Trial in Progress: Phase 1b Bridging Study of the Pharmacokinetics (PK), Safety, and Efficacy of Orally Administered Olverembatinib (HQP1351) in Patients with Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph⁺ ALL)

Background: Management of CML using tyrosine kinase inhibitors (TKIs) is often constrained by treatment failure, which portends a poor prognosis, particularly among patients who fail second-generation TKIs because of resistance. Treatment failure may be due to therapeutic resistance (whether BCR-ABL1 mutation-dependent or independent), intolerance, and/or suboptimal adherence. The BCR-ABL1 T315I ("gatekeeper") genotype is insensitive to first- and second-generation TKIs, and compound mutations complicate management with all members of the class (including third-generation TKI ponatinib). Olverembatinib (HQP1351) is a novel, potent, orally active BCR-ABL1 TKI with promising activity against CML, including antitumor activity regardless of genotype, and a preliminarily favorable safety profile. Methods: This open-label bridging trial is evaluating the PK, efficacy, and safety of olverembatinib administered orally every other day (QOD) in adults who have chronic-phase, accelerated-phase, or blast-phase CML (CP-CML, AP-CML, or BP-CML) and Ph⁺ ALL, with or without the T315I mutation, and have experienced resistance to or intolerance (including NCI CTCAE v5.0 grade ≥ 2 adverse events) of at least 3 TKIs. Eligible patients have no residual grade ≥ 2 adverse events (other than alopecia or skin pigmentation change) due to prior treatments, a maximum ECOG performance status of 2, and a minimum life expectancy of 3 months. Study participants are being randomly allocated in a 1:1:1 ratio to 3 dose cohorts: 30, 40, or 50 mg of oral olverembatinib QOD over a cycle length of 28 days, with 10 patients per cohort and randomization stratified according to CML phase (CP-CML, AP-CML, or BP-CML) or Ph⁺ ALL and T315I mutational status. Study endpoints comprise the PK profile of olverembatinib at Cycle 1 Day 1 and Day 27; efficacy endpoints of major cytogenetic and hematologic responses; and safety. The recommended phase 2 dose of olverembatinib will be determined based on a comprehensive assessment of PK, safety, and efficacy data in US and Chinese patients. As of July 14, 2021, 14 of 30 patients have been enrolled. Internal study identifier HQP1351-CU-101. Clinicaltrial.gov identifier: NCT04260022. Disclosures Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; BMS: Research Funding; NOVA Research: Honoraria; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Mukherjee: Genentech: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Partnership for Health Analytic Research: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; BioPharm: Consultancy; AAMDS in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria; Eusa Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Teaching and Speaking; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; McGraw Hill: Honoraria, Other: Editor of Hematology Oncology Board Review (ongoing); Bristol-Myers Squibb Co.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; Jazz Pharmaceuticals: Research Funding. Oehler: OncLive: Honoraria; Pfizer: Research Funding; Takeda: Consultancy; BMS: Consultancy. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Lu: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Fu: Ascentage Pharma Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Lower-Risk Myelodysplastic Syndromes: Erythropoiesis-Stimulating Agent Treatment Approaches and Outcomes in the United States

