will require hospitalization. Clinical judgement should be used in deciding which patients can be safely discharged home versus admitted to the hospital. Some factors that are associated with more severe diseases include hypoxemia, older age, elevated SOFA score, D-dimer above 1, lymphopenia, elevated ESR, and underlying cardiovascular disease.
Patients with mild symptoms not admitted to the hospital but suspected or confirmed with COVID-19 should be instructed to seek medical assistance or go to the hospital if their condition worsens. Risk factors include:
o Older age o Underlying medical condition (e.g., lung disease, cancer, heart failure, cerebrovascular disease, renal disease, liver
disease, diabetes, immunocompromising conditions, or pregnancy)
CDC lists the following as risk factors for severe illness: age (especially above 50 years), cardiovascular disease, diabetes, chronic respiratory or lung disease, hypertension, cancer, heart disease, chronic kidney disease, history of stroke
Supportive care is the corner-stone of COVID-19 therapy o Consider limiting IV fluids (which can exacerbate ARDS) unless otherwise indicated o Acetaminophen is recommended over NSAIDs (e.g., ibuprofen)
There have been conflicting reports and statements about the safety of NSAIDs during COVID-19 infection. The Food and Drug Administration as well as the European Medicines Agency cite a lack of scientific evidence to establish a link between ibuprofen use and worsening of COVID-19.
Nebulizer treatments can potentially aerosolize the virus and increase the risk of exposing others
High flow oxygen nebulizer treatments and non-invasive positive pressure ventilation (CPAP/BiPAP) are discouraged in patients with suspected or confirmed COVID19 as they create aerosolized particles
o Patients with MERS-CoV or influenza who were given corticosteroids were more likely to have prolonged viral replication, receive mechanical ventilation, and have higher mortality. However, the NIH COVID-19 Treatment Guidelines Panel recommends using dexamethasone (at a dose of 6 mg per day for up to 10 days) in patients with COVID-19 who are mechanically ventilated and in patients with COVID-19 who require supplemental oxygen but who are not mechanically ventilated. They recommend against the use of dexamethasone in patients with COVID-19 who do not require supplemental oxygen. This recommendation is based on data from the RECOVERY Trial [74]. Additional data has emerged supporting the use of steroids for severe COVID-19 pneumonia [93].
Concomitant infection with influenza or bacterial pneumonia with COVID-19 is unlikely, anti-influenza and antibacterial drugs should not be initiated or continued unless clinically indicated
There are no FDA-approved therapies for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) of COVID-19
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 3
WHO Classification of Clinical Syndromes Associated with COVID-19
Continued on the next page
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 4
WHO COVID DISEASE SEVERITY TABLE CONTINUED
Source: World Health Organization. Clinical management of severe respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance V 1.2 [accessed 18 March 2020]
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 5
COVID-19 Investigational Therapies: General Information
INVESTIGATIONAL THERAPIES This is not a comprehensive list of investigational therapies. Inclusion on this list is not a recommendation for or against use.
All registered clinical trials: https://clinicaltrials.gov/
Remdesivir (GS-5734) o Available for purchase through periodic allocation by department of health (see below), not FDA approved and
only available for research or under FDA Emergency Use Authorization o Compassionate use pathway only available for pregnant women and people less than 18 years of age
More information: https://rdvcu.gilead.com/
Convalescent Plasma o Expanded access protocol now ended- Now prescribing under the FDA’s Emergency Use Authorization o Resources: https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-
process-cber/recommendations-investigational-covid-19-convalescent-plasma o Current BHSF EBCC convalescent plasma resources: http://intranet.bhssf.org/en/departments-and-
directories/ebcc/Pages/COVID-Blood.aspx o See below detailed contacts pages
XPORT-COV-1001 o Anticipated to be enrolling soon at Baptist Hospital of Miami – Miami Cancer Institute o Investigational agent: selinexor (KRT-330) o Primary investigator: Guenther Koehne, M.D., Ph.D. o Co-investigator: Paula Dilanchian, Pharm.D., D.O.
ULSC-CV-01 o Status: undergoing protocol finalization o Investigational agent: umbilical cord mesenchymal cells o Primary investigator: Guenther Koehne, M.D., Ph.D.
POTENTIALLY HELPFUL CONTACTS
For Emergency Use IND process, please reach out to the Baptist Health South Florida IRB: [email protected]
Miami Cancer Institute Clinical Trials Office: 786-527-8116; [email protected]
Miami Cancer Institute Chief Research Officer: Scott Lipkin, DPM; [email protected]
Baptist Health South Florida Human Research Protection Program Director: Amanda Coltes-Rojas, MPH, CIP, CHRC; [email protected]
Baptist Health South Florida Center for Research Assistant Vice President: Susan Golembeski, Ph.D., CHRC, RN; [email protected]
Miami Cancer Institute Clinical trials Clinical Pharmacy Supervisor: Nicholas Chow, Pharm.D., BCOP; [email protected]
Baptist Health South Florida Antimicrobial Stewardship Clinical Program Manager: Timothy Gauthier, Pharm.D., BCPS; [email protected]
Miami Cancer Institute Deputy Director and Chief of Blood and Marrow Transplant, Hematologic Oncology and Benign Hematology: Guenther Koehne, M.D., Ph.D.; [email protected]
Infectious Diseases Physician: Paula Dilanchian, Pharm.D., DO; [email protected]
Doctor’s Hospital Director of Nursing Practice Management, Diabetes, and Wound Care: Edwina Brathwaite, Ph.D., MSN/Ed, MS/HAS, RN-BC ([email protected]) has been engaged in some convalescent plasma coordination activities
Boca Raton Regional Hospital Cath/EP Lab Nurse Manager: Maureen Avella, RN ([email protected]) has been engaged in some convalescent plasma coordination activities
