Impact of a multifaceted, outpatient antimicrobial stewardship intervention bundle on unnecessary antimicrobial prescribing in upper respiratory tract infections (URI)

Background. URIs are the most common indication for outpatient antibiotic prescribing. Given high rates of unnecessary prescribing, these indications have been identified as a high-priority target for outpatient antimicrobial stewardship programs (ASP). Our primary objective was to evaluate the impact of a system-wide, multifaceted, outpatient ASP intervention bundle on unnecessary antibiotic prescribing for URI. Methods. This quasi-experimental study was conducted from 2019 to 2021. ICD-10 codes for URIs were grouped into 3 tiers (i.e., tier I = antibiotics always indicated, tier II = sometimes, tier III = never). Encounters from 5 care specialties (i.e., family medicine, community internal medicine, express care, pediatrics, and emergency department) with a tier III URI primary ICD-10 code but without a secondary tier I or tier II code were included. COVID-19 ICD-10 codes were excluded. Interventions included construction of a prescribing data model, dissemination of clinician prescribing data and education, promotion of symptom management strategies, a patient-facing commitment poster, and a pre-populated URI order panel. Tools were designed at a system level and implemented by regional champions beginning in the 3rd quarter of 2020. The primary outcome was the rate of antibiotic prescribing, and the secondary outcome and counterbalance measure was the rate of repeat URI-related healthcare contact within 14 days. Outcomes were analyzed with chi-square with an alpha level of 0.05. Results. A total of 147403 encounters were included. The overall antibiotic prescribing rate decreased from 24.1% to 12.3% between 2019 and 2021 (p< 0.01). Significant reductions in tier III antibiotic prescribing were demonstrated for each region, care specialty, and syndrome evaluated (Table 1). A reduction in repeat healthcare contact was seen across the total cohort (9.5% in 2019 vs. 8.3% in 2021, p< 0.01);decreases in repeat contact rates were observed in those not initially receiving an antibiotic (10.3% vs. 8.6%, p< 0.01), but not in those who initially received an antibiotic (6.8% vs. 6.8%, p = 0.94). Tier III URI encounter level antimicrobial prescribing rates by region, care specialty, and syndrome Conclusion. A multifaceted, outpatient ASP intervention bundle decreased rates of unnecessary antimicrobial prescribing without increasing rates of 14-day repeat URI-related healthcare contact.

Implications of Pre-Transplant (tx) COVID-19 on SOT or HCT: A Multicenter Study

Purpose: Describe outcomes of patients (pt) with pre-tx COVID-19. Method(s): Multicenter study of SOT/HCT candidates who had a positive (pos) SARS-CoV-2 PCR pre-tx. Result(s): Pre-tx: Of 208 pt, median age was 56 (range 3-76). 87.8% were SOT candidates (40.5% kidney, 40.5% liver, 9.8% lung, 6.9% heart, 2.3% pancreas) and 13.9% were HCT candidates (54.2% allo, 45.8% auto). Pt underwent a median of 2 tests (range 1 - 14). In 41% of pt, > 1 neg PCR was required by the tx center before reactivation. Neg PCR was documented in 67.4% of pt at a median of 41 days (18-68) after pos PCR. Waitlist mortality was 11.0%;deaths were due to COVID-19 in 60% (12/20). Post-tx (all pt): 78 pt underwent tx at a median of 65.5 days (range 17-324) from COVID-19;71/78 have completed 4-weeks of follow-up. 24/78 (30.7%) pt were still PCR pos at time of tx (details below). 54/78 (69.2%) pt underwent routine PCR testing post-tx;62% were tested regularly for 8 weeks. Only 1 pt, who remained asymptomatic, developed recurrent pos PCR on surveillance testing 18 days post-tx. 1 pt had graft loss. There were no deaths at 4 weeks post-tx. Pt transplanted without a negative PCR: 24 pt with COVID-19 did not have neg PCR at time of tx: 9 (37.5%) kidney, 9 (37.5%) liver, 2 (8.3%) SLK, 1 (4.2%) lung, 1 heart (4.2%), 2 auto-HSCT (8.3%), 2 allo-HSCT (8.3%). Of 24 pt who were reactivated at a median of 21 days (range 8 - 38) from COVID-19 diagnosis, 7 underwent tx emergently (5 liver, 1 lung, 1 heart). 20/24 completed 4-weeks of follow-up;all were alive. PCR Cycle thresholds (Ct) increased over time, suggesting a reduction in SARS-CoV-2 viral loads with time elapsed since COVID-19 diagnosis. Conclusion(s): Short-term outcomes of transplantation in SOT/HCT candidates with prior COVID-19 were promising in this small cohort, even with a positive PCR going into transplant. Whether documentation of a negative PCR should be required for all tx candidates with a history of COVID-19 prior to transplantation should be investigated further, particularly among lung tx candidates. For certain tx candidates with COVID-19, relying time-based strategy instead of a test-based strategy may be safe.