Introduction: Myelodysplastic syndromes (MDS) comprise a group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, dysplasia in ≥ 1 cell line, cytogenetic and molecular abnormalities, and variable risk of progression to acute myeloid leukemia. Treatment goals for MDS classified as lower-risk (LR-MDS) include transfusion independence, improvement in hemoglobin (Hb) levels, and maintenance of or improvement in quality of life. Erythropoiesis-stimulating agents (ESAs) are the first-line (1L) treatment for anemia in most patients with LR-MDS lacking del(5q), but a proportion of patients do not respond to ESA treatment, or experience progression of anemia despite ESA treatment. The objective of this real-world analysis was to describe patient characteristics, treatment patterns (including ESA use), and outcomes in patients with LR-MDS. Methods: A retrospective, observational, US multisite, cohort study was conducted among adult patients initially diagnosed with LR-MDS between January 1, 2017 and June 25, 2020. Eligible patients had ≥ 1 year of follow-up after diagnosis (unless the patient died during this time) and did not receive luspatercept or any MDS treatment as part of a randomized, controlled trial. Community oncologists abstracted data from medical records, and descriptive statistics were used to summarize patient characteristics, treatment patterns, and outcomes. Data presented are from an interim analysis of an ongoing study; the last date of data collection for this analysis was July 6, 2021. Results: Among 125 eligible patients with LR-MDS, median follow-up time was 16 months, and 83% of patients were still alive at the time of data collection. In the 8 weeks prior to diagnosis, 54% of patients did not receive any red blood cell (RBC) or platelet transfusions, while 42% and 4% had low or moderate transfusion burden, respectively. Overall, 75% of patients were negative for del(5q), and 80% of patients were negative for ring sideroblasts (RS). At diagnosis of LR-MDS, serum erythropoietin levels were < 200 U/L in 49% of patients, ≥ 200 U/L in 25%, and unknown in 26%. In terms of disease management, 35% of patients did not receive any systemic therapy or transfusions, 14% received RBC and/or platelet transfusions, but no systemic therapy for MDS, and 50% were reported to have received ≤ 2 lines of systemic therapy following LR-MDS diagnosis (Table). Of the 42% of patients who received an ESA, 70% received an ESA for MDS as a single agent (SA) only, 15% as combination therapy only, and 8% as both SA and combination therapy. A further 8% received SA ESA followed by a non-ESA-based regimen. Among 45 patients who received SA ESA as 1L treatment, 18% went on to receive a hypomethylating agent (HMA) or immunomodulatory imide drug as an SA, or ESA combined with HMA or a granulocyte or granulocyte-macrophage colony-stimulating factor (G-CSF/GM-CSF) in a subsequent line. Among patients who received an ESA, 72% were still on ESA-based therapy at the time of data collection. Abstracting physicians reported that 17% of patients who received an ESA failed ESA treatment. Among these patients, physicians' determination of ESA failure was based on the National Comprehensive Cancer Network guidelines/International Working Group 2006 response criteria for 78% of patients, and on physicians' own clinical judgement for 22%. At data collection, ESA was still being administered to 22% of patients considered to have failed ESA treatment. Finally, 34% of those who received an ESA also received RBC transfusion(s) during ESA-based treatment and therefore were not transfusion independent for the entire duration of ESA-based treatment (Table). Conclusions: Results from this real-world cohort study indicate that over a third of patients with LR-MDS have been managed using watchful waiting only, with no systemic treatment or transfusions received; among those patients who received treatment, most received an ESA. Nearly one-fifth of patients in this study treated with an ESA were considered to have failed ESA treatment by abstracting physicians, though this proportion is likely to be higher with extended follow-up; 2 of 9 patients who failed ESA treatment were still receiving an ESA. Further research including longer follow-up is warranted to understand how patients with LR-MDS respond to different treatment regimens. Figure 1 Figure 1. Disclosures Zimmerman Savill: Cardinal Health: Current Employment; Roche/Genentech: Ended employment in the past 24 months. Gajra: Cardinal Health: Current Employment, Current equity holder in publicly-traded company. Price: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kish: Cardinal Health: Current Employment, Current equity holder in publicly-traded company, Research Funding. Brown-Bickerstaff: Cardinal Health: Current Employment. Falkenstein: Cardinal Health: Current Employment. Miller: Cardinal Health: Current Employment. Laney: Cardinal Health: Current Employment. Mukherjee: Acceleron: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; McGraw Hill: Honoraria, Other: Editor of Hematology Oncology Board Review (ongoing); Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; AAMDS in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria; Eusa Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Teaching and Speaking; Jazz Pharmaceuticals: Research Funding; Bristol-Myers Squibb Co.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BioPharm: Consultancy; Partnership for Health Analytic Research: Honoraria; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees.