Local infectious diseases physicians, clinical pharmacists, lab personnel, IRB personnel, clinical trials office, and others may also serve as potential contacts for further information Continued on next page
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 6
CONVALESCENT PLASMA CONTACTS
Hospital Local Lab Manager Local Ordering Physician
Baptist Hospital of Miami
Julisa M. Lampe, M.H.A., MT(AAB) BH Supervisor, Transfusion Services
[email protected] 786-596-3085
Mirtha Cuellar
BH, TS Manager [email protected]
786-596-6037
Dr. Gunther Koehne
786-527-8338 [email protected] Dr. Javier Perez Fernandez 786-596-6944 [email protected]
South Miami Hospital
Donna Rubin SMH, TS Manager
[email protected] 786-662-8539
Dr. Javier Perez Fernandez 786-596-6944
Doctor’s Hospital
Onelia Noa Mantilla DH Lab Manager
[email protected] 786-308-3245
West Kendall Hospital
Claudia Marrero WKBH Supervisor, Transfusion Services
[email protected] 786-467-2607
Katia Abaunza
WKBH Lab Manager [email protected]
786-467-4836
Homestead Hospital
Michelle Morrison-Barrett HH Supervisor, Transfusion Services
[email protected] 786-243-8519
Mariners Hospital
Cleo Puerto MH, Lab Manager
[email protected] 305-434-1212
Bethesda Hospital East & Bethesda Hospital West
Rita Kyada TS, Med Tech 3
[email protected] 561-737-7733
Dr. Indira Marmolejos
561-789-8943
Dr. Amy Schiffman [email protected] Phone: 561-289-6888 561-409-2800
Boca Raton Regional Hospital
Gwen Collins AVP for Pharmacy and Laboratory departments [email protected] Wadad Remsen Boca Supervisor, Transfusion Services [email protected] 561-955-3664
Samer Fahmy [email protected] Direct: 561-955-4546 Dr. Amy Schiffman [email protected] Phone: 561-289-6888 561-409-2800
CONTINUED ON NEXT PAGE
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 7
CONVALESCENT PLASMA CONTACT CONT’D
Research Staff Contact Information
Dr. Gunther Koehne Deputy Director and Chief of Blood & Marrow Transplant, Hematologic Oncology and Benign Hematology Miami Cancer Institute Phone: 786 - 527 -8338 Email: [email protected]
Susan Golembeski AVP, Center for Research Direct: 786-527-9893/ Cell: 305-298-5397 Email: [email protected]
Lara Arias Director, Research Administration & Sponsored Programs Center for Research Direct: 786-527-9895/ Cell: 360-631-6016 Email: [email protected]
Viviana Boronot Director of Research, Office of Research Administration Boca Raton Regional Hospital Direct: 561-955-4731 Email: [email protected]
Beatriz Rosell Beatriz Rosell Regulatory Research Coordinator Direct: 786-527-9890 Email: [email protected] Email: [email protected]
THERE ARE NO SYSTEM-WIDE DRUG RESTRICTIONS EXCEPT REMDESIVIR CRITERIA FOR USE. ENTITY-SPECIFIC RESTRICTIONS MAY APPLY.
Disclosure to the patient and/or caregiver regarding the use of off-label medications is recommended with chart documentation.
Hydroxychloroquine sulfate (Plaquenil®) & Chloroquine
FDA revoked the Emergency Use Authorizations for hydroxychloroquine and chloroquine on June 15, 2020 [51].
On June 22, 2020 the BHSF Antimicrobial Review Committee approved restricting hydroxychloroquine and chloroquine so pharmacy will not honor orders when the indication for therapy is COVID-19. Formal approval of
this system-wide restriction is anticipated in the near future.
Lopinavir/ritonavir (Kaletra®, LPV/r)
Evidence summary: Lopinavir inhibits viral protease activity and prevents the cleavage of the viral precursors into individual functional proteins resulting in the formation of immature, noninfectious particles [24]. Ritonavir is also a protease inhibitor, but it is used in this combination as a “booster”, because it increases lopinavir concentrations by inhibiting CYP-3A4 enzymes. LPV/r has been studied as monotherapy and as part of combination therapy for COVID-19 disease. It is not FDA-approved for use with COVID-19 and does not have an emergency use authorization.
Data from in vitro studies shows it does have activity versus SARS-CoV-19 [24]. Human data indicate LPV/r is not effective as monotherapy [25].
LPV/r may be clinically useful for COVID-19 management when used in combination therapy, but in what context remains unclear. ATS makes no suggestion either for or against treatment of COVID-19 with lopinavir-ritonavir (30% for, 26% no suggestion, 43% against intervention) [27].
In early July WHO announced the lopinavir/ritonavir arm of the Solidarity Trial was being discontinued, citing interim analysis show that it produces little or no reduction in mortality of hospitalized patients with COVID-19 when compared to standard of care [65].
The Society of Critical Care Medicine recommends against routine use of lopinavir/ ritonavir (weak recommendation, low quality of evidence) [16]. IDSA recommends lopinavir/ritonavir for COVID-19 only in the context of a clinical trial [28]. NIH recommends lopinavir/ritonavir only in the context of a clinical trial [29].
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 8
THERE ARE NO SYSTEM-WIDE DRUG RESTRICTIONS EXCEPT REMDESIVIR CRITERIA FOR USE. ENTITY-SPECIFIC RESTRICTIONS MAY APPLY.
Disclosure to the patient and/or caregiver regarding the use of off-label medications is recommended with chart documentation.
Remdesivir (GS-5734, RDV)
Evidence summary: Nucleotide analogue prodrug that is intracellularly metabolized into an analogue of adenosine triphosphate that inhibits viral RNA polymerases and has broad spectrum activity against members of the filoviruses. Initially studied for Ebola virus, remdesivir was also found to have in vitro activity versus a wide array of viruses, including SARS-CoV-2 [10]. It is currently being investigated as a therapeutic option in the management of patients with COVID-19 disease.
The FDA granted temporary Emergency Use Authorization (EUA) for remdesivir in early May 2020 based on NIH data that found remdesivir was better than placebo in regards to time to recovery (i.e., being well enough for discharge or returning to normal activity level) [40]. In August 2020 the FDA modified the EUA moving from it being applicable for hospitalized patients with severe disease to hospitalized patients without restriction on disease severity [90]. The NIH and IDSA guidelines do not recommend routine use of remdesivir in all levels of COVID-19 pneumonia severity.
