Non Susceptibility Research Articles

Molecular characterization of clinically isolated Pseudomonas aeruginosa with varying resistance to ceftazidime-avibactam and ceftolozane-tazobactam collected as a part of the ATLAS global surveillance program from 2020 to 2021.

Ceftazidime-avibactam (CZA) and ceftolozane-tazobactam (C/T) are important agents for treating multidrug-resistant P. aeruginosa infections. In this study, we evaluated the molecular characteristics of 300 globally collected clinical P. aeruginosa isolates non-susceptible (NS) to CZA, C/T, or both agents. Isolates were CZA-NS and C/T-NS (n = 57), CZA-susceptible (S) and C/T-NS (n = 145), or CZA-NS and C/T-S (n = 98) selected from the Antimicrobial Testing Leadership and Surveillance (ATLAS) surveillance program from 2020 to 2021. Characterization was by whole-genome sequencing. Analysis was performed to identify β-lactamase genes and mutations that impact efflux regulation, AmpC regulation, and target binding (PBP3). Of the 57 CZA-NS+C/T-NS isolates, 64.9% carried a metallo-β-lactamase (MBL), and a cumulative 84.2% carried any non-intrinsic β-lactamase [i.e., not Pseudomonas-derived cephalosporinase (PDC) or OXA-50-like]. Of the 145 CZA-S+C/T-NS isolates, 26.2% carried an extended-spectrum β-lactamase (ESBL) and no carbapenemase, 17.9% carried a serine-carbapenemase, and 42.1% were negative for non-intrinsic β-lactamases. Of 98 CZA-NS+C/T-S isolates, 34.7% carried mutations previously described as causing an upregulation of the MexAB-OprM efflux pump, while only 9.2% carried a non-intrinsic β-lactamase, and no resistance mechanism was identified in 29.6% of these isolates. MBLs were present in most isolates NS to both agents. More than half of the CZA-S+C/T-NS isolates carried serine β-lactamases. The most frequently identified resistance mechanism identified in CZA-NS+C/T-S isolates was a marker indicating the upregulation of MexAB-OprM. No mechanism was identified that is thought to support resistance to these agents in numerous isolates. This may be due in part to the fact that whole genome sequencing (WGS) cannot directly measure gene expression of chromosomal resistance mechanisms.

Population Analysis of Daptomycin-non-Susceptible Methicillin-Resistant Staphylococcus aureus Reveals the Presence of Variants That Contribute to Daptomycin Resistance.

In this study, population analysis (PA) of methicillin-resistant Staphylococcus aureus (MRSA), before and after long-duration daptomycin (DAP) treatment, was used to detect subpopulations with different susceptibilities to DAP and to verify the changes in the number of resistant cells. Furthermore, we aimed to characterize the bacteriology of the variants present in the non-susceptible cell subpopulation. A DAP non-susceptible (NS) MRSA phenotype (D2) that emerged from a DAP- susceptible MRSA phenotype (D1) during treatment of an open wound, was used for testing. We performed bacteriological and genetic analyses of cryptic DAP-NS MRSA variants detected by PA to study the variants present in the resistant cell subpopulation. PA results suggest that MRSA adapted to survival in the presence of DAP are selected leading to reduced susceptibility. Within the cell population growing in media containing 2.0mg/L of DAP, three variants with different pigment production and colony size were detected. Variant 3 was an orange colony due to enhanced production of staphyloxanthin. Our results revealed that the DAP minimum inhibitory concentration (MIC) value increased two-fold (4mg/L) in variant 3, in which pigment production was most enhanced, compared to the parental strain D2. In conclusion, our results indicate that long-duration DAP treatment can lead to the emergence and increased proportion of DAP-NS subpopulations. Furthermore, slow-growing variants that can be detected only under antimicrobial selective pressure are present among DAP-NS cells, suggesting that these variants may also contribute to the development of DAP resistance.

Seasickness susceptibility and the vestibular time constant: a prospective study.

Human passive motion during boat, car or airplane travel may trigger motion sickness. Seasickness is the most provoking manifestation of motion sickness. It imposes major constraints on quality of life and human performance. Based on seasickness susceptibility the population is usually categorized into susceptible (S) and non-susceptible (NS). During repeated exposure some susceptible individuals undergo habituation and obtain symptoms relief, reflecting a third group of habituating (H) individuals. Recently, accumulative evidence suggests that the vestibular time constant (Tc) is associated with motion sickness susceptibility and attenuation of symptoms. These studies demonstrated that repeated passive motion stimuli lead to temporary short-term (days) changes in Tc, whereas sea sickness habituation process lasts 3 to 6months. Therefore, the goal of the present study was to examine the behavior of Tc during the entire span of the seasickness habituation process between the H, S and NS groups to find an objective test for seasickness severity prediction. Tc of 30 subjects was prospectively evaluated pre, 3 and 6months post exposure to sea environment using a computerized rotatory chair system protocol. Seasickness severity was evaluated by Wiker questionnaire. Significantly shorter Tc was found in the S group compared with the NS and H groups. Further analysis revealed lower maximal Slow Phase Velocity (mSPV) and nystagmus frequency (total number of beats/second) in the S group. Our results suggest that Tc, mSPV and nystagmus frequency might serve as a prediction for seasickness severity. This study was retrospectively registered on December 7th 2022 and assigned the identifier number NCT05640258.