35. Acceptability of Proposed Stewardship Interventions to Reduce Preoperative Screening and Treatment of Asymptomatic Bacteriuria

Background In 2019, the IDSA Clinical Practice guidelines on asymptomatic bacteriuria (ASB) recommended that clinicians no longer screen or treat patients for ASB before non-urological surgeries. However, it remains to be seen whether these guideline recommendations alone will produce changes in practice. Understanding clinical decision-making about preoperative urine screening and treatment can help design effective interventions to facilitate guideline concordance and support antibiotic stewardship. Our project objective was to qualitatively assess barriers and facilitators to reducing preoperative urine testing and treatment. Methods We conducted semi-structured interviews with 24 participants (surgeons, advance practice providers, pharmacists, infectious disease physicians, epidemiologists) at 4 Veterans Administration hospitals. We solicited feedback on 4 proposed interventions (substitution, lab restrictions, audit and feedback, interactive workshop), and invited suggestions on other interventions. Three researchers separately coded 20% of interview notes to sort responses to each intervention into acceptable, possibly acceptable, and not acceptable. The team then compared coding, resolved differences by consensus, and refined the code dictionary to ensure intercoder agreement; then each member coded one third of remaining notes. Results Participants expressed concerns about de-implementing routine urine testing and treatment for specific procedures and specialties (e.g., cardiothoracic). Some actively sought to identify and treat ASB. Participants found audit and feedback and substitution of different infection-control practices most acceptable. Participants suggested changes to make interventions more acceptable or feasible (e.g., tailoring to procedure, educational tailoring). Participants also identified new potential interventions (e.g. order set changes, collaborative decision making, education on potential harms, identification of testing costs). Table 1. Acceptability of Proposed Interventions by Percentage of Participants. Percentages Do Not Add up to 100% Because Some Interviewees Did Not Answer Every Question. Conclusion Interventions to optimize urine screening and treatment for patients undergoing surgeries may require tailoring for surgical specialties, and should address clinical concerns about intervention feasibility. Disclosures Kalpana Gupta, MD, MPH, Abbott (Shareholder)DBC Pri-Med (Consultant)Glaxo Smith Kline (Consultant)Moderna (Shareholder)Nabriva Therapeutics (Consultant)Pfizer (Other Financial or Material Support, Grant to the institution)Qiagen (Consultant)Rebiotix (Consultant)Spero Therapeutics (Consultant)Utility Therapeutics (Consultant) Daniel Suh, MS MPH, General Electric (Shareholder)Merck (Shareholder)Moderna (Shareholder)Smile Direct Club (Shareholder) Bruce Alexander, PharmD, Bruce Alexander Consulting (Independent Contractor) Marin Schweizer, PhD, 3M (Grant/Research Support)PDI (Grant/Research Support)

1253. Antimicrobial Activity of Cefepime in Combination with Taniborbactam Against Clinical Isolates of Enterobacterales from 2018-2020 Global Surveillance