In a randomized controlled study evaluating 237 patients receiving remdesivir or placebo, Wang et al found hospitalized patients with severe COVID-19 had no better outcomes when remdesivir was given as compared to no remdesivir [41].
Goldman et al found patients with severe COVID-19 not requiring mechanical ventilation had similar outcomes when receiving a 5-day or 10-day course with remdesivir [44].
Gilead announced the Phase 3 SIMPLE trial in hospitalized patients with moderate COVID-19 pneumonia found 5-day remdesivir treatment were 65% more likely to have clinical improvement at day 11 compared to standard of care (95% CI 1.09-2.48, p=0.017) [45]. The 10-day course was not statistically better than standard of care in this population. No new safety signals were reported.
Beigel et al reported on 538 remdesivir for 10 days versus 521 placebo patients, finding remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 and LRTI [47]. The data indicated no benefit in patients receiving mechanical ventilation or ECMO, while patient receiving oxygen showed the most benefit (see Figure 2 in this article), although the data was not powered to detect a difference in this subgroup analysis.
Gilead reported that a comparative analysis of Phase 3 SIMPLE-severe and real world retrospective data including 312 and 818 patients respectively found remdesivir superior to clinical recovery and reduced mortality by 62% as compared to placebo [69]. The mortality rate for patients given remdesivir was 7.6% at day 14 compared with 12.5% for those not receiving remdesivir (aOR 0.38, 95% CI 0.22-0.68, p=0.001).
Olendar and colleagues compared remdesivir to standard-of-care (SOC) using phase 3 study data and ongoing retrospective real-world data for patients with severe COVID-19, finding at day 14 less patients died in the remdesivir group (7.6% versus 12.5%, OR 0.38, 95% CI 0.22-0.68, p=0.001) [78].
Kalligeros and colleagues reported on a single-center experience with remdesivir given to 99 hospitalized patients with severe COVID-19, finding the unadjusted and adjusted risk for 28-day in-hospital mortality was numerically but not statistically lower for patients on remdesivir versus those receiving supportive care without remdesivir [84].
Spinner and colleagues reported on a randomized, open-label, phase 3 trial including 584 patients with moderate COVID-19 finding patients receiving 5 days of remdesivir had a better clinical status compared to standard of care at 11 days after treatment initiation, however the clinical relevance of this is unclear and patients randomized to a 10-day course did not have a difference in clinical status as compared to standard of care [87].
Pasquini et al reported a retrospective analysis including 25 mechanically ventilated patients treated with remdesivir at a single Spanish hospital, reporting lower mortality versus a comparator group that did not receive remdesivir (56% versus 92% mortality with median follow-up of 52 days, p < 0.001) [89].
Martinot et al reported occurrence of a RdRP (D484Y) mutation (remdesivir resistance) following treatment [99].
Burwick et al reported on 86 women who received remdesivir during pregnancy or postpartum, finding a low rate of serious adverse events and concluded a high rate of recovery [103].
Beigel et al reported the remdesivir results for ACTT-1, which included 1062 patients (541 remdesivir vs 521 placebo) finding remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection [104]. A mortality benefit was not statistically significant.
In a news release, Lilly reported that addition of baricitinib to remdesivir reduced time to recovery for patients hospitalized with COVID-19 versus remdesivir alone [104]. This study is part of ACTT-2 and the full data set is not yet released.
CONTINUED ON THE NEXT PAGE
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 9
Remdesivir (Veklury, GS-5734, RDV) - Continued
Literature summary continued…
WHO released pre-print interim results of the SOLIDARITY Trial, reporting no benefit of remdesivir (n=2750) in time to recovery or mortality as compared to placebo (n=4088). [107]
Formulary status: Non-Formulary with criteria for use. Only available as an investigational agent, for compassionate use, or through the FDA Emergency Use Authorization with distribution through the U.S. Department of Health and Human Services.
o BHSF is provided with weekly allotments. As of this last update 10/16/2020 we have an adequate supply of drug in the system. We anticipate an option for delivery weekly through September 2020 with an amount to be specified by FL-DOH. Drug is sent through Amerisource Bergen. The price set by Gilead is be $520 per vial (comes in 100 mg vials) for US private insurance companies [62]. The procurement pathway after September is yet to be known
Adult dosing as per FDA EUA: o Clinical study allowed patients to stop therapy early if they were ready for discharge [47, see supplemental
appendix] o BHSF using 30 minutes as preferred infusion time to optimize Cmax and antiviral killing [58], however if patient
experiences infusion reaction may attempt slower 120 minute infusion o Loading dose
Day 1: 200 mg IV once o Maintenance dose
If not requiring invasive mechanical ventilation and/or ECMO:
Days 2-5: 100 mg IV once daily If requiring invasive mechanical ventilation and/or ECMO:
Days 2-10: 100 mg IV once daily
BHSF interdisciplinary Antimicrobial Review Committee does not recommend 10 day courses at this time (see literature above)
Pediatric (non-neonatal) dose: o Clinical study allowed patients to stop therapy early if they were ready for discharge [47, see supplemental
appendix] o BHSF using 30 minutes as preferred infusion time to optimize Cmax and antiviral killing [58], however if patient
experiences infusion reaction may attempt slower 120 minute infusion o Body weight up to 3.5 kg but below 40 kg:
Loading dose
Day 1: 5 mg/kg IV once Maintenance dose
If not requiring invasive mechanical ventilation and/or ECMO: o Days 2-5: 2.5 mg/kg IV daily
If requiring invasive mechanical ventilation and/or ECMO: o Days 2-10: 2.5 mg/kg IV daily
BHSF interdisciplinary Antimicrobial Review Committee does not recommend 10 day courses at this time (see literature above)
o Body weight > 40 kg: follow adult dosing
Remdesivir efficacy may be impacted by other potential anti-COVID-19 therapies o Concomitant hydroxychloroquine and chloroquine use with remdesivir may reduce remdesivir antiviral activity
against SARS-CoV-2 [52]
Beware drug-drug interactions (e.g., CYP-2D6, CYP-3A4, p-glycoprotein) and with hydroxychloroquine or chloroquine o Hydroxychloroquine and chloroquine may reduce the antiviral effect of remdesivir [52] o Drug-induced liver injury may be caused by interaction of remdesivir with p-glycoprotein inhibitors [61] o It has been suggested that since remdesivir is a prodrug predominantly metabolized by hydrolase activity, based