722. Risk Factors for Infection or Colonization with Ceftolozane/Tazobactam Non-Susceptible Extensively β-Lactam Resistant Pseudomonas aeruginosa

Abstract Background Treatment of infections due to multidrug resistant (MDR) Pseudomonas aeruginosa is complicated by co-resistance amongst traditional anti-pseudomonal β-lactams, as 50% of MDR isolates exhibit extensive β-lactam resistance (EBR, non-susceptible to cefepime, ceftazidime, piperacillin/tazobactam, and meropenem). Ceftolozane/tazobactam (C/T) was developed to combat MDR and EBR P. aeruginosa. Unfortunately, C/T resistance has proliferated. We designed this retrospective case-control study to identify risk factors for C/T non-susceptibility (NS) amongst EBR P. aeruginosa. Methods Between 2015 to 2020, hospitalized adult patients infected or colonized with EBR P. aeruginosa were identified. C/T susceptibility was defined per the 2023 Clinical and Laboratory Standards Institute (CLSI) guidelines (susceptible (S) if minimum inhibitory concentration (MIC) ≤ 4 mg/L, NS if MIC ≥ 8 mg/L). Patients with an EBR P. aeruginosa NS to C/T were classified as cases, whereas those with S isolates were controls. Patients with multiple EBR P. aeruginosa isolates over the study period were only included once. If a patient had a C/T NS isolate, they were classified as cases and the first C/T NS isolate was included as the index culture. If the patient did not have a C/T NS isolate over the study period, they were considered a control and the first C/T S isolate was the index culture. Bivariate and multivariate modeling was performed to identify independent predictors for C/T NS. Results 188 unique patients with C/T susceptibility performed were included in the study; 96 (51%) were C/T NS and 92 (49%) were C/T S. Table 1 shows the bivariate comparisons of key baseline characteristics between groups. Independent predictors of C/T NS are displayed in table 2. Conclusion Independent predictors for C/T NS amongst EBR P. aeruginosa isolates were a history of cancer, cystic fibrosis, and isolation of EBR P. aeruginosa in the past 90 days. While receipt of cefepime or ceftazidime in the past 90 days was associated with C/T NS in bivariate comparisons, the association did not remain in multivariate modeling. C/T exposure was not a statistically significant risk factor, but it was numerically associated with NS and the lack of significance was likely due to the small number of patients (n = 15) who received it. Disclosures Virginia M. Pierce, MD, FIDSA, UpToDate, Inc.: Authorship royalties jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant

2838. Clinical Application and Validation of a Predictive Antimicrobial Resistance Risk Categorization Framework for Patients with Uncomplicated Urinary Tract Infection

Abstract Background Empiric antibiotic (ABX) treatment for uncomplicated urinary tract infections (uUTIs) can be ineffective due to antimicrobial resistance (AMR). Understanding the risk of AMR using data-driven approaches can inform appropriate ABX selection. We developed an AMR pathogen risk categorization framework in E. coli caused uUTI using predictive modeling and evaluated its clinical validity. Methods Eligible females with uUTI confirmed by positive E. coli urine culture treated with nitrofurantoin (NTF), trimethoprim/sulfamethoxazole (SXT), fluoroquinolones (FQs), or beta-lactams (BLs) were identified from the Optum de-identified electronic health record data set (Oct 2015–Feb 2020). We developed predictive models using machine learning to quantify AMR probability for each ABX class. A framework with 3 risk categories (low, moderate, high) was constructed using the predicted probability (PP) of non-susceptibility (NS) (Table 1). Six patient profiles from differing risk categorizations were reviewed for clinical validity by 5 clinicians (4 medical doctors, 1 pharmacist). Results Of 87,487 eligible patients, approximately half were classified as low or high risk (44.0–49.1% across ABX classes). The proportion of patients with infections due to NS organisms was 5–12-fold higher among patients classified as high or moderate vs low risk (Figure 1). After review of the patient profiles (Table 2), clinical experts confirmed the consistency of modeled risk classification for all 6 patients with their own assessment of AMR risk across all drug classes. Patient 1 was aged 20 yrs, White, West residence, no UTI or ABX history 1 year prior to her uUTI; PP of NS was low (NTF 1.5%, SXT 16.6%, FQs 4.8%, BLs 8.4%) and was classified as low risk for all ABX classes. In contrast, patient 6 was post-menopausal, Black, Midwest residence, and had UTI episodes, prior AMR, and multiple healthcare visits 1 year prior to uUTI. She had high PP of NS (NTF 10.3%, SXT 97.2%, FQs 96.4%, BLs 48.0%) and was categorized as high risk for all ABX classes. Conclusion AMR risk varied greatly between patients. Our prediction model contextualizes patients’ AMR PP to 4 commonly prescribed ABX classes in the setting of uUTIs. Clinical application of this framework could inform appropriate empiric ABX selection for patients with uUTI. Disclosures Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support Wendy Y. Cheng, MPH, PhD, ORCID: 0000-0002-8281-2496, Analysis Group, Inc.: Wendy Y. Cheng is an employee of Analysis Group, Inc., a consulting company that received funding from GSK to conduct this study Kalé Kponee-Shovein, ScD, Analysis Group, Inc: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Fernando Kuwer, MSc, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Chi Gao, ScD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Ashish V. Joshi, PhD, GSK: Employee|GSK: Stocks/Bonds Fanny S. Mitrani-Gold, MPH, GSK: Employee|GSK: Stocks/Bonds Patrick Schwab, PhD, GSK: Employment|GSK: Stocks/Bonds Diogo Ferrinho, PharmD, GSK: Employee|GSK: Stocks/Bonds Malena Mahendran, MS, Analysis Group, Inc.: Malena Mahendran is an employee of Analysis Group, Inc., a consulting company that received funding from GSK to conduct this study Daniel Indacochea, PhD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Lisa Pinheiro, MFin, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Jimmy Royer, PhD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received funding from GSK to conduct the study Madison T. Preib, MPH, GSK: Employee|GSK: Stocks/Bonds Jennifer Han, MD, GSK: Employment|GSK: Stocks/Bonds Richard Colgan, MD, GSK: Advisor/Consultant

2154. Cross-resistance of Ceftolozane-Tazobactam and Imipenem-Relebactam Against Clinical P. aeruginosa Isolates from Bloodstream and Respiratory Tract Infections– SMART United States 2019-2021

Abstract Background Antimicrobial resistance among Pseudomonas aeruginosa is challenging with limited treatment options. Ceftolozane/tazobactam (C/T) maintains activity against P. aeruginosa resistant to commonly used β-lactams. Imipenem/relebactam (IMI/REL) can restore the activity of IMI against P. aeruginosa. C/T and IMI/REL can be affected by different mechanisms of resistance, and pathogens can be nonsusceptible to one agent but susceptible to the other. We evaluated the activity of C/T and IMI/REL against P. aeruginosa isolates collected from patients with lower respiratory tract (LRTI) and bloodstream (BSI) infections in the United States as part of the global SMART surveillance program. Methods In 2019-2021, 24 US clinical labs collected up to 100 consecutive, aerobic or facultative, gram-negative pathogens from LRTI and up to 50 from BSI. Of 8643 collected isolates, 1986 (23%) were P. aeruginosa. Susceptibility was determined with CLSI broth microdilution and 2023 CLSI breakpoints. Results Among P. aeruginosa BSI and LRTI isolates, 88% were susceptible (S) to both C/T and IMI/REL, 2% were nonsusceptible (NS) to both agents; 8% were S to C/T but not to IMI/REL, and 2% were S to IMI/REL but not to C/T (Table 1). Among MDR and DTR isolates, 45% and 29%, respectively, were S to both C/T and IMI/REL and 11% and 20%, respectively, were NS to both. Among C/T-NS isolates, 57.3% and 44.0% were S to IMI/REL and ceftazidime/avibactam (CZA), respectively (Table 2). Among IMI/REL-NS isolates, 83% were C/T-S, 69% CZA-S, and < 43% were S to all other studied β-lactams and LVX. Among CZA-R isolates, 61% and 47% remained S to C/T and IMI/REL, respectively. Conclusion Resistance to both C/T and IMI/REL was not common among recent clinical isolates of P. aeruginosa from the US, and both agents represent important treatment options. A significant proportion of isolates NS to one agent were S to the other, especially among MDR and DTR isolates. The data suggest that susceptibility to both agents should be tested. Disclosures Sibylle Lob, MD, Merck & Co., Inc.: Honoraria Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Fakhar Siddiqui, MD, MBA, Merck & Co Inc.: Employee Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation

1949. Activity of Aztreonam-Avibactam against Enterobacterales Resistant to Recently Approved Beta-Lactamase Inhibitor Combinations Collected Worldwide (ex-US; 2020–2022)

Abstract Background Aztreonam-avibactam (ATM-AVI) is under clinical development. Aztreonam is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs). ATM-AVI has shown activity against MBL-producing, carbapenem-resistant Enterobacterales (CRE) that are resistant to recently approved β-lactamase inhibitor combinations (BLIs) such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MEM-VAB), and imipenem-relebactam (IMI-REL). We evaluated a large collection of CRE isolates nonsusceptible (NS) to these BLIs. Methods 24,580 Enterobacterales isolates were consecutively collected (1/patient) in 2020–2022 from 64 medical centers located in Western Europe (W-EU; 27 centers in 10 countries), Eastern Europe (E-EU; 13 centers in 9 countries), Latin America (LATMA; 8 centers in 6 countries), and the Asia-Pacific region (APAC; 16 centers in 8 countries). Among these isolates, 1,016 (4.1%) were CRE. Isolates were susceptibility tested by CLSI broth microdilution. CRE isolates were screened for carbapenemase (CPE) genes by whole genome sequencing. Results ATM-AVI inhibited 99.6% of CREs (MIC50/90, 0.25/0.5 mg/L) and ≥ 98.9% of CRE isolates NS to CAZ-AVI, MEM-VAB, and/or IMI-REL at ≤8 mg/L (Table). The most active comparators against CREs were CAZ-AVI (64.6%S), MEM-VAB (57.4%S), and IMI-REL (50.7%S). The activity of these BLIs varied widely among region, with highest susceptibility rates observed in W-EU (76.9% for CAZ-AVI, 72.5% for MEM-VAB, 63.8% for IMI-REL), followed by LATAM (65.1% for CAZ-AVI, 70.6% for MEM-VAB, 62.8% for IMI-REL), E-EU (66.6% for CAZ-AVI, 46.7% for MEM-VAB, 43.5% for IMI-REL), and APAC (39.9% for CAZ-AVI, 37.8% for MEM-VAB, 27.7% for IMI-REL). The most common CPE types overall were KPC (44.5% of CREs), NDM (29.8%), and OXA-48-like (16.0%). KPC predominated in LATAM (64.1%) and W-EU (61.1% of CREs). MBL occurrence was highest in APAC (59.5% of CREs), followed by LATAM (34.0%), E-EU (28.9%), and W-EU (23.6%). NDM represented 85.4% of MBLs. Conclusion ATM-AVI demonstrated potent activity against CRE isolates resistant to CAZ-AVI, MEM-VAB, and/or IMI-REL independent of the CPE produced. The activity of recently approved BLIs varied broadly among regions and were very limited in E-EU and APAC. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

2146. Antimicrobial Activity of Aztreonam-avibactam, Ceftazidime-avibactam, and Meropenem-vaborbactam against Enterobacterales causing Bloodstream Infection in US Medical Centers (2020–2022)

Abstract Background As the frequency of Enterobacterales (ENT) producing metallo-β-lactamase (MBL) and/or OXA-48 is increasing in some US medical centers, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Aztreonam-avibactam (ATM-AVI) is under clinical development for treatment of infections caused by Gram-negative bacteria, including MBL producers. We evaluated the activities of ATM-AVI, ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MEM-VAB), and comparators against ENT isolated from patients with bloodstream infections (BSIs). Methods 4,802 ENT were consecutively collected (1/patient) from 72 US medical centers in 2020–2022 and susceptibility tested by CLSI broth microdilution method. ATM-AVI was tested with AVI at a fixed 4 mg/L. A pharmacokinetic/pharmacodynamic susceptible (S) breakpoint of ≤ 8 mg/L was applied for comparison. Carbapenem-resistant ENT (CRE) isolates were screened for carbapenemase (CPE) by whole genome sequencing. Results ATM-AVI was highly active against ENT (Table); only 2 isolates showed ATM-AVI MICs > 8 mg/L: 1 MEM-S E. coli and 1 E. aerogenes (CRE). All CPE producers and 98.0% of CREs were inhibited at an ATM-AVI MIC of ≤ 8 mg/L. CAZ-AVI and MEM-VAB were active against 81.6% and 65.3% of CREs, respectively. Ceftolozane-tazobactam (TOL-TAZ) was active against only 72.6% of ceftriaxone (CRO)-nonsusceptible (NS) isolates. ATM-AVI retained activity (MIC, ≤8 mg/L) against all MEM-VAB-NS and 90.0% of CAZ-AVI-NS isolates. The most common CPEs were KPC-2/3 (57.1% of CREs), OXA-48–like (16.3%), and NDM (12.2%). A CPE gene was not observed in 14.3% of CREs. CAZ-AVI and MEM-VAB were active against 100.0% of KPC producers, but CAZ-AVI showed limited activity against MBL producers and MEM-VAB showed limited activity against OXA-48–like and MBL producers. The most active comparators against CRE were tigecycline (95.9%S), gentamicin (49.0%S), and amikacin (44.9%S). Conclusion ATM-AVI demonstrated potent activity against a large collection ENT isolated from patients with BSI in US hospitals, including CREs and isolates resistant to recently approved β-lactamase inhibitor combinations. These results support further clinical development of ATM-AVI. Disclosures Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

2128. In Vitro Activity of Ceftibuten-Avibactam and Comparator Agents Against Resistant Enterobacterales from UTIs Collected Globally as Part of the ATLAS Surveillance Program, 2022

Abstract Background Increasing resistance among agents commonly prescribed to treat urinary tract infections (UTIs) indicate that new orally bioavailable agents are needed. Ceftibuten (CTB) is an orally administered third-generation cephalosporin and is in early clinical development being combined with an oral prodrug of avibactam (AVI). AVI is a non-β-lactam inhibitor of Ambler class A β-lactamases, including ESBLs and KPCs, class C (AmpC) β-lactamases, and some class D (OXA-48) β-lactamases. Ceftibuten-avibactam prodrug (CBA) is in early clinical development as a potential oral treatment for complicated urinary tract infections. This study evaluated the in vitro activity of CBA and oral comparators against Enterobacterales from UTIs with drug-resistant phenotypes collected globally as part of the 2022 Antimicrobial Testing Leadership and Surveillance (ATLAS) program. Methods 4,265 non-duplicate clinical isolates from UTIs were collected in 2022 in 55 countries. Susceptibility testing with CBA tested at a fixed concentration of 4 µg/mL AVI and comparators was performed by CLSI broth microdilution and interpreted using CLSI 2023 breakpoints. Nonsusceptible (NS)/resistant (R) phenotypes were based on 2023 CLSI breakpoints. MDR was defined as R to ≥1 agent from ≥3 drug classes. Results CBA was the most active compound tested against all Enterobacterales, with the MIC90 value decreasing from 32 µg/mL to 0.12 µg/mL. A total of 96% of all isolates were inhibited at a CBA MIC of ≤1 µg/mL. Percent susceptible of oral comparators ranged from 63.4% to 76.8%. CBA maintained activity against NS/R subsets of Enterobacterales (MIC90 range, 0.25 to 4 µg/mL; 85.0% to 93.2% inhibited at ≤1 µg/mL), including MDR isolates (MIC90, >64 µg/mL; 81.7% inhibited at ≤1 µg/mL). Conclusion Ceftibuten-avibactam demonstrated potent in vitro activity against multidrug-resistant Enterobacterales collected globally. Ceftibuten -avibactam prodrug could be an effective oral therapy for difficult-to-treat infections caused by multidrug-resistant Enterobacterales. Disclosures Meredith Hackel, PhD, Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Gregory Stone, PhD, Pfizer: Stocks/Bonds Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation

2237. Enterbacterales Resistance Patterns for Extended-spectrum beta-lactamases (ESBL) Positive and Multidrug Resistance (MDR) Urine Isolates Collected and Tested from 295 Outpatient US Facilities in 2019

Abstract Background Approximately 3 million cases of complicated Urinary Tract Infections (cUTI) occur annually in the U.S. with over 80% being diagnosed in the community setting. Antimicrobial resistance (AMR) and MDR are a growing threat. ESBL producing Enterbacterales (ENT) alone have increased by 53% from 2012 to 2017. Agents commonly used for treatment are becoming ineffective due to higher baseline resistance, resulting in treatment failures and unnecessary hospitalizations. Methods In total, 669,664 ENT (E. coli, K. pneumoniae, K. oxytoca, P. mirabilis) urine isolates were collected and tested from 295 US facilities (BD database) in 2019. All 30-day non-duplicate isolates collected were from adult outpatients (OPs). Antimicrobial susceptibility was done by each facility reference lab. The total number of isolates tested, and total non-susceptible (NS) isolates were tested and identified at the county level. Only counties with ≥ 30 tested isolates were reported. Those with < 30 isolates tested were indicated as < 1% NS (e.g., insufficient isolates tested). Counties without susceptibility results were populated to the nearest county either within or across state lines. We sought to examine both ESBL and ≥ 3 drug NS rates in the OP setting. Results Among all isolates, ESBL + and ≥ 3 drug NS rates represented 8.5% and 4.9%, respectively. A total of 14 states (28%) had resistance rates ≥20% for ESBL producing ENT. MO had the highest rate (28.6%), followed by 24.7% for KY, NC, TN, VA, and WV. GA was at 23.7%, while AZ, NM and TX were∼ 21.2%, and FL at 20.2%. The remain states DE, MD, and NJ were all at 20% (Figure 1). MDR (≥ 3 drug NS) rates ≥ 10% were noted for 11 states (22%). States in rank order included: MO (20%), KY, NC, TN, VA, and WV all at 14.7%. KY ranged from 14.7% to 10.1%, whereas GA was at 11.5% with 10.7% for both AL and FL. The remaining states included CA and HI both at ∼10% (Figure 2). Figure 1.Figure 2. Conclusion Important regional differences are noted for ESBL + and ≥ 3 drug resistance to urine isolates in the OP setting complicating oral antibiotic therapy. Certain states with higher resistance rates require education for the guideline selection of appropriate antibiotics. The approval of newer agents that overcome AMR are warranted and offer an alternative to limited existing oral therapy. Disclosures Mauricio Rodriguez, PharmD, MS-HEOR, BCPS, BCCCP, BCIDP, Spero Therapeutics: Employee Kalvin Yu, MD, FIDSA, Becton, Dickinson and Company: Employee of, and shareholder in, Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502 Vikas Gupta, PharmD, Becton, Dickinson and Company: Employee of, and shareholder in, Becton, Dickinson and Company, and the company received funding from GlaxoSmithKline plc. to conduct this study|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502.

1836. Frequency and Antimicrobial Susceptibility of Gram-negative Bacteria Isolated from Patients with Bloodstream Infections in United States (US) Medical Centers (2020-2021)

Abstract Background Antimicrobial resistance among Gram-negative bacteria (GNB) is a major problem in US hospitals. The development of various β-lactamase inhibitor combinations (BLICs) markedly increased the armamentarium to treat infections caused by GNB in recent years. We evaluated the frequency and antimicrobial susceptibility of GNB causing bloodstream infection (BSI). Methods 5,796 organisms were consecutively collected (1/patient) from patients with BSI in 31 US medical centers in 2020-2021. The collection included 2,893 (49.9%) GNB, which were susceptibility tested against ceftazidime-avibactam (CAZ-AVI), ceftolozane-tazobactam (C-T), meropenem-vaborbactam (MEM-VAB), imipenem-relebactam (IMI-REL), and many comparators by CLSI broth microdilution method. Enterobacterales (ENT) isolates with an ESBL phenotype were screened for β-lactamase genes by whole genome sequencing. Results The most common GNBs were E. coli (41.9%), K. pneumoniae (16.1%), P. aeruginosa (10.2%), and E. cloacae (6.8%). Ceftriaxone susceptibility rates were 80.1%, 82.9%, and 74.0% for E. coli, K. pneumoniae, and E. cloacae, respectively. CAZ-AVI and MEM-VAB showed almost complete activity (≥ 99.7%) against ENT, whereas IMI-REL exhibited limited activity against P. mirabilis and indole-positive Proteeae isolates and C-T showed limited activity against E. cloacae, ESBL-phenotype, and multidrug-resistant (MDR) isolates (Table). CAZ-AVI, MEM-VAB, and IMI-REL were active against 84.2%, 57.9%, and 52.6% of carbapenem-resistant ENT (CRE) isolates, respectively. PSA susceptibility to PIP-TAZ, MEM, and CAZ were 86.1%, 88.5%, and 88.5%, respectively. CAZ-AVI (97.6% susceptible [S]), C-T (97.6%S), IMI-REL (99.0%S), and tobramycin (TOB; 98.3%S) were the most active agents against PSA and retained good activity against piperacillin-tazobactam (PIP-TAZ) nonsusceptible (NS), MEM-NS, and multidrug-resistant (MDR) isolates. Conclusion CAZ-AVI and MEM-VAB were the most active agents against ENT and CAZ-AVI; C-T and IMI-REL were the most active BLICs against PSA. The new BLICs represent valuable treatment options for infections caused by MDR GBNs. CAZ-AVI exhibited a more balanced spectrum against ENT and PSA when compared to other BLICs. Disclosures Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Michael D. Huband, BS, AbbVie: Grant/Research Support|Melinta: Grant/Research Support Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

656. Comparative Activity of Newer β-Lactam/β-Lactamase Inhibitor Combinations against Pseudomonas aeruginosa isolates from United States Medical Centers (2020-2021)

Abstract Background P. aeruginosa (PSA) is one of the most common Gram-negative organisms causing infections in hospitalized patients. Prompt administration of an effective antimicrobial is crucial for patients with systemic PSA infection. We evaluated the in vitro activity of ceftazidime-avibactam (CAZ-AVI), ceftolozane-tazobactam (C-T), meropenem-vaborbactam (MEM-VAB), imipenem-relebactam (IMI-REL), and many comparator agents against contemporary PSA isolates from US hospitals. Methods 3,184 isolates were consecutively collected from 71 US medical centers in 2020-2021 and susceptibility tested by reference broth microdilution methods in a monitoring laboratory (JMI Laboratories). US FDA and CLSI breakpoints were applied. Results CAZ-AVI (97.0% susceptible [S]), C-T (98.0%S), IMI-REL (97.3%S), and tobramycin (TOB; 96.4%S) were the most active agents against the aggregate PSA isolate collection and retained good activity against piperacillin-tazobactam- (PIP-TAZ) nonsusceptible (NS), MEM-NS, and multidrug-resistant (MDR) isolates (Table 1). All other antimicrobials tested showed limited activity against PIP-TAZ-NS, MEM-NS, and MDR isolates. The most common infection types were pneumonia (45.9%), skin and skin structure infections (19.0%), urinary tract infections (UTI; 17.0%), and bloodstream infections (11.7%); CAZ-AVI, C-T, and IMI-REL showed consistent activity against isolates from these infection types. Susceptibility to PIP-TAZ and MEM were lower among isolates from pneumonia compared to other infection types (Table 2). CAZ-AVI remained active against 31.7% and 52.5% of C-T-NS and IMI-REL-NS isolates, respectively. C-T remained active against 54.7% and 68.9% of CAZ-AVI-NS and IMI-REL-NS isolates, respectively, and IMI-REL remained active against 64.2% and 64.8% of isolates NS to CAZ-AVI and C-T, respectively. Conclusion CAZ-AVI, C-T, and IMI-REL were highly active and exhibited similar coverage against a large contemporary collection of PSA isolates from US hospitals. Cross resistance among these new β-lactamase inhibitor combinations varied markedly, indicating that all 3 should be tested in the clinical laboratory. These 3 agents represent valuable therapeutic options for PSA infection treatment. Disclosures Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support SJ Ryan Arends, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Shionogi: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

2051. Relebactam enhances Imipenem activity across the Imipenem susceptibility spectrum among Pseudomonas aeruginosa isolates collected in the United States--SMART 2018-2020

Abstract Background The Beta-Lactamase Inhibitors (BLIs) Relebactam (REL) and Avibactam (AVI) both inhibit class A and C beta-lactamases and are approved in combination with the beta-lactam antibiotics imipenem (IMI/REL) and ceftazidime (CAZ/AVI), respectively. Our goal was to evaluate the effect of these BLIs on susceptibility of Pseudomonas aeruginosa isolates that are either nonsusceptible (NS), Intermediate (I) or Susceptible (S) to the partner beta-lactam antibiotic. Methods In 2018-2020, ∼20 unique participating sites in the United States each collected up to 250 consecutive aerobic gram-negative isolates per year (50 each from urine, intraabdominal and blood; 100 from lower respiratory tract). Susceptibility to Imipenem (IMI) and Ceftazidime (CAZ) were determined alone as well as in combination with their cognate BLIs. MICs were determined using broth microdilution and evaluated by CLSI interpretive criteria. Results A total of 2,537 P. aeruginosa isolates were evaluated. Among IMI-NS isolates (MIC >2 μg/mL) REL restored IMI susceptibility to 75% and among CAZ-NS isolates (MIC >8 μg/mL) AVI restored CAZ susceptibility to 73%. For IMI-I isolates (MIC of 4 μg/mL), the presence of REL restored susceptibility to 98%, and 95% had MICs at least one dilution less than the susceptible breakpoint. For CAZ-I isolates (MIC of 16 μg/mL), AVI restored susceptibility to 84% of isolates, and 62% had MICs at least one dilution below the susceptible breakpoint. The addition of REL shifted the mode IMI MIC of IMI-S (MIC ≤ 2 μg/mL) isolates 4-fold, from 2 to 0.5 μg/mL, whereas there was no change in the mode CAZ MIC of CAZ-S (MIC ≤ 8 μg/mL) isolates in the presence of AVI. Conclusion Both REL and AVI restore susceptibility to P. aeruginosa isolates nonsusceptble to their cognate beta-lactam antibiotics (IMI and CAZ, respectively). However, REL had greater enhancement of IMI towards IMI-I isolates when compared to the effect of AVI on CAZ towards CAZ-I isolates. REL substantially enhances IMI activity towards IMI-S isolates whereas no such enhancement was observed for AVI upon CAZ activity towards CAZ-S isolates. REL is differentiated by its ability to enhance the activity of the cognate beta-lactam (IMI) across the susceptibility spectrum. Disclosures Charles A. DeRyke, PharmD, Merck & Co., Inc. Merck Research Laboratories: Stocks/Bonds Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds.

222. Clinical and microbiological outcomes for Enterobacterales uropathogens in the Phase 3 ADAPT-PO Study of oral tebipenem pivoxil hydrobromide

Abstract Background Enterobacterales (ENT) are frequently implicated in complicated urinary tract infection, including acute pyelonephritis (cUTI/AP), with Escherichia coli (EC) being the most prevalent. Extended-spectrum β-lactamase (ESBL)-producing organisms are increasing and often coresistant to existing oral antibiotics such as the fluoroquinolones (FQ) and trimethoprim-sulfamethoxazole (TMP-SMX). Tebipenem pivoxil hyrdrobromide (TBP-PI-HBr) — a novel oral carbapenem under development — was shown to be non-inferior to IV ertapenem (ETP) in the treatment of cUTI/AP in the ADAPT-PO trial. The goal of this analysis was to assess clinical response (CR) and by-pathogen microbiological responses (MR) for ENT pathogens, including those with resistant phenotypes. Methods ADAPT-PO was a Phase 3 multinational, double-blind trial evaluating oral TBP-PI-HBr vs. IV ertapenem in 1372 hospitalized adult patients with cUTI/AP. Patients were randomized 1:1 to oral TBP-PI-HBr or IV ertapenem for 7-10 days. CR and MR at the test-of-cure (TOC) for patients with ENT including resistant phenotypes were assessed in the microbiological intent-to-treat population (micro-ITT). Results 90.2% of patients in the micro-ITT population were infected with ENT; EC was the most prevalent (64.2%), followed by Klebsiella pneumoniae (14.3%), Proteus mirabilis (6.7%) and Enterobacter cloacae (2.2%). ESBL-positive, FQ non-susceptible (NS) and TMP-SMX-R phenotypes were 23.5%, 38.4% and 41.8% of ENT, respectively. MIC90 vales for both TBP and ETP against ENT were 0.12 µg/mL. At TOC, the CR for TBP-PI-HBr and ETP and all ENT were 92.7% and 94.0%, respectively, and MR was 59.7% and 65.9%, respectively. CR at TOC for ESBL positive ENT was 87.6% and 95.3%, respectively and MR was 54.7% and 61.6%, respectively. Similar MR rates were observed among EC and resistant EC phenotypes. Conclusion At TOC CR rates for ENT pathogens were high and similar between treatment groups, including resistant subsets. MR rates for all pathogens were lower in both treatment groups, translating to to a phenomenon consistent with other cUTI trials representing asymptomatic bacteriuria. TBP-PI-HBr and ETP showed similar MR rates for EC, the most prevalent uropathogens, including resistant phenotypes. Disclosures Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Paul B. Eckburg, MD, AN2 Therapeutics: Stocks/Bonds|Spero Therapeutics: Advisor/Consultant Lori A. Muir, B.Sc., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Lori A. Muir, B.Sc., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Aaron Dane, MSc, Amplyx: Advisor/Consultant|AN2 therapeutics: Advisor/Consultant|Artizan: Advisor/Consultant|Cidara: Advisor/Consultant|ContraFect: Advisor/Consultant|Correvio: Advisor/Consultant|Davolterra: Advisor/Consultant|Destiny Pharma: Advisor/Consultant|Entasis: Advisor/Consultant|F2G Limited: Advisor/Consultant|GSK: Advisor/Consultant|Humanigen: Advisor/Consultant|Kymab: Advisor/Consultant|Modis: Advisor/Consultant|Orca: Advisor/Consultant|Pfizer: Advisor/Consultant|Phico: Advisor/Consultant|Pled Pharma: Advisor/Consultant|Rare Thyroid: Advisor/Consultant|Roche: Advisor/Consultant|Scynexis: Advisor/Consultant|Sinovent: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Transcrip: Advisor/Consultant|Venatorx: Advisor/Consultant Gary E. Moore, PhD, Spero Therapeutics: Advisor/Consultant David Melnick, MD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Angela K. Talley, MD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds.

Multicenter surveillance of antimicrobial susceptibilities and resistance mechanisms among Enterobacterales species and non-fermenting Gram-negative bacteria from different infection sources in Taiwan from 2016 to 2018

To explore the invitro antimicrobial susceptibility among clinically important Gram-negative bacteria (GNB) in Taiwan. From 2016 through 2018, a total of 5458 GNB isolates, including Escherichia coli (n=1545), Klebsiella pneumoniae (n=1255), Enterobacter species (n=259), Pseudomonas aeruginosa (n=1127), Acinetobacter baumannii complex (n=368), and Stenotrophomonas maltophilia (n=179), were collected. The susceptibility results were summarized by the breakpoints of minimum inhibitory concentration (MIC) of CLSI 2020, EUCAST 2020 (for colistin), or published articles (for ceftolozane/tazobactam). The resistance genes among multidrug-resistant (MDR) or extensively drug-resistant (XDR)-GNB were investigated by multiplex PCR. Significantly higher rates of non-susceptibility (NS) to ertapenem and carbapenemase production, predominantly KPC and OXA-48-like beta-lactamase, were observed in Enterobacterales isolates causing respiratory tract infection than those causing complicated urinary tract or intra-abdominal infection (12.7%/3.44% vs. 5.7%/0.76% or 7.7%/0.97%, respectively). Isolates of Enterobacter species showed higher rates of phenotypic extended-spectrum β-lactamase and NS to ertapenem than E. coli or K. pneumoniae isolates. Although moderate activity (54-83%) was observed against most potential AmpC-producing Enterobacterales isolates, ceftolozane/tazobactam exhibited poor invitro (44.7-47.4%) activity against phenotypic AmpC Enterobacter cloacae isolates. Additionally, 251 (22.3%) P. aeruginosa isolates exhibited the carbapenem-NS phenotype, and their MDR and XDR rate was 63.3% and 33.5%, respectively. Fifteen (75%) of twenty Burkholderia cenocepacia complex isolates were inhibited by ceftolozane/tazobactam at MICs of ≤4μg/mL. With the increase in antibiotic resistance in Taiwan, it is imperative to periodically monitor the susceptibility profiles of clinically important GNB.

Evidence of immunometabolic dysregulation and airway dysbiosis in athletes susceptible to respiratory illness.

SummaryBackgroundRespiratory tract infection (RTI) is a leading cause of training and in-competition time-loss in athlete health. The immune factors associated with RTI susceptibility remain unclear. In this study, we prospectively characterise host immune factors in elite athletes exhibiting RTI susceptibility.MethodsPeripheral blood lymphocyte flow cytometry phenotyping and 16S rRNA microbial sequencing of oropharyngeal swabs was performed in a prospective elite athlete cohort study (n = 121). Mass cytometry, peripheral blood mononuclear cell (PBMC) stimulation and plasma metabolic profiling was performed in age-matched highly-susceptible (HS) athletes (≥4RTI in last 18 months) (n = 22) compared to non-susceptible (NS) (≤1RTI in last 18 months) (n = 23) athletes. Findings were compared to non-athletic healthy controls (HC) (n = 19).FindingsAthletes (n = 121) had a reduced peripheral blood memory T regulatory cell compartment compared to HC (p = 0.02 (95%CI:0.1,1.0)) and reduced upper airway bacterial biomass compared to HC (p = 0.032, effect size r = 0.19). HS athletes (n = 22) had lower circulating memory T regulatory cells compared to NS (n = 23) athletes (p = 0.005 (95%CI:-1.5,-0.15)) and HC (p = 0.002 (95%CI:-1.9,-0.3) with PBMC microbial stimulation assays revealing a T-helper 2 skewed immune response compared to HC. Plasma metabolomic profiling showed differences in sphingolipid pathway metabolites (a class of lipids important in infection and inflammation regulation) in HS compared to NS athletes and HC, with sphingomyelin predictive of RTI infection susceptibility (p = 0.005).InterpretationAthletes susceptible to RTI have reduced circulating memory T regulatory cells, metabolic dysregulation of the sphingolipid pathway and evidence of upper airway bacterial dysbiosis.FundingThis study was funded by the English Institute of Sport (UK).

202. Comparative Activity of Ceftazidime-Avibactam, Imipenem-Relebactam and Meropenem-Vaborbactam Tested Against Carbapenem-Nonsusceptible Enterobacterales that Are Carbapenemase-Negative

202. Comparative Activity of Ceftazidime-Avibactam, Imipenem-Relebactam and Meropenem-Vaborbactam Tested Against Carbapenem-Nonsusceptible <i>Enterobacterales</i> that Are Carbapenemase-Negative

203. Activity of Cefepime in Combination with Taniborbactam (formerly VNRX-5133) Against Pseudomonas aeruginosa from a Global 2018-2020 Surveillance Collection

BackgroundTaniborbactam is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor (BLI) with potent and selective inhibitory activity against both serine- and metallo-β-lactamases (MBLs). Taniborbactam restores the activity of cefepime (FEP) against many multidrug resistant organisms, including cephalosporin- and carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa (PA). We evaluated the in vitro activity of the investigational combination cefepime-taniborbactam and comparators against clinical isolates of PA collected during a 2018-2020 surveillance.MethodsMICs of FEP with taniborbactam fixed at 4 µg/mL (FTB) and comparators were determined against 3,219 PA collected from 221 sites in 52 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints. Acquired β-lactamase (BL) genes were identified via PCR/Sanger sequencing or whole-genome sequencing (WGS) for 516 isolates with meropenem (MEM) MIC ≥8 µg/mL, and for 94 randomly selected isolates with FEP or ceftazidime MIC ≥16 µg/mL. 186 isolates with FTB MIC ≥16 µg/mL, 16 with FTB MIC=8 µg/mL and one with FTB MIC=4 µg/mL were subjected to WGS.ResultsOverall, 28.7%, 26.2% and 20.3% of PA isolates were nonsusceptible (NS) to piperacillin-tazobactam (TZP), MEM or FEP, respectively (Table). FTB demonstrated potent activity (MIC50/90, 2/8 µg/mL; 94.2% inhibited at ≤8 µg/mL) against PA overall and inhibited between 63.4% (ceftazidime-avibactam [CZA] NS) and 82.1% (TZP NS) of isolates in the NS subsets compared to 0% to 69.1% S for comparators. Against the 111 strains carrying VIM or NDM MBL genes, 67.6% had FTB MICs ≤8 µg/mL, with 11.7% having FTB MICs of 16 µg/mL. Plausible explanations for elevated FTB MICs included IMP MBL genes, penicillin binding protein 3 variations, and/or possible efflux pump up-regulation. ConclusionFTB demonstrated potent in vitro activity against PA with different resistance profiles, including NS to FEP, MEM, and TZP, and to the BL/BLI combinations CZA, ceftolozane-tazobactam, and meropenem-vaborbactam. FTB was the most active agent tested against PA harboring VIM and NDM MBLs. These findings support the continued development of FTB as a potential new treatment option for challenging infections due to MDR PA.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)

