key: cord-0928052-2rfslbxw
authors: Rodriguez, George D.; Wu, Yuexiu; Karnik, Krupa; Ruddy, Samantha; Kula, Anna; Warren, Nathan; Yashayev, Roman; Sajid, Fizza; Prasad, Nishant; Yoon, James; Turett, Glenn; Yung, Lok; Urban, Carl; Lee, Chan-Ho; Abraham, Jessie; Cooke, Joseph T.; Sharma, Manish; Jaffer, Amir; Segal-Maurer, Sorana
title: Implementation of a Collaborated Antimicrobial Stewardship Program and Outpatient Parenteral Antimicrobial Therapy (OPAT) Unit-driven Monoclonal Antibody Therapy Program for COVID-19 at a NYC Hospital
date: 2022-03-03
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2022.02.056
sha: b5677124abd559099f28126c44d5c0aacef25444
doc_id: 928052
cord_uid: 2rfslbxw

Objectives To assess the processes and clinical outcomes of a joint collaboration between Antimicrobial Stewardship Program (ASP) and the Outpatient Parenteral Antimicrobial Therapy (OPAT) unit for delivery of monoclonal antibody therapy for mild-to-moderate COVID-19. Methods We carried out a retrospective, interim analysis of our COVID-19 monoclonal antibody therapy program. Outcomes included clinical response, incidence of hospitalization, and adverse events. Results 175 patients (casirivimab-imdevimab, n=130; bamlanivimab, n=45) were treated between Dec 2020 and Mar 1, 2021. The median time from symptom onset was 6 (IQR 4,8) days at time of treatment. Of 135 patients available for follow up, 71.9% and 85.9% of patients reported symptom improvement within 3 and 7 days of treatment, respectively. Nine (6.7%) patients required a COVID-19 related hospitalization within 14 days of treatment for progression of symptoms. Seven (4%) patients experienced an infusion-related reaction. Conclusions An ASP-OPAT collaboration is a novel approach to implement an efficient and safe monoclonal antibody therapy program for the treatment of mild-to-moderate COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has inflicted global devastation, causing nearly 400 million infections and resulting in over 5.7 million deaths (John's Hopkins 2021). The Food and Drug Administration (FDA) approved four monoclonal antibody therapies, bamlanivimab and casirivimab-imdevimab (November 2020) followed by bamlanivimab-etesevimab (February 2021) and sotrovimab (May 2021), for emergency use to treat high-risk patients with mild to moderate coronavirus diseases 2019 to prevent progression to severe disease and/or hospitalization (REGENERON 2021 , NIH 2021 . At NewYork-Presbyterian Queens, we began administration of outpatient monoclonal antibodies against SARS-CoV-2 in December 2020 coordinated through our Antimicrobial Stewardship Program (ASP) and administered through our Outpatient Parenteral Antimicrobial Therapy (OPAT) Unit. We report results of the interim analysis of our quality assurance initiative, highlighting our novel process.

NewYork-Presbyterian Queens (NYPQ) is a 535-bed academic, community-based medical center in Flushing, Queens, NY and was at the epicenter of the first wave of COVID-19 in the United States. As a result, over 5,000 adult patients were admitted and treated for between March 2020 and April 2021. Criteria for admission and treatment followed the National Institutes of Health COVID-19 Treatment Guidelines (NIH 2021). As a clinical service, our ASP was responsible for reviewing, implementing, and monitoring COVID-19 treatments to facilitate a safe and standardized approach. Established in 1999, our ASP consists of a multi-disciplinary team including an Infectious Diseases (ID) attending physician, a managing ID clinical pharmacist, and three senior, ID-trained physician assistants. In November 2020, ASP took on an additional role to collaborate with the hospital's high volume OPAT unit to provide outpatient monoclonal antibody therapy (MAb) to identified patients. The OPAT infusion unit is a hospitalbased outpatient service operating 7am to 4pm, 365 days a year, for over 10 years, and staffed by a full team of infusion nurses, two nurse practitioners, a navigator, a dedicated case manager, and Infectious Diseases residents and attending physician. It was chosen as an appropriate site due to its stable structure with daily appointments and ability to implement infection control practices (described below).