on rapid distribution, metabolism, and clearance after IV administration, the likelihood of clinically significant drug interactions is low [85]
CONTINUED ON THE NEXT PAGE
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 10
Remdesivir (Veklury, GS-5734, RDV) - Continued
Not recommended for patients with: o ALT levels > 5 X upper limit of normal
Defined by ALT over 325 by BHSF lab ranges See full prescribing criteria for liver monitoring and guidance
o Creatinine clearance < 30 mL/min or dialysis or continuous veno-venous hemofiltration
Product contains EBCD which can accumulate in renal impairment
Baseline and daily lab monitoring during therapy is required as per the FDA EUA, see Prescriber Fact Sheet for full information
Beware remdesivir has the potential for infusion-mediated reactions
Beware potential for extravasation has been reported, which has been treated successfully with a warm compress
Gilead webpage listing inclusion/exclusion criteria: https://rdvcu.gilead.com/
Gilead Remdesivir website: www.remdesivir.com
For information about compassionate use: [email protected]
For full prescribing information and other helpful resources: https://www.remdesivir.com/us/resources/
Remdesivir Criteria For Use: Next Page
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 11
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 12
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 13
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 14
Tocilizumab (Actemra®)
Evidence summary: Cytokine release syndrome (CRS) may be an important component of the critical illness associated with COVID-19. This agent does not possess antiviral activity and therefore should only be utilized as adjunctive therapy in the setting of suspected CRS. Tocilizumab has an FDA-approval for CRS (due to chimeric antigen receptor-T cell therapy) that is severe or life threatening. Tocilizumab is not FDA-approved for use related to COVID-19 and does not have an emergency use authorization.
Xu and colleagues reported on 21 severe or critical COVID-19 patients treated with tocilizumab, finding favorable outcomes and no deaths [18].
Luo et al reported a retrospective assessment of 15 patients given tocilizumab at a single center, finding reduction in CRP and IL-6 [19]. Three of their patients died, all of whom were critically ill at the time of tocilizumab administration.
Capra et al reported a non-randomized study of 85 hospitalized patients with COVID-19 pneumonia who were not mechanically ventilated and received either 400 mg or 324 mg of tocilizumab once. Compared to a control group, patients who received tocilizumab had greater survival (p=0.004), adjusting for baseline clinical characteristics [39].
Tonati et al reported on 100 patients (no comparator) treated with tocilizumab 8 mg/kg by two infusions with a third optional infusion, finding mixed short-term outcomes, but 10 day respiratory condition was overall favorable. They found three cases of severe adverse effects including two cases of septic shock leading to death and one instance of GI perforation requiring urgent surgery [43].
There has been a case reported of drug-induced liver injury associated with tocilizumab used for treatment of COVID-19 [46].
Price and colleagues reported an observational study including 239 patients who received tocilizumab [54]. The authors assessed patients in a nested-fashion examining severity of illness, finding similar survival amongst severe and non-severe cohorts. There was no comparator group of patients that did not receive tocilizumab.
Guaraldi et al report an assessment of 1351 patients, including 365 in a standard of care arm, 78 in a subcutaneous tocilizumab group, and 47 in an IV tocilizumab group [57]. The authors found more death in the standard of care group as compared to either tocilizumab group (p<0.001). Tocilizumab receipt was also associated with reduced risk of invasive mechanical ventilation or death (HR 0.61, CI 0.400.92, p = 0.02). Patients in the tocilizumab arms were more likely to get diagnosed with new infections (13% versus 4%, p < 0.001).
It has been suggested that cytokine storm is not as relevant to COVID-19 as some have proposed, although the pathophysiologic processes are yet to be full understood [59].
It has also been suggested that immune modulation in COVID-19 should be done in a personalized immunophenotype-driven approach [60].
A small single center nested assessment of hospitalized patients with severe COVID-19 receiving tocilizumab plus corticosteroids at admission versus after 24 hours of admission found mortality was greater when tocilizumab was given after 24 hours of hospitalization (6.25% vs 34.9% mortality, P < 0.01) [70].
A single center study of 154 patients (78 tocilizumab and 76 control) who had COVID-19 and required mechanical ventilation found tocilizumab was associated more superinfections (56% vs 26%, p < 0.001), no difference in 28-day case fatality (22% vs 15%, p=0.42), and a 45% reduction in hazard of death (HR 0.55, CI 0.33-0.9) [72]. The tocilizumab group was younger, less likely to have chronic pulmonary disease, and had a lower D-dimer at time of intubation.
A pre-print article investigating low-dose tocilizumab in the treatment of COVID-19 found doses of 40 to 200 mg were associated with rapid improvement in clinical and laboratory measures of hyper inflammation in hospitalized patients with COVID-19 [79].
Roche provided the first update on a randomized controlled trial of tocilizumab in a July 2020 media release. The company reports the phase III COVACTA trial did not meet its primary endpoint of improved clinical status in patients with COVID-19 associated pneumonia, or the key secondary endpoint of reduced patient mortality [81,92].
Biran and colleagues reported a retrospective observational cohort including 210 patients who received tocilizumab plus 420 propensity-score matched patients who did not [86]. They found there was numerically less death in the tocilizmab group (49% vs 61%), but did not find improved median survival in tocilizumab patients upon multivariable Cox regression analysis with propensity matching.
Rodriguez-Bano and colleagues reported on 779 patients from 60 Spanish hospitals including 88 patients treated with tocilizumab. They found tocilizumab was associated with a lower hazard of death alone in the inverse probability of treatment weights analysis, which led the authors to conclude tocilizumab should be prioritized for RCTs of COVID-19 patients with hyper-inflammatory state [88].
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 15
Continued on the next page
Fox et al reported on cytokine levels in a relatively small cohort of critically ill patients with COVID-19 versus levels with other critical illnesses, finding lower levels of TNF, IL-6, and IL-8 in patients with COVID-19 than patients in septic shock with ARDs (P<0.01 for all) [94].