176. Antibiotic Resistance Patterns, Seasonality, and Correlation with the Influenza Season in the United States: A Multicenter Evaluation Reveals Surprising Association Between Influenza Season and Gram Negative Pathogens

BackgroundInfluenza infection may affect bacterial transmission dynamics and seasonality of antimicrobial resistance (AMR). There is a paucity of data on the association of influenza season and AMR rates. We aimed to describe trends of AMR and their correlation with the influenza season in ambulatory and inpatient settings in the United States (US). MethodsWe used the BD Insights Research Database (Franklin Lakes, NJ USA) to identify 30 day non-duplicate isolates collected from patients >17 years old with susceptibility profile of Gram-negative (GN) (Enterobacterales (ENT), P. aeruginosa (PSA), A. baumannii spp. (ACB), and S. maltophilia (Sm)) and Gram-positive (GP) pathogens (S. aureus (SA), and S. pneumoniae (Sp)) in up to 257 US healthcare institutions from 2011-19. We defined the outcomes as rates per 100 admissions and % of non-susceptibility (NS), stratified by community and inpatient settings, resistance type (resistance to carbapenem (Carb-NS), quinolone (FQ-NS), macrolide (Macr NS), penicillin (PCN NS), and extended spectrum cephalosporin (ESC NS)) and isolate origin (respiratory and non-respiratory). Influenza data were presented as the % of positive laboratory tests. We used descriptive statistics and generalized estimating equations models to evaluate the monthly trends of AMR outcomes and correlation with the influenza season.ResultsWe identified 16 576 274 confirmed non-duplicate pathogens, of which 154 841 were GN Carb-NS, 1 502 796 GN FQ-NS, 498 012 methicillin resistant SA (MRSA), and 44 131 Macr-NS, PCN-NS, and ESC-NS Sp. Among the Carb-NS pathogens, Influenza rate was correlated with % ACB-NS [β= 0.205, p< .001]. In the FQ-NS group, influenza was associated with overall % ENT-NS [β= 0.041 p< .001] and % PSA-NS [β= 0.039, p = .015]. For the GP pathogens, all Sp. rates were correlated with increased influenza positivity % (See Table). Only MRSA rates of respiratory source were associated with influenza [β= .066, p=.028].Summary of Multivariate regressions of AMR and % Flu by Source and Setting (controlling for hospital level factors): 2011-2019 Data in each cell is presented as the coefficient and p-value is in parentheses. ^adjusted for region, teaching, urban, bed size, and season. + p<.10 *p <.05 **p <.01 ***p <.001ConclusionOur study revealed surprising association between influenza epidemics and GN resistance and corroborated the evidence of correlation between respiratory GP and influenza infections. These insights may help inform targeted antimicrobial stewardship initiatives during influenza season.Disclosures Amine Amiche, PhD, Sanofi (Employee, Shareholder) Heidi Kabler, MD, Sanofi Pasteur (Employee) Janet Weeks, PhD, Becton, Dickinson and Company (Employee) Kalvin Yu, MD, BD (Employee) Vikas Gupta, PharmD, BCPS, Becton, Dickinson and Company (Employee, Shareholder)

789. Susceptibility of Phenotypic Subsets of Pseudomonas aeruginosa Isolates to Cefiderocol and Comparator Agents from SIDERO-WT 2014-2019

Abstract Background Multidrug-resistant (MDR) phenotypes are frequently observed among P. aeruginosa (PsA) isolated from hospitalized patients. This study describes the in vitro activities of cefiderocol (CFDC) and comparator agents against various non-susceptible (NS) phenotypic subsets of MDR PsA isolates from the SIDERO-WT multi-national surveillance program. Methods Clinical PsA isolates were collected from North America (NA) and Europe in 2014-2019 and tested for susceptibility at a central laboratory. MICs (μg/ml) were determined for CFDC, ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), colistin, cefepime, meropenem (MEM), and ciprofloxacin by broth microdilution according to CLSI guidelines. Aztreonam-avibactam (avibactam fixed concentration of 4 µg/ml) and imipenem/relebactam (I/R) were only tested during SIDERO-WT Year 5 (i.e. 2019). Susceptibility was interpreted according to current FDA and 2021 CLSI breakpoints. Results The different phenotypic subsets and susceptibility of tested compounds are shown in the table. Among 7700 PsA isolates, 47.7% and 23% were from respiratory and gastrointestinal sources of infection. CFDC inhibited 97.5% and 99.9% of all PsA at its FDA-S and CLSI-S MIC breakpoint of ≤1 and ≤4, respectively. CFDC had the lowest MIC90 of all tested agents and &amp;gt;99% S at an MIC ≤4 for all phenotypic subsets. At a MIC ≤1, CFDC displayed high susceptibility rates against all subsets including ≥88% S against CZA-NS, C/T-NS, I/R-NS, and MEM+I/R-NS isolates. Against MDR subsets, comparator agents consistently demonstrated lower activity than CFDC; 88% of MEM+C/T-NS and MEM+CZA-NS isolates had a CFDC MIC≤1 while 15.6% and 20.3% were S to I/R, respectively. 86% of MEM+CZA+C/T-NS and 80.4% CZA+C/T+I/R-NS isolates were S to CFDC. CFDC inhibited 98.1% and 99.4% of PsA isolates from NA (n = 3548) at a MIC of ≤1 and ≤4, respectively. In NA isolates that were MEM+C/T-NS; 85.7% of PsA isolates had a MIC ≤1 to CFDC and 33.3% and 28.6% were S to CZA and I/R, respectively. MEM: Meropenem; NS: Non-susceptible; CZA: Ceftazidime/avibactam; C/T: Ceftolozane/tazobactam; I/R: Imipenem/relebactam Conclusion CFDC demonstrated potent in vitro activity against a variety of phenotypic subsets of MDR P. aeruginosa isolates as compared to agents that are commonly used to treat MDR PsA infections including strains NS to other agents. These data support the use of CFDC as an important treatment option for MDR PsA. Disclosures Sean Nguyen, PharmD, Shionogi Inc (Employee) David Fam, PharmD, Shionogi (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Roger Echols, MD, Shionogi (Consultant) Yoshinori Yamano, PhD, Shionogi (Employee)