The management and responsibilities of the ASP/MAb service rotated weekly among the clinical pharmacist and physician assistants. During times of extremely high referral volume (i.e. more than 10 patients per day), two members of ASP were assigned to the initiative. Institutional Review Board approval was not obtained, as this was a quality assurance and patient safety project.

Adult patients ≥ 18 years old were considered eligible for treatment if they met the high risk criteria defined in the FDA's Emergency Use Authorization (Appendix) which remained constant over the time of this evaluation. Treatment was not provided to patients who had received at least one dose of a SARS-CoV-2 vaccine due to the lack of guidance from the FDA.

Subsequently, the criteria was updated accordingly to reflect updated FDA guidance, which included broader inclusion criteria, decrease in age requirement, monoclonal antibody selection depending the epidemiological influences, and guidance to provide regardless of vaccination status. The clinical data, criteria for use, and referral process were presented to the hospital's medical group outpatient providers and Emergency Department (ED) leadership via teleconference by ASP. In addition, a one-page summary of eligibility criteria and referral contact information was shared with providers. Patients were identified in the following ways: by their outpatient provider (i.e., primary care provider or sub-specialist provider) following either in-person or remote telehealth visit; by an ED provider if evaluated in our ED; or by a member of ASP upon daily review of all positive SARS-CoV-2 test results obtained either from ED discharged patients or from those having undergone pre-procedure testing at affiliated outpatient practices.

The referring outpatient provider was instructed to contact ASP to refer a patient for treatment.

This occurred via phone, text, email, or fax, 7 days a week during the hours of 7:30 am -5:00 pm. A member of ASP then contacted the patient via telephone to obtain information regarding underlying comorbidities, current medications, COVID-19 symptoms and duration, and to provide information regarding monoclonal antibody treatment (including the emergency use approval status, mechanism of action, goal of therapy, potential adverse events, administration process, and logistics). For patients referred by ED providers, the patient received the same information either by a member of ASP or by the ED provider prior to being discharged from the ED or via follow-up phone call by ASP within 24 hours of ED discharge. Administration in the ED was not possible due to the high volume of patients undergoing evaluation and lack of resources to ensure FDA-required monitoring during and following infusion. In addition, a member of ASP would contact any qualifying patient with a positive SARS-CoV-2 test who was not referred by the ED on behalf of the ED Director. For all other positive SARS-CoV-2 results, ASP would contact the ordering provider and the patient as applicable. Patients were scheduled by ASP for the earliest available appointment time, generally within 24 hours of referral.

Interpreter services were used as necessary to communicate with patients. Treatment was provided in OPAT 7 days a week, from 9am -4pm. A daily schedule was provided to staff screening visitors and patients at hospital entrances and arrangements were made to escort the patients directly to the location where the infusion was provided. Initially, a single, negativepressure, patient room was designated to accommodate treatment. As the number of referrals increased, treatment was provided in an adjacent, larger, negative-pressure procedure room that was adapted to accommodate four patients simultaneously. Care was delivered by a dedicated OPAT unit nurse and provider, limiting potential staff exposure and optimizing infection prevention and control practices. Patients were scheduled in three sessions daily of three hours each (maximum of twelve patients daily).

One hour prior to patients' scheduled arrival, a member of ASP or OPAT ordered the medication in order to allow time to thaw, prepare, and deliver it on time.

Patients were responsible for their transportation to OPAT (via self, family, friend, or paid car services). In the rare occasion when patients were unable to access transportation, our OPAT case manager explored transportation benefits included with patients' healthcare insurance. Upon arrival to the procedure room for the infusion, an OPAT nurse and provider greeted the patient and performed a formal evaluation. The latter was important as some patients deteriorated between the referral and admission to OPAT, requiring transfer to ED for necessary acute care.