Ramiro et al reported on 172 patients described as having Cytokine Storm, retrospectively identifying 86 matched patients for the 86 patients who had received high dose methylprednisolone for 5 consecutive days with or without tocilizumab (if the patient worsened) finding favorable outcomes in the intervention group, but the study was limited by a small sample size with numerous differences in baseline characteristics [95].
Periera and colleagues reported a case-control study in solid organ transplant patients with severe COVID-19, finding no decreased mortality at 90-days [96].
In a news release it was reported that Genentech’s Phase III EMPACTA study showed reduced need of ventilation for patients receiving tocilizumab for COVID-19 pneumonia. No mortality benefit was found. The full data set is not yet available [97].
Martinez-Sanz et al published a retrospective observational study utilizing data from 17 hospitals derived from a central database [98]. 261 patients were in the tocilizumab group while 969 patients were in the control group. They report reduced risk for death or ICU admission with death (p<0.02 for both) in patients with higher CRP levels (>150 mg/L).
Sampogna et al report spinal cord dysfunction occurring in 3 patients after COVID-19, 2 of which patients received tocilizumab. [100]
The Society of Critical Care Medicine state there is insufficient evidence to issue a recommendation on the use of tocilizumab in critically ill adults with COVID-19 [16]. The American Thoracic Society makes no suggestion for or against use of tocilizumab in hospitalized patients with COVID-19 who have evidence of pneumonia (30% for intervention, 56% no suggestion, 14% against) [27]. IDSA recommends tocilizumab only in the context of a clinical trial [28]. NIH recommends against the use of IL-6 inhibitors for COVID-19 outside the context of a clinical trial [28]. Numerous institutional protocols in the United States have recommended consideration for tocilizumab in patients with COVID-19 severe or critical illness, however the trend has gone away from this as COVACTA and other results have been released. Sarilumab (Kevzara) is another IL-6 inhibitor that has been investigated for COVID-19 [91]. The phase 3 trial of this drug in patients with COVID-19 who required mechanical ventilation did not meet the primary or key secondary endpoints when added to best supportive care compared to best supportive care alone. This was released in a Sanofi press release in September 2020.
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 16
Tocilizumab (Actemra®) - Continued
**Tocilizumab does not have antiviral activity**
Formulary status: Non-Formulary
FDA- approved indications: o Cytokine release syndrome due to chimeric antigen receptor-T cell therapy o Giant cell arteritis o Rheumatoid arthritis
Proposed mechanism of action in COVID-19: IL-6 receptor antagonist leading to a reduction in cytokine and acute phase reactant production
Should only be considered for patients failing alternative therapies who have severe COVID-19 disease, and clinical evidence of cytokine storm.
Suggested inclusion criteria (must meet all): o Obtain approval from specialist if restricted locally o Discuss with patient and/or family risk:benefit and document agreement to use o Hospitalized patient who is intubated
The appropriate time to give tocilizumab is unclear, it may be reasonable to give prior to intubation o Lab-confirmed SARS-CoV-2 or highly suspicious for COVID-19 if pending lab test result o Extensive, bilateral lung disease, with severe COVID-19 illness per WHO criteria o Clinical evidence of cytokine storm with acute clinical worsening
Elevated IL-6 – is a send out test, result unavailable does not necessarily preclude use Other markers (persistent high fever, elevated D-dimer, elevated C-reactive protein, elevated ferritin,
low fibrinogen)
Suggested exclusion criteria (must not meet any): o Current invasive bacterial, viral (non-COVID-19), or fungal infection o AST/ALT above 5x upper limit of normal (soft exclusion, depends on underlying cause) o Platelets below 50,000 o Long-term oral anti-rejection or immunomodulatory drugs o Recent history of GI perforation o History of hypersensitivity to tocilizumab or any excipients
Adult dose: infuse over 60 minutes o Option #1 (recommended):
400 mg IV x 1 dose followed by an additional 400 mg IV dose if fever persists after 12 hours o Option #2:
30 to 100 kg: 400 mg IV x 1 dose and for > 100 kg: 600 mg IV x 1 dose
Pediatric (non-neonatal) dose: infuse over 60 minutes o Less than 30 kg: 12 mg/kg IV x 1 dose (round to nearest 50 mg) o 30 kg or more: 8 mg/kg IV x 1 dose (maximum 400 mg per dose), if fever persists after 12 hours
Repeat dosing subsequent to receiving initial dose(s) is not recommended due to lack of data & increased risks o Beware that invasive pulmonary aspergillosis has been reported in increased frequency amongst COVID-19
intubated patients [80]
Has a half-life of up to 13 days in adults o The long half-life may predispose patients to infection at a later time
IL-6, C-reactive protein, D-dimer, and LDH levels should be used to diagnose cytokine release syndrome and monitor therapy
Assess for Hepatitis B with surface antigen and core antibody. Test results do not preclude treatment. o If either antigen or antibody are positive, obtain a viral load (HBV DNA) o If detectable viral load, consider starting antiviral therapy
The H-score may be a useful tool for evaluating patients for cytokine storm
Use caution in patients with a history of GI perforation, diverticulitis, or elevated LFTs
All patients receiving tocilizumab should be ruled out for latent TB prior to administration per package insert. Does not preclude treatment.
Product is expensive (single adult dose is thousands of dollars)
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 17
REFERENCES & READINGS
1. World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected. [accessed 19 March 2020]
2. Centers for Disease Control and Prevention. Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). [accessed 19 March 2020]
3. Yao X, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases. 2020; Ciaa237.
4. Chinese government’s New Coronavirus Pneumonia Diagnosis and Treatment Plan (Version 7). Translated into English. Accessed 19 March 2020.
5. Guastalegname M, et al. Could chloroquine/hydroxychloroquine be harmful in coronavirus disease 2019 (COVID-19) treatment? CID. ePub ahead of print.
6. Chen Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. MedRxiv. Pre-print, available pending peer review certification. Accessed 31 March 2020.
7. Magagnoli J, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. MedRxiv. Pre-print, available pending peer review certification. Accessed 23 April 2020.