Treatment with anti-spike monoclonal antibodies in allogeneic HCT and CAR T-cell recipients with mild to moderate COVID-19: The Mayo Clinic experience

Background: Prognosis of COVID-19 is poor in the setting of immunosuppression. Casirivimab/imdevimab (REGEN-COV), bamlanivimab, and sotrovimab are investigational monoclonal antibodies (MoAbs) authorized for treatment of mild/moderate COVID-19 for patients (pts) 12 years or older and who are at high-risk for progression to severe COVID-19. These neutralizing antibodies, against SARS-CoV-2 spike proteins, have been shown to decrease risk of progression to severe disease. Recipients of allogeneic stem cell transplants (allo-SCT) or chimeric antigen T cell therapy (CAR T cell) represent a high risk population. However, treatment outcomes with these MoAbs in these pts are not well described. Methods: This retrospective study included 33 consecutive adult pts who developed mild/moderate COVID-19 and received anti-spike SARS-CoV-2 MoAbs between December 2020 and November 2021. Allo-SCT (N=27) or CAR T cell (N=6) recipients were included, and outcomes were analyzed separately. Pts received REGEN-COV (N=19), bamlanivimab (N=11), or sotrovimab (N=1), missing (N=2). Results: In the allo-SCT cohort (N=27), median age at time of COVID-19 was 55 (23-76) years. Median time from allo-SCT to COVID-19 was 31 (22-64) months. Two pts received CAR T-cell therapy prior to allo-SCT. Diagnoses included leukemia or myeloid diseases (82%), lymphoma (11%), or myeloma (7%). Transplant characteristics are summarized (Table). Thirteen pts were vaccinated against SARS-CoV-2 prior to breakthrough COVID-19. Events considered included hospitalization due to COVID- 19, disease progression, or death from any cause. The 6-month event-free and overall survivals were 81% and 91%, respectively. In the CAR T cell recipients cohort (N=6), 4 pts received axicabtagene ciloleucel for diffuse large B-cell or follicular lymphoma and 2 received brexucabtagene autoleucel for mantle cell lymphoma. The median follow-up was 8 (1-11) months. Two pts received autologous SCT prior to COVID-19. Median time from CAR T cell therapy to COVID-19 was 10 (3-24) months. Three pts were vaccinated prior to COVID-19. Only 1 pt was hospitalized due to severe COVID- 19 requiring mechanical ventilation leading to death. Conclusions: These results show a potential benefit of MoAbs in high-risk pts, namely allo-SCT or CAR T cell recipients. Future studies should evaluate the role of prophylactic use MoAbs in these populations. A comparative analysis with a matched control cohort (who did not receive MoAbs) will be provided at the meeting.

Response to COVID-19 Vaccination Post-CAR T Therapy in Patients with Non-Hodgkin Lymphoma and Multiple Myeloma