All outstanding questions were answered, as well as completion of a written informed consent.

The infusion was administered over 60 minutes and patients were observed for 60 minutes postinfusion for signs of delayed hypersensitivity reactions. Following infusion and completion of observation period, patients were escorted back to the main hospital entrance and released to return home.

Either bamlanivimab and casirivimab-imdevimab were planned to be used according to supply as both were available and considered therapeutically equivalent at the start of the program, otherwise, patients received specific MAb as requested by the provider. If a request was not made, casirivimab-imdevimab was the default infusion until supply was exhausted. Under the EUA and New York State provisions, the medication was provided without cost to the patients.

We opted for infusion of only casirivimab-imdevimab upon release of data suggesting a decreased in vitro susceptibility of bamlanivimab to potential, newly circulating strains (e.g. 

Feedback from the OPAT team and outpatient providers was provided to ASP both in real-time and during scheduled meetings to enhance the process. A member of ASP was responsible for contacting the patient via telephone after treatment to follow up. Patients were asked to recall symptom improvement at days 3, 7, and 30, presence of residual symptoms, development of adverse effects, and need for hospitalization.

Between December 2020 and March 1, 2021, we treated 175 patients (casirivimab-imdevimab, n=130; bamlanivimab, n=45). Outpatient providers referred 137 patients and 38 were identified by ASP via ED providers/SARS-CoV-2 positive test screening. An average of 15 to 20 minutes was spent with each patient discussing the medication and coordinating the visit. Median age was 66 (IQR 59,74) years (54.9% over 65 years old), 51% male, 31.4% diabetic, and 12.6% with a BMI ≥ 35 kg/m 2 . One-quarter of patients were immunocompromised based on an underlying condition or treatment. Two-thirds of patients were age ≥ 55 years with a history of cardiovascular disease, hypertension, or pulmonary disease. Differences in race and qualification were observed between patients treated with casirivimab-imdevimab and bamlanivimab. The median time from symptom onset was 6 (IQR 4,8) days at time of treatment (Table 1) . Of the 175 patients, 135 were available for follow-up, two patients did not complete treatment due to infusion reactions (both with chills, rigors, and hypotension, one requiring a dose of epinephrine), and 38 patients did not respond to follow-up phone calls. Of 135 patients available for follow up, 71.9% and 85.9% of patients reported symptom improvement within 3 and 7 days of treatment, respectively. The majority of patients treated (79.6%) reported their overall physical health at 30 days to be "good", "very good" or "excellent", with 60.7% of patients reporting feeling back to their "usual pre-COVID-19 health" at day 30. Nine (6.7%) patients required a COVID-19 related hospitalization within 14 days of treatment for progression of symptoms. The median duration of symptom onset at time of treatment for these patients was 7 (IQR 4, 9) days. Seven (4%) patients experienced an infusion-related reaction, including chills (3), fever (1), rigors (2), hypertension (2), and hypotension (2). Twelve (6.9%) patients reported an adverse event after the infusion. This included diarrhea (4), headache (3), rash (3), fever (2), chills (2), constipation (1), and an oral ulcer (1), all of which resolved within 24 to 48 hours (Table 2) . Formal statistical analysis was not performed as this was a single arm study.

Operationalizing the Emergency Use Authorization poses challenges to healthcare systems, as it requires considerable outpatient resources to properly identify patients, communicate drug information with providers and patients, and prepare and administer safely. Our results highlight the outcome of a novel collaborative effort between seasoned OPAT and ASP teams to The hospital-based OPAT infusion unit model serves as an extension to the acute care setting, providing intravenous therapy without the need for invasive venous catheters and the benefit of skilled healthcare providers to monitor closely for efficacy and safety. Alternative models have expanded to skilled nursing facilities and patient homes, including an emphasis on the use of oral antimicrobials for difficult to treat infections, termed complex outpatient antimicrobial therapy (COpAT) (Norris AH, et al., Mahoney MV, et al.) . The influence of ASP in OPAT can be limited depending on structure and resources. Prior to the COVID-19 pandemic, ASP and our hospital-based OPAT collaborated frequently on empiric and definitive antimicrobial selection, expertise with pharmacokinetics and/or pharmacodynamics, therapeutic drug monitoring, treatment of complex non-tuberculous mycobacterial infections, and monitoring for adverse events. In addition, ASP provided education to OPAT staff and helped our case managers interface with pharmaceutical companies to obtain treatment for indigent patients.