8. Jie Z, et al. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus. CMA. 2020. 12; 43(3): 185.88. 9. McHenry AR, et al. Stability of extemporaneously prepared hydroxychloroquine sulfate 25-mg/mL suspension in plastic bottles
and syringes. IJPC. 2017; 21(3): 241-54. 10. Wang, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell
Research. 2020;30:269-71. 11. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated
pneumonia in clinical studies. Biosci Trends 2020 Feb 19 [Epub ahead of print]; doi:10.5582/bst.2020.01047. 12. Colson P, Rolain JM, Lagier JC et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J of
Antimicrob Agents (2020); https://doi.org/10.1016/j.ijantimicag.2020.105932 13. Gautret P, et al. Hydroxychloroquine and azithromycin as a treatment for COVID-19: results of an open-label non-randomized
clinical trial. IJAA. Published online March 20, 2020. 14. Gautret P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19
patients with at least a six-day follow-up: an observational study. ePub ahead of print. 15. Molina JM, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and
azithromycin in patients with severe COVID-19 infection. Medicine et Maladies Infectieuses. 2020. ePub ahead of print. 16. Alhazzani W, et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease
(COVID-19). Accessed 20 March 2020. 17. Mehta P. COVID-19: consider cytokine storm syndromes and immunosuppression. The LANCET. Published March 16, 2020. 18. Xu X, et al. Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXIV. ePub. Accessed 16 March 2020. 19. Luo P. Tocilizumab treatment in COVID-19: a single center experience. Journal of Medical Virology. 2020. ORCID iD: 000-0002-
5829-5142. Published Online. 20. Massachusetts General Hospital COVID-19 Treatment Guideline. Version 1.0. Accessed 20 March 2020. 21. McCreary EK, Pogue JM. COVID-19 Treatment: A review of early and emerging options. Open Forum Infectious Diseases. 2020;
ePub ahead of print. 22. Zhou D, et al. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and
progression. JAC. 2020. ePub ahead of print. 23. Acute Care ISMP Medication Safety Alert. April 9, 2020. Volume 25, Issue 7. 24. Chu CM et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59: 252–
56 25. Cao B, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. NEJM. 2020; 382(19): 1787-1799. 26. Best, et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. J Acquir Immune Deficiency
Syndrome. 2011;58:385-91. 27. Wilson KC et al. COVID-19: interim guidance on management pending empirical evidence. From an American Thoracic Society-
led International task force. Available: https://www.thoracic.org/professionals/clinical-resources/disease-related-resources/covid-19-guidance.pdf. Accessed 9 April 2020.
28. Bhimraj A, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Posted online 4/11/2020: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
29. National Institutes of Health COVID-19 Treatment Guidelines. Posted online April 21, 2020: https://www.covid19treatmentguidelines.nih.gov/introduction/
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 18
REFERENCES & READINGS- Continued
30. Liu W, Li H. COVID-19: attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv. 2020.
31. Silva Borba MG, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A randomized Clinical Trial. JAMA. 2020.
32. FDA MedWatch Alert: Hydroxychloroquine or chloroquine for COVID-19: Drug safety communication – FDA cautions against use outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. Available: http://s2027422842.t.en25.com/e/es?s=2027422842&e=326687&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=10891ab600d847389b9d4e84dd29101f&elqaid=12261&elqat=1. Accessed 24 April 2020.
33. Mercuro NJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiology. 2020. DOI: 10.1001/jamacardio.2020.1834
34. Cao B, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. NEJM. 35. Remdesivir Fact Sheet For Health Care Professionals: https://www.gilead.com/-/media/files/pdfs/remdesivir/eua-fact-sheet-for-
hcps_01may2020.pdf. Accessed 7 may 2020. 36. Rosenberg ES, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients
with COVID-19 in New York State. JAMA. Published online May 11, 2020. 37. Tang W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomized
controlled trial. BMJ. 2020; 369: m1849. 38. Mahevas M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen:
observational comparative study using routine care data. BMJ 2020; 369: m1844. 39. Capra R, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. Eur J Intern Med.
2020 DOI: 10.1016/j.ejim.2020.05.009 40. US DHHS NIH. News Release. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID. April 29, 2020. 41. Wang Y, et al. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicenter trial. The
Lancet. 2020; 395 (10236): 1569-1578. 42. Mehra MR, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational
registry analysis. The Lancet. 2020. DOI: 10.1016/S0140-6736(20)31180-6. 43. Tonati P, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute
respiratory failure: a single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020 DOI: 10.1016/j.autrev.2020.102568.
44. Goldman JD, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. NEJM. 2020. DOI: 10.1056/NEJMoa2015301. 45. Gilead Press Release. Gilead announces results from phase 3 trial of remdesivir in patients with moderate COVID-19. June 01
2020. Available: https://www.gilead.com/news-and-press/press-room/press-releases/2020/6/gilead-announces-results-from-phase-3-trial-of-remdesivir-in-patients-with-moderate-covid-19. Accessed 1 June 2020.
46. Muhovic D, et al. First case of drug-induced liver injury associated with the use of tocilizumab in a patient with COVID-19. Liver International. May 2020. DOI: 10.1111/liv.14516
47. Biegel JH, et al. Remdesivir for the treatment of COVID-19 – preliminary report. NEJM. 2020. DOI: 10.1056/NEJM 48. Boulware DR, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. NEJM. 2020. DOI:
10.1056/NEJM2016638. 49. No clinical benefit from use of hydroxychloroquine in hospitalized patients with COVID-19. RECOVERY Trial. Available:
https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19 Accessed 5 June 2020.
50. Mehra MR, et al. RETRACTED: hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. 2020; DOI: http://doi.org/10.1016/S0140-(6736)2031180-6
51. Memorandum explaining basis for revocation of emergency use authorization for emergency use of chloroquine phosphate and hydroxychloroquine sulfate. US FDA. Available: https://www.fda.gov/media/138945/download. Accessed 15 June 2020.