Background Taniborbactam (formerly VNRX-5133) is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with potent and selective direct inhibitory activity against both serine- and metallo-β-lactamases (Ambler Classes A, B, C and D). Taniborbactam restores the activity of cefepime against many difficult to treat organisms, including cephalosporin- and carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa. The activity of the investigational combination cefepime-taniborbactam (FTB) and comparator agents was evaluated against clinical isolates of Enterobacterales from a 2018-2020 global surveillance study. Methods MICs of cefepime with taniborbactam fixed at 4 µg/mL and comparators were determined following CLSI M07-A11 guidelines against 10,543 Enterobacterales. Isolates were from community and hospital infections collected from 259 sites in 56 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints. A set of 827 isolates with meropenem MIC ≥4 µg/mL (n=421) or with cefepime and/or ceftazidime MIC ≥2 µg/mL (n=406) was evaluated for the presence of MBLs, KPC, ESBLs, and OXA-48 group genes via PCR and sequencing. Forty-eight isolates with FTB MIC values of 16 µg/mL or greater were interrogated by WGS. Results Overall, 23.0% and 15.9% of isolates were nonsusceptible (NS) to cefepime and piperacillin-tazobactam (TZP), respectively (Table). FTB had potent activity against all Enterobacterales, with MIC50/90 values of 0.06/0.25 µg/mL and 99.5% inhibited at ≤8 µg/mL. FTB maintained activity against MBL-, KPC-, OXA-48 group, and ESBL-positive isolates (MIC90 range, 1 to >16 µg/mL; 80.5% to 100% inhibited at ≤8 µg/mL). Isolates with elevated FTB MICs had IMP-type enzymes, variation in the cefepime target (penicillin binding protein 3), permeability defects in combination with acquired β-lactamases, and/or possible up-regulated efflux. Results Table Conclusion Taniborbactam significantly restored the in vitro activity of cefepime against Enterobacterales, including isolates nonsusceptible to recently-approved BL/BLI combinations and expressing serine and metallo-β-lactamases. This support the continued development of FTB as a potential new treatment option for challenging infections due to resistant Gram-negative pathogens. Disclosures Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Mark G G. Wise, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

872. Number of Sexual Partners and Patient-Reported Outcomes among Older Adults Living With HIV

Background Many older (age 50+) adults living with HIV (OALWH) are sexually active. However, little is known about the relationship between number of sexual partners and mental health outcomes among OALWH. Methods Data were utilized from the Aging with Dignity, Health, Optimism and Community (ADHOC) cohort, an observational study of OALWH from ten US clinics. To measure sexual activity, participants were asked “How many sexual partners have you had in the last year?” with response options ranging from zero to “greater than five.” Loneliness was measured using the Three-item Loneliness Scale, and depression was measured using the Patient Health Questionnaire-2. Significance was determined by Kruskal-Wallis tests followed by unadjusted pairwise comparisons. Results Of 1,027 participants, the mean (SD) age was 58.9 (6.1) and 876 (85%) were male. 312 (30%) had zero sexual partners in the past year, 308 (30%) had one partner, 197 (19%) had 2-5 partners, and 210 (20%) had >5 partners. Of the participants with one partner, 230 (75%) were married, coupled or partnered, and 78 (25%) were single, widowed, separated, or divorced (Single). Figure 1 shows that people with one partner were significantly less lonely than any other group (p< 0.01 for pairwise comparisons), and all other groups were statistically similar to each other. This pattern was also seen with depression (p< 0.01 for pairwise comparisons, Figure 2). Among subgroup of people with one sexual partner, those who were married, coupled or partnered were less lonely (4.41 vs. 5.67, p< 0.01) and less depressed (0.95 vs 1.38, p=0.02) than those who were single, widowed, separated, or divorced. Conclusion Among OALWH, people with one sexual partner were less lonely and depressed than people with zero or with ≥2 partners. Furthermore, people with one sexual partner who were married or in a committed relationship were less lonely and depressed than people with one sexual partner who were not. Disclosures Peter Mazonson, MD, MBA, ViiV Healthcare (Grant/Research Support) Jeff Berko, MPH, BS, ViiV Healthcare (Scientific Research Study Investigator) Theoren Loo, MPH, ViiV Healthcare (Grant/Research Support) Giselle D. Coelho, MD. MPHTM, Lilly (Research Grant or Support)Medscape, Clinical Care Options (Independent Contractor)Viiv, Gilead, Janssen (Advisor or Review Panel member, Research Grant or Support) Erik Lowman, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)ViiV (Grant/Research Support) Peter Shalit, MD, PhD, Abbvie (Grant/Research Support)Gilead Sciences (Consultant, Grant/Research Support, Speaker’s Bureau)Glaxo Smithkline (Consultant, Grant/Research Support)Janssen (Consultant, Grant/Research Support, Speaker’s Bureau)Merck (Grant/Research Support, Speaker’s Bureau)Thera (Speaker’s Bureau)ViiV Healthcare (Speaker’s Bureau) Frank Spinelli, MD, ViiV Healthcare (Employee)