The COVID-19 pandemic introduced additional infection control risks for patients in OPAT, capacity challenges within the acute care setting, and ultimately an opportunity for ASP expansion and collaboration to expand OPAT services to deliver optimal care to the community (Rivera, C, Mansour O, et al) . Our unique ASP/OPAT collaborative workflow allowed us to overcome usual challenges of providing monoclonal antibody infusion requiring monitoring to outpatients. Our experienced ASP expanded its responsibilities to outpatient COVID-19 to coordinate logistics and communicate directly with patients, and to provide oversight to our OPAT unit. Periodic meetings were essential for feedback to optimize the process. Hospital leadership provided extensive support including select administration area with negative pressure, dedicated nursing, protective personal equipment and pharmacy services. Clinical leadership, ASP, and OPAT developed contingency plans for patients either too ill for treatment or experiencing a severe adverse event and streamlined access to onsite ED services.

We observed a higher number of patients requiring a COVID-19 related hospitalization as compared to the original trials (6.9% vs. ~1-2%) (REGENERON 2021, ACTI-3/TICO LY-CoV555 Study Group, et al. 2020 , Weinreich DM, et al. 2021 . Patients treated at our facility had greater underlying risk than those described in the original trials (REGENERON 2021, ACTI-3/TICO LY-CoV555 Study Group, et al. 2020 , Weinreich DM, et al. 2021 Group, et al. 2020 , Weinreich DM, et al. 2021 . Of note, patients requiring hospitalization due to progression of disease had a slightly higher median duration of symptoms of 7 days (IQR 4, 9) . Similar findings were reported by related hospitalization rate of 7.8 % with the use of bamlanivimab (Kumar RN, et al. 2021 ). In addition, Verderese et al. treated patients with either bamlanivimab or casirivimab-imdevimab compared to placebo and observed a COVID-19 related hospitalization rate of 5.8% in the treatment arm compared to 11.4% in the placebo arm (Verderese JP, et al. 2021) . In both studies, the authors reported a patient population with risk factors more closely aligned to our experience than the original clinical trials.

We observed differences in baseline demographics such as sex, race, and qualifying risk factors between the bamlanivimab and casirivimab-imdevimab groups. We feel these differences may be due to chance based on our methodology of introducing casirivimab-imdevimab first, followed by bamlanivimab once supply was exhausted. Patient factors did not influence the monoclonal antibody selected by our program. We believe as awareness of the program increased over time, an increase in referrals from throughout our surrounding region may have affected referrals both in volume as well as possibly different patient demographics. Of note, patient outcomes including COVID-19 hospitalization and subjective reporting of symptom resolution were not influenced by treatment type and were consistent throughout the period of our report.

Our initiative is not without limitations. First, this is a single-arm, non-placebo-controlled, quality assurance initiative. Secondly, our experience is subject to provider bias, as outpatients were referred to us rather than our program screening all potential patients. Given the novelty of the medication, providers may have lacked awareness of the treatment or hesitated to refer.

Referral bias may have influenced our patient demographics as referring providers may have chosen patients who were sicker and/or had co-morbid conditions they felt would experience greater benefit from receiving the infusions rather than all patients who simply met criteria. In addition, we did not collect the total number of referrals, nor the reasons for ineligibility due to the high volume of calls and limited staffing (ASP team was continuing all regular in-patient job duties in addition to out-patient COVID-19 program). Thirdly, being at the epicenter of COVID-19 at the time of this study, it is possible that there was a delay in primary care visit availability that may have resulted in our median duration of symptom onset prior to treatment higher than that observed in the original clinical trials (not all patients were able to access or master telehealth successfully). Fourthly, we were unable to perform follow-up on 23% of patients and this may have affected our data analysis and possible difference in hospitalization rate. Potential resolutions to address this loss to follow-up may be contacting the referring provider to obtain follow-up or harnessing additional non-clinical staff for aid in continued attempts at contact. In addition, we did not assess for patient satisfaction during our follow-up. Though we received frequent positive and constructive feedback that influenced our processes, we did not record such data due to the limited resources mentioned above. Lastly, follow-up calls for symptom resolution were subject to recall bias, as we did not request daily diaries after treatment.

Since the data presented above, our program has cared for an additional 600 patients. Patients received either intravenous casirivimab-imdevimab, bamlanivimab-etesevimab, or more recently sotrovimab with the emergence of the omicron variant. We did not note changes in above reported outcomes or those seen in previously published data (Dougan M, et al. 2021) . The most common side effects reported by our patients, though infrequent, were chills several hours after the infusion, occasionally accompanied by headache or GI upset, all which resolved within hours. We had no known COVID-19 related hospitalizations after infusions were completed.

We continued to adjust our practice based on new data and criteria in accordance with changing FDA guidance (i.e., changes in eligibility criteria and decreasing infusion times). (REGENERON 2021 , NIH 2021 . Although we have not administered any treatment subcutaneously, this alternative route of administration has been discussed as a potential time saving modality if referral volume were to increase substantially (McCreary EK, et al., O'Brien MP, et al. 2021) . More recently, EUA has been accorded to use of these agents for post-exposure prophylaxis (REGENERON 2021 , Cohen MS, et al. 2021 , O'Brien MP, et al. 2021 . For this, we have considered separate treatment locations for confirmed SARS-CoV-2 positive patients and those referred for post-exposure prophylaxis to limit potential transmission of COVID-19.

More data to support such an approach is needed.

Our data demonstrates the favorable safety profile of monoclonal antibody therapy for COVID-19, supporting administration in non-acute care setting. This would allow wider access to individuals lacking mobility or support structure. Opportunities for the future include implementation of best practices like those described in this report of the ASP and OPAT infusion unit collaborations to provide COVID-19 treatment. ASP teams can provide the expertise and education regarding treatments to referring providers and OPAT units can look into best ways to deliver care. It may be helpful for OPAT infusion units to partner with homeinfusion services to coordinate and safely administer future agents. Successfully seeking financial support and/or grants will require incorporation of metrics such as hospital admission avoidance and patient satisfaction scores, as well as decreased burden on acute care facilities.

We found a collaborative approach consisting of ASP, ID and OPAT teams allowed for a rapid, safe, and effective implementation of the EUA protocol for the administration of COVID-19 monoclonal antibody treatments. Our interim analysis of our quality assurance initiative and realworld experience with a diverse patient population supports their use in preventing progression of disease and/or hospitalization in patients who are high-risk for developing severe disease. 4 (4) 3 (3) 3 (3) 2 (2) 2 (2) 1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) All categorical data listed as n (%) 1 Casirivimab-imdevimab (n=130), bamlanivimab (n=45)

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19

John's Hopkins COVID-19 Dashboard

Bamlanivimab prevents COVID-19 morbidity and mortality in nursing-home setting

Bamlanivimab plus etesevimab in mild or moderate Covid-19

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Data in figure includes percent from total number of patients evaluated

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Covid-19 Related Hospitalization? Symptom improvement within 3 days? Symptom improvement within 7 days? Return to usual health (pre-COVID-19) at 30 days?

We acknowledge our dedicated OPAT infusion unit staff, our referring outpatient primary care and ED providers, patient access team, and entire Pharmacy Department.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Monoclonal antibody therapy was provided by the U.S. federal government without cost to the patient.

Written informed consent was obtained from each patient prior to receiving any treatment.