52. Coronavirus (COVID-19) Update: FDA warns of newly discovered potential drug interaction that may reduce effectiveness of a COVID-19 treatment authorized for emergency use. US FDA. Available: https://www.fda.gov/media/138945/download. Accessed 16 June 2020.
53. Dexamethasone reduces death in hospitalized patients with severe respiratory complications of COVID-19. University of OXFORD. Available: http://www.ox.ac.uk/news/2020-06-16-dexamethasone-reduces-death-hospitalised-patients-severe-respiratory-complications. Accessed 16 June 2020.
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 19
REFERENCES & READINGS- Continued
54. Price CC, et al. Tocilizumab treatment for cytokine release syndrome in hospitalized COVID-19 patients: survival and clinical outcomes. CHEST. DOI: 10.1016/j.chest.2020.06.006
55. Paccoud O, et al. Compassionate use of hydroxychloroquine in clinical practice for patients with mild to severe COVID-19 in a French university hospital. CID. 2020. DOI: 10.1093/cid/ciaa791
56. “Solidarity” clinical trial for COVID-19 treatments: update on hydroxychloroquine. Posted 27 May 2020, updated 17 June 2020. Available: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. Accessed 19 June 2020.
57. Guaraldi G, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. LANCET Rheumatol. 2020. DOI: 10.1016/S2665-9913(20)30210-1.
58. Humeniuk R, et al. Safety, tolerability, and pharmacokinetics of remdesivir, an antiviral treatment of COVID-19 in healthy subjects. Clinical and Translational Science. 2020. DOI: 10.1111/cts.12840.
59. Sinha P, et al. Is a “cytokine storm” relevant to COVID-19? JAMA Internal Medicine. 2020. DOI: 10.1001/jamainternmed.2020.3313
60. Hall MW, et al. Immune modulation in COVID-19: strategic considerations for personalized therapeutic intervention. Clinical Infectious Diseases. 2020. DOI: 10.1093/CID/CIAA904.
61. Leegwater E, et al. Drug-induced liver injury in a COVID-19 patient: potential interaction of remdesivir with p-glycoprotien inhibitors. Clinical Infectious Diseases. 2020. DOI: 10.1093/cid/ciaa883.
62. An open letter from Daniel O’Day, chairman and CEO, Gilead Sciences. 29 June 2020. Available: https://stories.gilead.com/articles/an-open-letter-from-daniel-oday-june-29 Accessed 7 July 2020.
63. 63. Lee T, et al. An observational cohort study of hydroxychloroquine and azithromycin for COVID-19: (Can’t Get No) Satisfaction. International Journal of Infectious Diseases. 2020. DOI: 10.1016/j.ijid.2020.06.095.
64. 64. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19. 1 July 2020. Available: https://www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19. Accessed 7 July 2020.
65. 65. Huet T, et al. Anakinra for severe forms of COVID-19: a cohort study. The Lancet Rheumatology. 2020. 2; e393-400. DOI: 10.1016/s2665-9913(20)30164-8.
66. Tempestilli M, et al. Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19. Journal of Antimicrobial Chemotherapy. 2020. DOI: 10.1093/jac/dkaa239.
67. Wiersinga JW, et al. Pathophysiology, transmission, diagnosis, and treatment of coronavirus diseases 2019 (COVID-19). JAMA. 2020. DOI: 10.1001/jama.2020.12839.
68. Davis MR, et al. That escalated quickly: remdesivir’s place in therapy for COVID-19. Infect Dis Ther. 2020. DOI: 10.1007/s40121-020-00318-1
69. Gilead presents additional data on investigational antiviral remdesivir for the treatment of COVID-19. Press Release Available: https://www.gilead.com/news-and-press/press-room/press-releases/2020/7/gilead-presents-additional-data-on-investigational-antiviral-remdesivir-for-the-treatment-of-covid-19. Accessed 10 July 2020.
70. Martinez-Urbistondo D. Early combination of tocilizumab and corticosteroids: an upgrade in anti-inflammatory therapy for severe COVID. CID. 2020.
71. Review of “Hydroxychloroquine and azithromycin as treatment of COVID-19: results of an open label non-randomized clinical trial Gautret et al 2010, DOI: 10.1016/j.ijantimcag.2020.105949. IJAA. 2020. DOI: 10.1016/j.ijantimicag.2020.106063.
72. Somers EC, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. CID. 2020. DOI: 10.1093/cid/ciaa954.
73. Mitja O, et al. Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial. CID. 2020. DOI: 10.1093/CID/CIAA1009
74. Skipper CP, et al. Hydroxychloroquine in nonhopsitalized adults with early COVID-19. A randomized trial. Annals of Internal Medicine. 2020. DOI: 10.7326/M20-4207.
75. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19 – Preliminary Report. NEJM. 2020. DOI: 10.1056/NEJMoa2021435.
76. Keller MJ, et al. Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19. Journal of Hospital Medicine. 2020. DOI: 10.12788/jhm.3497
77. Cavalcanti AB, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate COVID-19. NEJM. 2020. DOI: 10.1056/NEJMoa2019014
78. Olende SA, et al. Remdesivir for severe COVID-19 versus a cohort receiving standard care. 2020. DOI: 10.1093/CID/CIAA1041 79. Strohbehn GW, et al. COVIDOSE: low-dose tocilizumab in treatment of COVID-19. MedRxiv PREPRINT. Available:
https://www.medrxiv.org/content/10.1101/2020.07.20.20157503v1. Accessed 30 July 2020.
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 20
REFERENCES & READINGS- Continued
80. Bartoletti M, et al. Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study. CID. 2020. DOI: 10.1093/cid/ciaa1065
81. Roche provides an update on phase III COVACTA trial of Actemra/RoActemra in hospitalized patients with severe COVID-19 associated pneumonia. 29 July 2020. Available: https://www.roche.com/media/releases/med-cor-2020-07-29.htm. Accessed 30 July 2020.
82. Rochwerg B, et al. Remdesivir for severe covid-19: a clinical practice guideline. BMJ. 2020; 370: m2924. DOI: 10.1136/bmj.m2924
83. U.S. Food & Drug. Frequently asked questions on the emergency use authorization for remdesivir for certain hospitalized COVID-19 patients. Posted 7/30/2020. Available at: https://www.fda.gov/media/137574/download. Accessed 3 August 2020.