1066. In Vitro and in Vivo Antimicrobial Activity of Cefiderocol and Comparators against Achromobacter spp

Background Achromobacter spp. is intrinsically resistant to multiple antibiotics, and the treatment options are limited. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active against a wide variety of aerobic Gram-negative bacteria, including carbapenem-resistant strains. In this study, in vitro and in vivo antibacterial activity of CFDC against Achromobacter spp. was evaluated. Methods A total of 334 global isolates collected by IHMA from 39 countries in 2015-2019 were used. Minimum inhibitory concentrations (MICs) of CFDC and comparators were determined by broth microdilution method using iron-depleted CAMHB or CAMHB, respectively, as recommended by CLSI guidelines. In vivo efficacy of CFDC was compared with meropenem (MEM), piperacillin-tazobactam (PIP/TAZ), ceftazidime (CAZ), and ciprofloxacin (CIP) in a neutropenic murine lung infection model (n=5), and compared with MEM in a immunocompetent rat lung infection model (n=3-7) caused by 2 A. xylosoxydans. In the murine model, treatment was given 2, 5, and 8 hours post-infection, and the numbers of viable cfu in lungs were determined 24 hours post-infection. In the rat model, the humanized PK in plasma resulting from CFDC 2 g every 8 h (3-h infusion) or meropenem 1 g every 8 h (0.5-h infusion) were recreated via continuous intravenous infusion for 4 days, following which cfu in lungs were determined. Results CFDC showed in vitro activity with MIC50/90 of 0.06/0.5 µg/mL against 334 Achromobacter spp. Only 7 isolates (2.1%) had MICs > 4 µg/mL. These were the lowest values among all compound tested (Table). In the murine model, CFDC caused > 1.5 log10 decrease of viable cfu in lungs at 100 mg/kg dose (%fT >MIC: < 50%) from baseline control against both of strains (CFDC MIC: 0.5 and 2 µg/mL) (P< 0.05). No decrease of cfu in lungs was observed for the comparators at 100 mg/kg (MEM, PIP/TAZ, CAZ, and CIP MICs were >16, >64, >32, and >8 µg/mL, respectively). In the rat model, humanized CFDC dosing reduced the viable cfu by >1 log10 CFU/lung compared with baseline controls (P< 0.05). MEM showed no significant activity. In vitro activity of CFDC and comparator agents against Achromobacter spp. 334 Achromobacter spp. isolates collected from 2015 and 2019. The majority of isolates tested were A. xylosoxidans (312/334; 93.4%), followed by A. insolitus (11/334; 3.3%), Achromobacter sp. (8/334; 2.4%), A. denitrificans (2/334; 0.6%), and A. piechaudii (1/334; 0.3%). Conclusion CFDC showed potent in vivo efficacy reflecting in vitro activity against A. xylosoxidans. The results suggested that CFDC has the potential to be an effective therapeutic option for Achromobacter spp. infections. Disclosures Ryuichiro Nakai, MSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Ayaka makino, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Yoshinori Yamano, PhD, Shionogi (Employee)