Background:COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Among patients with hematologic malignancies, seroconversion rates also appear to be influenced by recent treatment and the type of treatment they have received. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. Current national guidelines recommend COVID-19 vaccination to be offered to CAR T recipients as early as three months thereafter. We retrospectively evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Methods:This retrospective study was conducted at three Mayo Clinic sites on NHL and MM patients that received CAR T infusions from Sept 2016 to June 2021. Baseline characteristics were ascertained from medical records. All NHL and MM patients who had received CAR T at any point and were alive at the time that the COVID-19 vaccine first became available were eligible for inclusion for antibody response evaluation. For antibody response to vaccination, antibody spike values > 0.80 U/mL were considered positive. Results: Out of 104 CAR T infusions, 73 patients are alive at the time of this submission. We have had 7 patients with known COVID-19 pre-CAR T and all 7 are currently alive (5 have antibody titers and 2 have not been tested yet). Nineteen patients developed known COVID infection post-CAR T (13 alive and 6 deceased). The mortality of COVID post-CAR T in our sample was 31.5%. Furthermore, of the 13 patients that survived COVID-19, they received CAR T an average of 416 days prior to COVID-19 infection (median = 337, range = 54 - 1406);the 6 patients who died from COVID-19 had received CAR T an average of 250 days prior to COVID-19 infection (median = 164, range = 7 - 846). All 6 deceased patients did not receive COVID-19 vaccination pre-CAR T. Out of 17 CAR T patients tested for antibody spike titers post COVID-19 vaccination, 76.4% were able to mount an antibody response. More patients with MM had a higher titer response to the vaccine (>250 U/mL) compared to the NHL counterparts (0.80-249 U/mL). All patients that received the vaccine, regardless of antibody response, were alive at the time of this submission. Conclusions:The majority of CAR T recipients with NHL and MM are able to mount an antibody response following COVID-19 vaccination in our relatively small sample. The frequency of seroconversion among CAR T recipients seems to be similar to patients with hematologic malignancy who had received a hematopoietic cell transplant reported elsewhere. These findings are limited by our small sample size and may be influenced by the timing of vaccination relative to CAR T. Furthermore, almost half of our patients received IVIG post CAR T which could potentially cause false positive antibody results as pooled immunoglobulin preparations may contain COVID-19 antibodies from vaccinated healthy donors. To better understand the characteristics of the immunologic response against SARS-CoV-2 in patients post-CAR T, larger multicenter studies exploring both humoral and cellular immunity will be needed. JEWN, MI and JM are co-first authors and PV, HM and AR are co-senior authors. [Formula presented] Disclosures: Munoz: Physicians' Education Resource: Honoraria;Seattle Genetics: Honoraria;Bayer: Research Funding;Gilead/Kite Pharma: Research Funding;Celgene: Research Funding;Merck: Research Funding;Portola: Research Funding;Incyte: Research Funding;Genentech: Research Funding;Pharmacyclics: Research Funding;Seattle Genetics: Research Funding;Janssen: Research Funding;Millennium: Research Funding;Gilea /Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau;Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier: Consultancy;Targeted Oncology: Honoraria;OncView: Honoraria;Kyowa: Honoraria. Bergsagel: Oncopeptides: Consultancy, Honoraria;Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse;Pfizer: Consultancy, Honoraria;Celgene: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Genetech: Consultancy, Honoraria;GSK: Consultancy, Honoraria. Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding;LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding;Genentech: Research Funding;InnoCare: Research Funding;Novartis: Research Funding;MorphoSys: Research Funding;Eli Lilly: Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Fonseca: Juno: Consultancy;Kite: Consultancy;Aduro: Consultancy;OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy;AbbVie: Consultancy;Patent: Prognosticaton of myeloma via FISH: Patents & Royalties;Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees;Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees;BMS: Consultancy;Amgen: Consultancy;Sanofi: Consultancy;Merck: Consultancy;Mayo Clinic in Arizona: Current Employment;Celgene: Consultancy;Takeda: Consultancy;Bayer: Consultancy;Janssen: Consultancy;Novartis: Consultancy;Pharmacyclics: Consultancy. Palmer: Sierra Oncology: Consultancy, Research Funding;CTI BioPharma: Consultancy, Research Funding;Protagonist: Consultancy, Research Funding;Incyte: Research Funding;PharmaEssentia: Research Funding. Dingli: Novartis: Research Funding;GSK: Consultancy;Apellis: Consultancy;Alexion: Consultancy;Sanofi: Consultancy;Janssen: Consultancy. Kapoor: Sanofi: Research Funding;AbbVie: Research Funding;Takeda: Research Funding;Karyopharm: Consultancy;Cellectar: Consultancy;BeiGene: Consultancy;Pharmacyclics: Consultancy;Sanofi: Consultancy;Amgen: Research Funding;Ichnos Sciences: Research Funding;Regeneron Pharmaceuticals: Research Funding;Glaxo SmithKline: Research Funding;Karyopharm: Research Funding. Kumar: Roche-Genentech: Consultancy, Research Funding;Oncopeptides: Consultancy;Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS: Consultancy, Research Funding;Beigene: Consultancy;Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Research Funding;Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding;Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Tenebio: Research Funding;Merck: Research Funding;Carsgen: Research Funding;KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Amgen: Consultancy, Research Funding;Bluebird Bio: Consultancy;Antengene: Consultancy, Honoraria;Sanofi: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board;Vividion: Other: Advisory Board;Kyowa Kirin: Other: Advisory Board;Daichii Sankyo Inc: Other: Advisory Board;Purdue Pharma: Other: Advisory Board;Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding;Merck: Research Funding;Gamida Cell: Consultancy;Takeda: Research Funding;Juno: Consultancy;Bluebird Bio: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Novartis: Consultancy;Janssen: Consultancy, Research Funding;Sorrento: Consultancy;Legend: Consultancy;Vineti: Consultancy. Murthy: CRISPR Therapeutics: Research Funding.