84. Kalligeros M, et al. Remdesivir use compared to supportive care in hospitalized patients with severe COVID-19: a single-center experience. OFID. 2020. DOI: 10.1093/ofid.ofaa319.
85. Hodge C, et al. Drug interactions: a review of the unseen danger of experimental COVID-19 therapies. Journal of Antimicrobial Chemotherapy. 2020. DOI: 10.1093/JAC/dkaa340.
86. Biran N, et al. Tocilizumab among patients with COVID-19 in the intensive care unit: a multicenter observational study. The LANCET Rheumatology. 2020. DOI: 10.1016/S2665-9913(20)30277-0.
87. Spinner CD, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19. A randomized clinical trial. JAMA. 2021. DOI: 10.1001/jama.2020.16349.
88. Rodriguez-Bano J, et al. Treatment of tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicenter cohort study (SAM-SOVID-19). Clinical Microbiology and Infection. 2020. DOI: 10.1016/j.cmi.2020.08.010
89. Pasquini Z, et al. Effectiveness of remdesivir in patients with COVID-19 under mechanical ventilation in an Italian ICU. Journal of Antimicrobial Chemotherapy. 2020. DOI: 10.1093/jac/dkaa321.
90. COVID-19 Update: FDA Broadens Emergency Use Authorization for Veklury (remdesivir) to Include All Hospitalized Patients for Treatment of COVID-19. FDA News Release. Available: https://www.fda.gov/news-events/press-announcements/covid-19-update-fda-broadens-emergency-use-authorization-veklury-remdesivir-include-all-hospitalized. Accessed 31 August 2020. Direct updated EUA link: https://www.fda.gov/media/137564/download.
91. Sanofi and Regeneron provide update on kevzara (sarilumab) phase 3 U.S. trial in COVID-19 patients. Available at: https://www.sanofi.com/en/media-room/press-releases/2020/2020-07-02-22-30-00. Accessed 1 September 2020.
92. Rosas I, et al. Pre-Print: Tocilizumab in hospitalized patients with COVID-19 pneumonia. MedRxiv. Available at: https://www.medrxiv.org/content/10.1101/2020.08.27.20183442v1. Accessed 3 September 2020.
93. Prescott HC and Rice TW. Corticosteroids in COVID-19 ARDS: Evidence and hope during the pandemic. 2020. DOI: 10.1001/jama.2020.16747
94. Kox M, et al. Cytokine levels in critically ill patients with COVID-19 and other conditions. JAMA. 2020. DOI: 10.1001/jama.2020.17052.
95. Ramiro S, et al. Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study. Rheumatic Diseases. 2020; 79: 1143-1151.
96. Pereira MR, et al. Tocilizumab for severe COVID-19 in solid organ transplant recipients: a matched case-control study. American Journal of Transplantation. 2020. DOI: 10.1111/ajt.16314
97. Genentech’s Phase III Empacta Study showed Actemra reduced the likelihood of needing mechanical ventilation in hospitalized patients with COVID-19 associated pneumonia. News Release on Business Wire. Available at: https://www.businesswire.com/news/home/20200917006062/en/Genentech%E2%80%99s-Phase-III-EMPACTA-Study-Showed-Actemra-Reduced-the-Likelihood-of-Needing-Mechanical-Ventilation-in-Hospitalized-Patients-With-COVID-19-Associated-Pneumonia. Accessed 23 September 2020.
98. Martinez-Sanz J, et al. Effects of tocilizumab on mortality in hospitalized patients with COVID-19: a multicenter cohort study. Clinical Microbiology and Infection. 2020. DOI: 10.1016/j.cmi.2020.09.021
99. Martinot M, et al. Remdesivir failure with SARS-CoV-2 RNA-dependent RNA-polymerase mutation in a B-cell immunodeficient patient with protracted COVID-19. Clinical Infectious Diseases. 2020. DOI: 10.1093/cid/ciaa1474.
100. Sampogna G, et al. Spinal cord dysfunction after COVID-19 infection. Spinal Cord Series and Cases. 2020. DOI: 10.1038s41394-020-00341-x.
101. Abella BS, et al. Efficacy and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis among healthcare workers: a randomized clinical trial. JAMA Internal Medicine. 2020. DOI: 10.1001/jamainternmed.2020.6319.
102. Effect of hydroxychloroquine in hospitalized patients with COVID-19. NEJM. 2002. DOI: 10.1056/NEJMoz2022926.
There are no FDA-approved anti-COVID-19 medications. The risk:benefit should be carefully evaluated and discussed with the patient as well as documented in the chart prior to using any therapy. BHSF does not mandate use of any specific therapy.
Last updated: October 16, 2020 at 12:30 EST // Baptist Health South Florida – Antimicrobial Stewardship Program // Page 21
REFERENCES & READINGS- Continued
103. Burwick RM, et al. Compassionate use of remdesivir in pregnant women with severe COVID-19. CID. 2020. DOI: 10.1093/CID/CIAA1466
104. Beigel JH, et al. Remdesivir for the treatment of COVID-19 – Final Report. NEJM. 2020. DOI: 10.1056/NEJMoa2007764. 105. News release: Barcitinib has significant effect on recovery time, most impactful in COVID-19 patients requiring oxygen. Lilly.
Available at: https://investor.lilly.com/news-releases/news-release-details/baricitinib-has-significant-effect-recovery-time-most-impactful. Accessed 9 October 2020.
106. The RECOVERY Collaborative Group. Effect of hydroxychloroquine in hospitalized patients with COVID-19. NEJM. 2020. DOI: 10.1056/NEJM0a2022926.
107. WHO Solidarity Trial Consortium. PRE-PRINT. Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results. Posted 15 October 2020. Available: https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1.full.pdf+html. Accessed 16 October 2020.
The COVID-19 pandemic is rapidly evolving. New data is coming out every day. We will continue to take guidance from our clinicians, review documents released by professional organizations, and monitor the literature. We are aware there are other
potential therapies under investigation for COVID-19. This document will be updated periodically.
Contact: [email protected]