1058. In Vitro and In Vivo Antibacterial Activity of Cefiderocol against Burkholderia spp

Background Burkholderia spp. is an opportunistic pathogen associated with respiratory infections. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active in vitro against carbapenem-resistant Gram-negative bacteria including Burkholderia spp. This study examined in vitro and in vivo activity of CFDC against Burkholderia spp. Methods MICs of CFDC and 13 marketed antibacterial drugs against 462 clinical isolates of Burkholderia spp. collected in 2014 - 2019 in 13 countries were determined by broth microdilution method according to CLSI guidelines. Only for CFDC, iron-depleted CAMHB was used. In a rat lung infection model, B. cepacia ATCC 25416 (CFDC MIC: ≤ 0.031 μg/mL, MEM MIC: 4 μg/mL) was used. Male CD (SD, immunocompetent, n=4-5) rats were infected by intrabronchial inoculation of the bacterial suspension including 1% nutrient agar. The humanized PK in plasma by administration of CFDC 2 g every 8 h (3-h infusion) and MEM 1 g every 8 h (0.5-h infusion) were recreated via the continuous intravenous infusion for 4 days, and the viable cfu in lungs were counted. Results Against 462 strains, including 185 MEM non-susceptible isolates, CFDC showed MIC50/MIC90 of ≤ 0.031/1 µg/mL, which was the lowest among the tested antibiotics. Among 185 MEM non-susceptible isolates, 94% of the isolates exhibited ≤ 4 µg/mL of CFDC MIC. In a rat lung infection model, CFDC and MEM showed bactericidal activity with 2.8 and 2.4 log10 CFU/lung decrease compared with non-treated control, respectively. By recreating the humanized PK exposure in this model, 100% and ca.35% of fT >MIC of CFDC and MEM in plasma has been achieved, respectively. The bactericidal activities of both compounds vs B. cepacia ATCC 25416 would be reasonable because the fT >MIC achieved in this model exceeds the target fT >MIC (75% for CFDC and 26% for MEM against Acinetobacter baumannii, respectively) required to cause 1 log10 reduction in murine thigh infection models1,2). 1) M. Sabet. 2019. AAC 2) R. Nakamura. 2019. AAC In vitro activity of CFDC and comparator agents against Burkholderia spp. Conclusion CFDC has potential for treating respiratory tract infections caused by Burkholderia spp. In critically ill patients, the recommended dosing regimen achieves 100% of fT >MIC of ≤ 4 ug/mL3).3) N. Kawaguchi. 2021. AAC Disclosures Merime Oota, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

1225. In Vitro Activity of Aztreonam-Avibactam and Comparator Agents Against Enterobacterales Collected from Geriatric Patients in ICU and non-ICU wards, ATLAS Surveillance Program 2016-2019

Background Elevated resistance rates have been reported in ICUs. Aztreonam (ATM) combined with avibactam (AVI) is being developed for use against drug-resistant Enterobacterales (Ebact), including metallo-β-lactamase (MBL)-positive isolates. We examined the activity of ATM-AVI and comparators against Ebact isolates collected from geriatric patients in ICU and non-ICU wards as part of the ATLAS surveillance program. Methods 23754 non-duplicate Ebact isolates were collected in 53 countries in Asia/Pacific (excluding mainland China and India), Europe, Latin America, and Middle East/Africa from patients ≥65 years with lower respiratory tract (LRTI), urinary tract (UTI), skin and soft tissue (SSTI), intra-abdominal (IAI), and bloodstream (BSI) infections. Susceptibility testing was performed by CLSI broth microdilution and values interpreted using CLSI 2021 breakpoints. PCR and sequencing were used to determine the β-lactamase genes present in isolates with meropenem MIC >1 µg/mL, and Escherichia coli, Klebsiella spp. and Proteus mirabilis with ATM or ceftazidime MIC >1 µg/mL. Results Susceptibility of the studied comparator agents was generally slightly lower among Ebact from BSI than other infection types (Table). Susceptibility was also generally lower among Ebact from ICU than non-ICU wards by up to 10 percentage points, and MIC90 values were up to 32-fold higher. ATM-AVI MIC90 values were within one doubling-dilution across all studied strata (0.12-0.25 µg/mL), were comparable to or lower than for meropenem in all strata, and were 2 to ≥9 dilutions lower than all other tested comparators. MBL-positive Ebact were found in 1.5% of LRTI (n=91), 1.2% of UTI (n=70), 1.1% of SSTI (n=52), 1.3% of BSI (n=49), and 0.7% of IAI isolates (n=22). MBL-positive rates were higher among ICU (1.7%, n=101) than non-ICU isolates (1.0%, n=183). ATM-AVI MIC90 values were 0.5 µg/mL against MBL-positive isolates from all ward and infection types except SSTI (MIC90 0.25 µg/mL) and BSI (MIC90 1 µg/mL), 2-4 dilutions lower than tigecycline and at least 5-10 dilutions lower than the other comparators. Results Table Conclusion ATM-AVI could provide a valuable therapeutic option for treatment of infections caused by Ebact in patients ≥65 years old in both ICU and non-ICU wards. Disclosures Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Francis Arhin, PhD, Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

998. Forward and Reverse Translational Approaches to Predict Efficacy of the Neutralizing Respiratory Syncytial Virus (RSV) Antibody MK-1654

Background MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) with an extended half-life in late development to prevent RSV infection in infants. Neutralizing mAbs, like MK-1654, have great potential for prophylaxis against viral infection. However, well-validated approaches for clinical dose and efficacy predictions are lacking. Methods Summary-level literature data from RSV prevention studies were used in a model-based meta-analysis (MBMA) to describe the relationship between RSV incidence rates and serum neutralizing antibody (SNA) titer. The model was validated using viral challenge experiments in cotton rats and phase 3 RSV-A efficacy results in infants for an anti-RSV F mAb, REGN-2222. A phase 2b human RSV challenge study (HCS) in adults was also conducted with MK-1654. Participants (N=70) received 100, 200, 300, or 900 mg of MK-1564 or placebo and were challenged intranasally with RSV 29 days later. RSV viral load and symptomatic infection were monitored. Data from the HCS were compared to model predictions. The MBMA was used to predict efficacy of MK-1654 in a virtual population of pre- and full- term infants. Results The relationship between SNA titer and RSV incidence rate defined using the viral load data from the cotton rat approximated the relationship identified for infants from the clinical MBMA. The MBMA was quantitatively consistent with the phase 3 efficacy results against RSV A for REGN-2222. In the HCS, RSV nasal viral load measured by RT-qPCR and quantitative culture as well as symptomatic infections were decreased in MK-1654 recipients compared to placebo. Incidence rates of RSV infection in the HCS were also consistent with MBMA predictions. The model-based clinical trial simulations for MK-1654 indicated a high probability of substantial efficacy against RSV-associated medically attended lower respiratory tract infection ( >75% for 5 months) for doses ≥75 mg. Conclusion Our MBMA successfully quantified the relationship between RSV SNA and clinically relevant endpoints, including lower respiratory tract infection in infants. MBMA-based efficacy predictions support continued development of the MK-1654 antibody for the prevention of RSV in infants. Disclosures Brian M. Maas, PharmD, Merck & Co., Inc. (Employee, Shareholder) Jos Lommerse, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Radha Railkar, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Luzelena Caro, PhD, Merck & Co., Inc. (Employee, Shareholder) Jingxian Chen, PhD, Merck & Co., Inc. (Employee, Shareholder) Wen Liu, MPH, Merck & Co., Inc. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Qinlei Huang, MS, Merck & Co., Inc. (Employee, Shareholder) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Li Qin, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Jie Meng, MSc, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Han Witjes, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Emilie Schindler, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Benjamin Guiastrennec, PharmD, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Francesco Bellanti, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Daniel Spellman, PhD, Merck & Co., Inc. (Employee, Shareholder) Brad Roadcap, MS, Merck & Co., Inc. (Employee, Shareholder) Amy Espeseth, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Aubrey Stoch, MD, Merck & Co., Inc. (Employee, Shareholder) Eseng Lai, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Kalpit A. Vora, PhD, Merck & Co., Inc. (Employee, Shareholder) Antonios O. Aliprantis, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)

639. Time to Recurrence of Clostridioides difficile Infection (rCDI) is Rapid Following Completion of Standard of Care Antibiotics: Results from ECOSPOR-III, a Phase 3 Double-Blind, Placebo-Controlled Randomized Trial of SER-109, an Investigational Microbiome Therapeutic

Background The natural history of CDI recurrence after antibiotics may be helpful to understand the window of opportunity for microbiome repair. ECOSPOR III evaluated the efficacy of SER-109, an investigational microbiome therapeutic, compared to placebo with rates of rCDI as the primary endpoint. SER-109 was superior to placebo in reducing the rate of rCDI following standard-of-care antibiotics at 8 weeks (12.4% vs 39.8%, respectively; P < 0.001). Herein, we describe results from the secondary endpoint, time to recurrence, in this well-characterized study population. Methods A total of 182 C. difficile toxin+ adults with ≥ 3 CDI episodes and symptom resolution on CDI antibiotics were randomly assigned to SER-109 (4 capsules orally x 3 days) or placebo. Recurrence for this analysis was defined as ≥ 3 unformed stools/day for ≥ 48 hours, ± C. difficile stool toxin test, and an investigator decision to treat. Time to CDI recurrence was analyzed using observed data and Kaplan-Meier methods. Data were not imputed for subjects lost to follow-up or discontinued from study. Subjects who did not have a CDI recurrence were censored on the date of study completion, study discontinuation or death. Results Through 24 weeks, 11/89 (12.4%) SER-109 and 36/93 (38.7%) placebo subjects had rCDI (P < 0.001). Of all recurrence events in the study population, 16/47 (34.0%) were observed within 1 week; 30/47 (63.8%) within 2 weeks; and 34/47 (72.3%) within 4 weeks after randomization, highlighting the rapid onset of recurrence. On the other hand, 12/47 (25.5%) recurrences occurred between 4 and 12 weeks, highlighting late onset of recurrence in a subset of patients (Table). Significantly lower rates of recurrence in patients on SER-109 compared to placebo was maintained throughout the 24-week follow-up (Figure). Time of rCDI K-M Plot Conclusion SER-109, an investigational oral microbiome therapeutic, maintained significant efficacy in reducing rCDI vs placebo through 24 weeks. About two-thirds of all recurrences occurred within 14 days of antibiotic completion highlighting the need for rapid repair of the disrupted microbiome. However, the significant number of late recurrences in the placebo arm also highlights that rCDI trials limited to 4 weeks of follow-up after treatment completion may underestimate recurrences. Disclosures Thomas J. Louie, MD, Artugen (Advisor or Review Panel member)Crestone (Consultant, Grant/Research Support)Da Volterra (Advisor or Review Panel member)Finch Therapeutics (Grant/Research Support, Advisor or Review Panel member)MGB Biopharma (Grant/Research Support, Advisor or Review Panel member)Rebiotix (Consultant, Grant/Research Support)Seres Therapeutics (Consultant, Grant/Research Support)Summit PLC (Grant/Research Support)Vedanta (Grant/Research Support, Advisor or Review Panel member) Matthew Sims, MD, PhD, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor) Richard Nathan, DO, none (Other Financial or Material Support, I am PI on several clinical trials. If you need that information, I would be happy to supply it.) Princy N. Kumar, MD, AMGEN (Other Financial or Material Support, Honoraria)Eli Lilly (Grant/Research Support)Gilead (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)GSK (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)Merck & Co., Inc. (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria) Elaine E. Wang, MD, Seres Therapeutics (Employee) Elaine E. Wang, MD, Seres Therapeutics (Employee, Shareholder) Robert Stevens, PharmD, Seres Therapeutics (Employee, Shareholder) Kelly Brady, MS, Seres Therapeutics (Employee, Shareholder) Barbara McGovern, MD, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder)