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BackgroundAztreonam/avibactam is under development to treat infections caused by Gram-negative bacteria. We evaluated the in vitro activities of aztreonam/avibactam and comparators against a global collection of carbapenem-resistant Enterobacterales (CRE), including ceftazidime/avibactam-resistant isolates.MethodsIsolates were consecutively collected (24 924; 1/patient) from 69 medical centres in 36 countries during 2019–21. Isolates were susceptibility tested by CLSI broth microdilution. All CRE isolates (n = 1098; 4.4%) were in silico screened for carbapenemase (CPE) genes after genome sequencing. CRE susceptibility results were stratified by CPE, geography and resistance phenotype.ResultsAztreonam/avibactam inhibited 99.6% of CREs at ≤8 mg/L (MIC50/90, 0.25/0.5 mg/L), including 98.9% (345/349) of ceftazidime/avibactam-resistant isolates. Aztreonam/avibactam activity was consistent across geographical regions (98.9%–100.0% inhibited at ≤8 mg/L), but susceptibility to comparators varied markedly. Susceptibility (CLSI criteria) for ceftazidime/avibactam and meropenem/vaborbactam ranged from 80.2% and 77.5% in Western Europe to 39.5% and 40.3% in the Asia-Pacific region, respectively. Aztreonam/avibactam retained activity against isolates non-susceptible to colistin (99.7% inhibited at ≤8 mg/L) or tigecycline (98.6% inhibited at ≤8 mg/L). A CPE gene was identified in 972 CRE isolates (88.5%). The most common CPEs were KPC (43.1% of CREs), NDM (26.6%) and OXA-48–like (18.7%); 57 isolates (5.2%) had >1 CPE gene. Aztreonam/avibactam inhibited 99.9% of CPE producers at ≤8 mg/L, whereas ceftazidime/avibactam and meropenem/vaborbactam exhibited limited activity against isolates producing MBL and/or OXA-48-like enzymes.ConclusionsAztreonam/avibactam activity was not adversely affected by clinically relevant CPEs. Our results support aztreonam/avibactam development to treat infections caused by CRE, including MBL producers.

The occurrence of urinary-tract Enterobacterales pathogens producing ESBL enzymes in community and nosocomial settings continues to increase, as does the coresistance to fluoroquinolones, trimethoprim-sulfamethoxazole and nitrofurantoin often exhibited by these pathogens. This scenario complicates the clinical empirical and guided management of UTI by precluding the use of oral and many intravenous options.

BackgroundThe Clinical and Laboratory Standards Institute (CLSI) lowered the Enterobacterales-susceptible/-resistant breakpoints for amikacin in 2023 from ≤16/≥64 mg/L to ≤4/≥16 mg/L and the breakpoints for gentamicin and tobramycin from ≤4/≥16 mg/L to ≤2/≥8 mg/L. Because aminoglycosides are frequently used to treat infections caused by multidrug-resistant (MDR) and carbapenem-resistant Enterobacterales (CRE), we evaluated the impact of these changes on the susceptibility rates (%S) of Enterobacterales collected from US medical centers.MethodsA total of 9809 Enterobacterales isolates were consecutively collected (1/patient) from 37 US medical centers in 2017–2021 and susceptibility was tested by broth microdilution. Susceptibility rates were calculated using CLSI 2022, CLSI 2023, and US Food and Drug Administration 2022 criteria. Aminoglycoside-nonsusceptible isolates were screened for genes encoding aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methyltransferases (16RMT).ResultsThe CLSI breakpoint changes mostly affected amikacin, especially against MDR (94.0%S to 71.0%S), extended-spectrum β-lactamase (ESBL)-producing (96.9%S to 79.7%S), and CRE (75.2%S to 59.0%S) isolates. Plazomicin was active against 96.4% of isolates and retained potent activity against CRE (94.0%S), ESBL-producing (98.9%S), and MDR (94.8%S) isolates. Gentamicin and tobramycin showed limited activity against resistant subsets of Enterobacterales. The AME-encoding genes and 16RMT were observed in 801 (8.2%) and 11 (0.1%) isolates, respectively. Plazomicin was active against 97.3% of the AME producers.ConclusionsThe spectrum of activity of amikacin against resistant subsets of Enterobacterales was drastically reduced when interpretative criteria based on pharmacokinetic/pharmacodynamic parameters that are currently used to establish breakpoints for other antimicrobials were applied. Plazomicin was markedly more active than amikacin, gentamicin, or tobramycin against antimicrobial-resistant Enterobacterales.

BackgroundAs the frequency of metallo-β-lactamase (MBL)-producing Enterobacterales is increasing worldwide, effective antimicrobials to treat the infections caused by these organisms are urgently needed.MethodsThe activity of aztreonam-avibactam and comparators were evaluated against 27 834 Enterobacterales isolates collected from 74 US medical centers in 2019–2021. Isolates were susceptibility tested by broth microdilution. An aztreonam-avibactam pharmacokinetic/pharmacodynamic breakpoint of ≤8 mg/L was applied for comparison. Antimicrobial susceptibility and the frequency of key resistance phenotypes were assessed then stratified by year and infection type. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemase (CPE) genes by whole genome sequencing.ResultsAztreonam-avibactam inhibited >99.9% of Enterobacterales at ≤8 mg/L. Only 3 isolates (0.01%) had an aztreonam-avibactam minimum inhibitory concentration (MIC) >8 mg/L. The CRE rates were 0.8%, 0.9%, and 1.1% in 2019, 2020, and 2021, respectively; 99.6% (260 of 261) of CRE isolates were inhibited at an aztreonam-avibactam MIC of ≤8 mg/L. The CRE susceptibility to meropenem-vaborbactam decreased from 91.7% in 2019 to 83.1% in 2020 and 76.5% in 2021 (82.1% overall). The CRE, multidrug-resistant, and extensively drug-resistant phenotypes were markedly higher among isolates from pneumonia compared with other infections. The most common carbapenemase among CRE was Klebsiella pneumoniae carbapenemase (65.5% of CRE), followed by New Delhi metallo-β-lactamase (11.1%), oxacillinase (OXA)-48-like (4.6%), Serratia marcescens enzyme (2.3%), and imipenemase (1.5%). Among non-CPE-producing CRE isolates (n = 44; 16.9% of CRE), 97.7% were inhibited at ≤8 mg/L aztreonam-avibactam and 85.4% were meropenem-vaborbactam susceptible.ConclusionsThe frequencies of MBL and OXA-48-type producers increased markedly. Aztreonam-avibactam demonstrated potent and consistent activity against Enterobacterales across infection types and over time.

BackgroundThe temporal and longitudinal trends of β-lactamases and their associated susceptibility patterns were analyzed for Escherichia coli and Klebsiella pneumoniae isolates consecutively collected in 56 United States hospitals during 2016–2020.MethodsIsolates (n = 19 453) were susceptibility tested by reference broth microdilution methods. Isolates that displayed minimum inhibitory concentration (MIC) values ≥2 mg/L for at least 2 of the following compounds—ceftazidime, ceftriaxone, aztreonam, or cefepime—or resistance to the carbapenems were submitted to whole genome sequencing for identification of β-lactamases. Longitudinal and temporal trends were determined by slope coefficient. New CTX-M and OXA-1 variants were characterized.ResultsExtended-spectrum β-lactamases (ESBLs) were detected among 88.0% of the isolates that displayed elevated cephalosporin/aztreonam MICs without carbapenem resistance. blaCTX-M-15 was detected among 55.5% of the ESBL producers. ESBL rates were stable over time, but significant increases were noted among bloodstream infection and K pneumoniae isolates, mainly driven by an increase in blaCTX-M. Carbapenem resistance and carbapenemase genes were noted among 166 and 145 isolates, respectively, including 137 blaKPC, 6 blaSME, 3 blaOXA-48–like, and 3 blaNDM. Ceftazidime-avibactam and carbapenems were very active (>99% susceptibility) against ESBL producers without carbapenem resistance. Ceftazidime-avibactam inhibited 97.0% of the carbapenem-resistant isolates. This agent and meropenem-vaborbactam inhibited 96.4% and 85.0% of the 2020 isolates, respectively.ConclusionsOverall, ESBL-producing isolates were stable, but an increase was noted for K pneumoniae isolates driven by CTX-M production. Carbapenem-resistant Enterobacterales rates decreased in the study period. The prevalence of metallo-β-lactamases and OXA-48–like remains low. Continuous surveillance of β-lactamase–producing isolates is prudent.

Recently, porphyrin units have been attached to graphene nanoribbons (Por-GNR) enabling a multitude of structures. Here we report first-principles calculations of two prototypical, experimentally feasible, Por-GNR hybrids, one of which displays a small band gap relevant as electrodes in devices. Embedding a Fe atom in the porphyrin causes spin-polarized ground state (S = 1). Using density functional theory and nonequilibrium Green’s function, we examine a 2-terminal setup involving a Fe-Por-GNR between small band gap, Por-GNR electrodes. The coupling between the Fe-d and GNR band states results in a Fano anti-resonance feature in the spin transport, making the conductance highly sensitive to the Fe spin state. We demonstrate how mechanical strain or chemical adsorption on the Fe give rise to spin-crossover to S = 2 and S = 0, directly reflected in the transmission. Our results provide a deep understanding which can open an avenue for carbon-based spintronics and chemical sensing.

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Background It has been reported that the oncoprotein E7 from human papillomavirus type 16 (HPV16-E7) can induce the excessive synthesis of centrosomes through the increase in the expression of PLK4, which is a transcriptional target of E2F1. On the other hand, it has been reported that increasing MPS1 protein stability can also generate an excessive synthesis of centrosomes. In this work, we analyzed the possible role of MPS1 in the amplification of centrosomes mediated by HPV16-E7. Results Employing qRT-PCR, Western Blot, and Immunofluorescence techniques, we found that E7 induces an increase in the MPS1 transcript and protein levels in the U2OS cell line, as well as protein stabilization. Besides, we observed that inhibiting the expression of MPS1 in E7 protein-expressing cells leads to a significant reduction in the number of centrosomes. Conclusions These results indicate that the presence of the MPS1 protein is necessary for E7 protein to increase the number of centrosomes, and possible implications are discussed.

La COVID-19 ha supuesto una disrupción sin precedentes en las cadenas de valor globales, que se está prolongando tanto por las olas de la pandemia como por la invasión de Rusia a Ucrania. En este artículo se propone una estrategia, basada en un SVAR identificado con restricción de signos, para estimar el impacto de los cuellos de botella sobre la inflación y la actividad, diferenciándolo del efecto de otras perturbaciones de oferta. La caída del PIB es significativa y persistente, más en la eurozona que en España. La inflación, por su parte, tiende a aumentar, si bien la menor actividad contiene el impacto de los cuellos de botella.

American Sign Language is a popular language for deaf individuals. Communication is made easier for these people through sign language. However, in a digital era like today, there is a need for these people to be able to communicate online, and even get help from technology to communicate in person with non sign language speakers. This research will present a program able to translate American sign language to plain English. This study aims to use the OpenCV library to recognize hand signals, also a trained model to identify images so that the program can then translate them to words and letters. The program uses a data set of over 2000 images which will be in this case the largest data set available. With over 90\% of accuracy it results in a basic computer program with the largest data set available that would make possible for users to communicate with a wide variety of words and expressions.

Background Lefamulin is a novel pleuromutilin protein synthesis inhibitor approved in the US, Canada, and Europe for the oral and intravenous treatment of community-acquired bacterial pneumonia (CABP) in adults due to typical and atypical pathogens. This study evaluated the in vitro activity of lefamulin and comparators against bacterial isolates from patients with community-acquired respiratory tract infections and hospitalized patients with pneumonia in the US and Latin America. Methods 1,907 unique isolates were collected within the SENTRY surveillance program from 29 medical centers in the US and 8 medical centers in Latin America (Argentina, Brazil, Chile, Colombia, Mexico, Panama). Isolates were susceptibility tested by CLSI reference broth microdilution methods. CLSI breakpoints (M100, 2022) were applied. Results Lefamulin inhibited 100% of S. pneumoniae isolates at or below its susceptible (S) breakpoint of ≤ 0.5 mg/L, regardless of resistance to other antibiotics used to treat CABP (MIC90 values of 0.12 or 0.25 mg/L, Table). The penicillin-resistant (R; 12.7%), azithromycin-R (43.7%), and tetracycline-R S. pneumoniae (20.4%) displayed reduced susceptibility to the other CABP drugs tested, except moxifloxacin ( > 98.2% S) and lefamulin (100% S). Lefamulin was highly potent against S. aureus, including MRSA, azithromycin-R, and moxifloxacin-R isolates, with 100% of isolates inhibited at or below the lefamulin S breakpoint of ≤ 0.25 mg/L. Susceptibility to azithromycin and moxifloxacin was particularly low for MRSA (13.9% and 25.0%, respectively). The fastidious Gram-negative H. influenzae and M. catarrhalis, of which 24.0% and 98.8%, respectively, were ß-lactamase positive, were S to lefamulin ( > 93%) and the other tested CABP drugs ( > 89%). Table. Susceptibility of pneumonia pathogens from US and Latin America to lefamulin and other CABP drugs Conclusion Lefamulin displayed potent in vitro activity against contemporary CABP pathogens from the US and Latin America. Its activity was unaffected by resistance to other antibiotic classes, including fluoroquinolones, macrolides, β-lactams, and tetracyclines. Lefamulin represents a valuable empiric treatment option for ambulatory and hospitalized patients with CABP, particularly when the causative pathogen is not identified or in settings with high prevalence of resistance. Disclosures Susanne Paukner, PhD, Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds SJ Ryan Arends, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Shionogi: 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 Steven P. Gelone, PharmD, Nabriva Therapeutics: Board Member|Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds|Nabriva Therapeutics: Stocks/Bonds 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.

Background The frequency of metallo-β-lactamase (MBL)-producing Enterobacterales (ENT) is increasing in United States (US). Effective antibiotics to treat infections caused by these organisms are urgently needed. We evaluated the activity of aztreonam-avibactam (ATM-AVI) and comparators against a large collection of clinical ENT isolates from US hospitals. Methods 27,834 ENT isolates were consecutively collected from 74 US medical centers in 2019-2021 and susceptibility tested by broth microdilution. An ATM-AVI PK/PD breakpoint of ≤8 mg/L was applied for comparison. The antimicrobial susceptibility and frequency of key resistance phenotypes were assessed and stratified by year and infection type: bloodstream (BSI; 5,159 isolates; 18.5%), pneumonia (4,013; 14.4%), skin and skin structure (SSSI; 3,418; 12.3%), urinary tract (UTI; 13,177; 47.3%), or other (2,067; 7.4%). Carbapenem-resistant ENT (CRE) from 2019-2020 were screened for carbapenemase (CPE) genes by whole genome sequencing (WGS). Results ATM-AVI inhibited >99.9% of ENT at ≤8 mg/L. Only 3 isolates (0.01%) had an ATM-AVI MIC > 8 mg/L. ENT susceptibility to ceftriaxone varied from 84.0% in 2019 to 82.1% in 2021; it was lowest among isolates from pneumonia (75.3%; Table). CRE rates were 0.8%, 0.9%, and 1.1% in 2019, 2020, and 2021, respectively; 99.6% (260/261) of CRE isolates were inhibited at an ATM-AVI MIC of ≤ 8 mg/L. CRE susceptibility to meropenem-vaborbactam (MEM-VAB) decreased from 91.7% in 2019 to 83.1% in 2020 and 76.5% in 2021 (82.1% overall). CRE, multidrug-resistant, and extensively drug-resistant phenotypes were markedly higher among isolates from pneumonia compared to other infections. The most common CPE among CRE from 2019-2020 (n=163) were KPC (70.6% of CRE), NDM (8.0%), and SME (3.7%). Among non-CPE-producing CRE isolates (n=27; 16.6% of CRE), 100.0% were inhibited at ≤8 mg/L of ATM-AVI and 80.0% were MEM-VAB-susceptible. Isolates with an elevated ATM-AVI MIC ( > 8 mg/L) exhibited PBP3 and/or porin alterations. Conclusion ATM-AVI demonstrated potent and consistent activity against ENT across infection types and over time. The activities of the comparator β-lactams decreased slightly during the study period and were lowest among isolates from pneumonia. 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 Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: 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.

Background Aztreonam-avibactam (ATM-AVI) is under clinical development for the treatment of serious infections caused by Gram-negative bacteria, including MBL producers. Four other β-lactamase inhibitor combinations (BL/BLI) have been recently approved by the US FDA: ceftazidime-avibactam (CAZ-AVI), ceftolozane-tazobactam (C-T), meropenem-vaborbactam (MEM-VAB), and imipenem-relebactam (IMI-REL). We evaluated the in vitro activity of these 5 BL/BLIs and comparators against P. aeruginosa (PSA) causing cystic fibrosis (CF) pulmonary exacerbation. Methods 383 PSA isolates (1/patient) were recovered from 35 medical centers in the US (n=187) and 12 European countries (EU; n=196) in 2018-2021 and susceptibility tested by CLSI broth microdilution method. Results ATM-AVI inhibited 83.4%/85.2% of isolates from US/EU at ≤8 mg/L. CAZ-AVI (MIC50/90, 2/8 mg/L; 96.3%/95.4% susceptible [S] in US/EU) was the most active agent, followed by IMI-REL (94.7%/92.5%S in US/EU) and C-T (89.8%/91.3%S in US/EU). MEM-VAB (not approved for PSA in the US) and MEM showed similar activity. Tobramycin (TOB)-S rates were 73.3%/85.7% in US/EU (Table 1). Among TOB-non-S (NS) isolates, 84.6% were CAZ-AVI-S and 73.1% were inhibited at ATM-AVI MIC of ≤8 mg/L. CAZ-AVI retained good activity against C-T-NS (61.1%S), IMI-REL-NS (62.1%S), piperacillin-tazobactam (PIP-TAZ)-NS (86.7%S), meropenem (MEM)-NS (86.6%S), and ciprofloxacin (CIP)-NS (92.1%S) isolates (Table 2). Multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes were observed among 40.1%/30.1% and 24.6%/16.8% of isolates from US/EU, respectively. Among MDR isolates, 90.7%/84.7% were CAZ-AVI-S, 65.3%/66.1% were inhibited at ≤8 mg/L of ATM-AVI, and 78.7%/76.3% were TOB-S in US/EU. CAZ-AVI and TOB retained activity against 87.0%/75.8% and 39.1%/63.6% of XDR isolates in US/EU, respectively. Conclusion ATM-AVI and CAZ-AVI exhibited potent activity against PSA isolated from CF patients in US and EU and retained good activity against isolates resistant to other antimicrobials, including MDR and XDR organisms; both compounds showed greater activity than TOB. ATM-AVI and CAZ-AVI may represent a valuable option to treat CF patients with pulmonary exacerbations due to PSA infection. 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 Leonard R. Duncan, PhD, AbbVie: 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 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.

Background Therapeutic options for Enterobacterales species known to overexpress chromosomal AmpC (AmpC producers) are limited since these organisms can develop resistance to BLs during therapy. Novel BL/BLIs, such as meropenem-vaborbactam (MEV), ceftazidime-avibactam (CZA), and imipenem-relebactam (IMR), display activity against isolates producing serine-carbapenemases, extended-spectrum β-lactamases, and AmpC enzymes. In this study, we evaluated the activity of novel BL/BLIs against a collection of AmpC producers collected in from US hospitals during 2021. Activity of newer BL/BLI combinations against AmpC producers Methods A total of 1,252 AmpC producers including were consecutively collected in 31 US hospitals. Isolates were susceptibility tested by reference broth microdilution methods. CLSI breakpoints were applied. Results The activity of new BL/BLIs is summarized displayed in the Figure. MEV (MIC50/90, 0.03/0.06 mg/L) and amikacin were the most active agents tested against these isolates, inhibiting 99.8%. CZA (MIC50/90, 0.12/0.5 mg/L) inhibited 99.5%. IMR (MIC50/90, 0.12/1 mg/L) was active against 95.9%. Cefepime and meropenem were active against 92.0% and 97.6% of these isolates, respectively. Piperacillin-tazobactam and ceftolozane-tazobactam (MIC50/90, 0.5/8 mg/L) displayed activity against 76.4% and 83.6% of the AmpC producers, respectively. Tigecycline was active against 96.8% of the isolates; only 53.8% of the isolates had a colistin MIC of ≤2 mg/L. A total of 39 (3.2%) AmpC producers were nonsusceptible to imipenem and/or meropenem. MEV (MIC50/90, 0.25/2 mg/L) was active against 92.3%. IRL (MIC50/90, 0.25/2 mg/L) and CZA (MIC50/90, 1/ > 32 mg/L) were active against 89.7% of the carbapenem nonsusceptible AmpC producers. Against cefepime-resistant AmpC producers (n=45; 3.6%), MEV, IMR, and CZA had 93.3%, 88.9%, and 86.7% activity. Conclusion Infections caused by AmpC producers often are challenging to treat. Understanding the activity of new BL/BLIs is important as the use of cefepime and meropenem can also lead to resistance to these agents. MEV, IRL, and CZA displayed good activity against AmpC producers. When analyzing carbapenem-nonsusceptible or cefepime-resistant isolates, MEV was slightly more active but more potent than other BL/BLI combinations. Disclosures 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 Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: 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 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 Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support.

Background Tebipenem (TBP), an oral carbapenem in development for treatment of complicated urinary tract infections and acute pyelonephritis, is active vs. uropathogens which produce extended-spectrum beta-lactamases (ESBLs) such as Escherichia coli (Ec) and Klebsiella pneumoniae (Kp). Bacteria acquire resistance to antibiotics via multiple routes, including by chromosomal mutation. In this study, spontaneous resistance to TBP among Enterobacterales, including those resistant to clinically relevant antibacterials, was assessed Methods The frequency of resistance (FOR) to TBP, meropenem (MEM) and ertapenem (ETP) was assessed for Ec (n = 8), Kp (n = 9), and other Enterobacterales (n = 7). Approximately 108 CFU were plated on agar containing 4x or 8x the MIC and incubated for 24h. Resistance was confirmed by MIC testing (CLSI M07Ed11). Serial passages were performed with two Ec and two Kp isolates, each of which included a wild type and ESBL+ isolate, using TBP, MEM and ETP over a 14-day period. Whole genome sequencing was conducted and assembled mutant sequences were aligned vs. β-lactamase-encoding genes, porins OmpF/OmpK35, OmpC/OmpK36, and OmpK37 (Kp only) and penicillin binding proteins (PBPs) 1a, 1b, 2, and 3 and compared with parent strains. Results FOR values for TBP, MEM and ETP at 4x to 8x the MIC ranged from < 6.87 × 10-9 to 5.54 × 10-5, with similar results obtained for all species and genotypes, including ESBL+ isolates and those with porin alterations. In the serial passage, MICs for each agent vs. four isolates over the 14-day period were ∼ five to seven 2x dilutions higher than baseline, resulting in similar MIC values to those observed in the FOR studies (0.12 to 2 µg/mL). Mutants isolated in the presence of TBP, MEM or ETP had similarly decreased susceptibility to each compound. In general, mutants selected during the single- and multi-step resistance studies showed alterations of OmpC in Ec and its homologue OmpK36 in Kp. Conclusion These data suggest TBP has a low propensity for spontaneous resistance at 4x to 8x MIC in vitro and was similar to MEM and ETP in both single-step and serial passage studies. Cross-resistance to TBP, MEM or ETP among mutants suggests common mechanisms contribute to elevated MICs, including through reduced permeability. Disclosures Brian D. VanScoy, B.S., Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics,: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Haley Conde, B.S., Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics,: Grant/Research Support|Antabio SAS,: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica,: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC,: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited,: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma,: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceutical: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Rodrigo E. Mendes, PhD, Spero Therapeutics: Grant/Research Support Nicole Cotroneo, B.S., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds.

Background Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action that confers activity against most strains of target pathogens, such as Escherichia coli, Staphylococcus saprophyticus, and Neisseria gonorrhoeae, including those resistant to current antibiotics. This study reports on the in vitro activity of gepotidacin and other oral antibiotics tested against E. coli clinical isolates collected from patients with UTIs for a gepotidacin UTI global surveillance study as part of the SENTRY Antimicrobial Surveillance Program. Methods A total of 1,978 E. coli isolates were collected between 2019-2021 from 47 medical centers within the US. All isolates were cultured from urine specimens collected from patients seen in emergency and outpatient medical services representative of community-acquired infections. Bacterial identifications were confirmed by MALDI-TOF. Isolates were tested for susceptibility by CLSI methods at a central laboratory (JMI Laboratories). MIC results for oral antibiotics licensed for the treatment of uUTI, multidrug-resistant (MDR), and extended-spectrum β-lactamase (ESBL) subsets were interpreted per CLSI criteria. Results Gepotidacin (MIC50/90, 2/4 mg/L) displayed good activity against 1,978 E. coli isolates, with 98.3% of all observed gepotidacin MICs ≤4 mg/L (Table). Susceptibility (S) rates for other oral agents tested against these isolates were: amoxicillin-clavulanate (83.7%S), ampicillin (50.9%S), ciprofloxacin (79.1%S), fosfomycin (99.7%S), mecillinam (94.2%S), nitrofurantoin (98.2%S), and trimethoprim-sulfamethoxazole (71.3%S). When tested against the drug-resistant subsets, gepotidacin maintained similar MIC50/90 values (1-2/4 mg/L). Gepotidacin was also active against ESBL and MDR E. coli isolates, inhibiting 94.7% and 95.9%, respectively, at gepotidacin concentrations ≤ 4 mg/L. Conclusion Gepotidacin demonstrated potent in vitro activity against contemporary community-acquired E. coli urine isolates. This activity was maintained among isolates demonstrating resistance to other oral standard of care antibiotics including ESBL, FQ-R, and MDR E. coli. Disclosures SJ Ryan Arends, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Shionogi: Grant/Research Support Nicole E. Scangarella-Oman, MS, GlaxoSmithKline plc.: Employee and shareholder Lindsey Tholen, BS (ASCP), GSK: Board Member|GSK: work for hire|Shionogi: Grant/Research Support Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: 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.

Background Gepotidacin is a novel first in class triazaacenaphthylene antibiotic in Phase 3 clinical trials for the treatment of gonorrhea and uncomplicated urinary tract infection (UTI). This study evaluates the epidemiology of E. coli (EC) causing UTI in US patients and the activity of gepotidacin and comparators against various subsets, including those with characterized resistance mechanisms. Methods 1,993 EC collected from 45 US sites were included as part of the Gepotidacin UTI Global Surveillance Study as part of the SENTRY Antimicrobial Surveillance Program (2019-2020). Isolates were tested for susceptibility (S) by CLSI methods and CLSI interpretations were applied. Isolates that met MIC criteria for screening of extended-spectrum β-lactamase (ESBL) genes were subjected to genome sequencing followed by ESBL gene screening and epidemiology typing (MLST, O:H, and fimH). Results A total of 84.4% (1,682/1,993) EC were ESBL negative (Table). Among these isolates, 16.5% (278/1,682) were not S to the fluoroquinolones (FQ) ciprofloxacin and/or levofloxacin, whereas 26.2% (440/1,682) were not S to trimethoprim-sulfamethoxazole (SXT). An ESBL phenotype was noted in 15.6% (311/1,993) of EC, which tended to be mostly not S to the FQs (79.7%), SXT (61.7%), amoxicillin-clavulanate (52.9%), and oral cephalosporins (99.7%). Most ESBL isolates carried CTX-M alleles alone (81.4%; 253/311), whereas 9.6% (30/311) had plasmid AmpC genes. Approximately half (56.3%; 175/311) of ESBL isolates belonged to clonal complex (CC) 131, of which 70.9% (124/175) were O25b:H4 and carried fimH30. Overall, gepotidacin had MIC90 of 2-4 mg/L against various phenotypic/genotypic subsets. Conclusion High rates of EC not S to commonly used oral agents (FQs and SXT) were observed. ESBL phenotype further compromised the activity of oral agents, including oral cephalosporins. Gepotidacin had potent and stable in vitro activity against various subsets, including the resistant CC131 O25b:H4 clone. These data support the further clinical development of gepotidacin as a treatment option for UTI caused by EC, including resistant isolates against which other oral treatment options are limited. Disclosures 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 John H. Kimbrough, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Nicole E. Scangarella-Oman, MS, GlaxoSmithKline plc.: Employee and shareholder Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: 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.

Background Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with activity against Gram-negative bacteria. CFDC and comparator activities were analyzed against resistant and molecularly characterized P. aeruginosa (PSA) and A. baumannii-calcoaceticus complex (ACB) as part of the SENTRY Antimicrobial Surveillance Program. Methods 2,241 PSA and 682 ACB were consecutively collected from 63 US sites in 2020-2021. Susceptibility testing was performed by broth microdilution and CFDC testing used iron-depleted media. FDA and CLSI breakpoints were used for CFDC. CLSI criteria were applied to comparators, except for imipenem-relebactam (IMR) that used FDA breakpoints. Isolates with a resistance phenotype to ≥ 3 classes were defined as multidrug resistant (MDR). ACB and PSA with imipenem and/or meropenem (MER) MIC ≥4 μg/mL or ceftazidime (CAZ) and/or cefepime MIC ≥ 16 μg/mL were subjected to next-generation genome sequencing for screening of acquired carbapenemase genes. Results 31.6% (709/2,241) and 16.9% (379/2,241) of PSA met the MIC screening criteria and showed an MDR phenotype, respectively (Table). Carbapenemase genes were detected in 6 (< 1%) PSA. CFDC had similar MIC against PSA that did not (MIC50/90, 0.06/0.25 μg/mL) and did (MIC50/90, 0.12/0.5 μg/mL) meet the MIC screening criteria. CFDC also had similar MIC50 values (0.12 μg/mL) against the MDR and carbapenemase-positive PSA populations, whereas other agents had compromised activity. 42.5% (290/682) of ACB met the MIC screening criteria, while 35.9% (245/682) had an MDR phenotype, and 27.3% carried carbapenemase genes (all OXA carbapenemase, except for 2 blaNDM-1). In general, CFDC, IMR, meropenem-vaborbactam, MER, ceftazidime-avibactam, and CAZ had activity against ACB that did not meet the MIC screening criteria, but only CFDC (MIC50/90, 0.25-0.5/2 μg/mL) was active against the resistant ACB subsets. Conclusion Many PSA showed a resistance phenotype but acquired carbapenemase genes remained rare in this subset. In contrast, resistance and presence of carbapenemase genes were high in ACB. CFDC showed potent activity against PSA and ACB subsets in US hospitals, including across resistant and molecularly characterized subsets, where treatment options were limited. Disclosures 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 Cory Hubler, BS, Melinta: Grant/Research Support|Shionogi: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: 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 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 Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: 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.

Background Cefiderocol (CFDC) is a siderophore cephalosporin that hijacks the Gram-negative bacteria iron transport system to facilitate cell entry and reach its target. CFDC remains stable to hydrolysis in the presence of serine β-lactamases (ESBLs, KPC, and OXA-type carbapenemases) and metallo-β-lactamases (MBL). CFDC and comparator activities were analyzed against Enterobacterales (ENT), including molecularly characterized isolates, as part of the SENTRY Antimicrobial Surveillance Program in the USA. Methods 8,328 ENT were collected from 32 sites in 2020-2021. Susceptibility testing was performed by broth microdilution. CFDC testing used iron-depleted media. CLSI breakpoints were used. E. coli, K. pneumoniae, and P. mirabilis with ceftriaxone, ceftazidime, or aztreonam MIC ≥2 μg/mL, and any ENT displaying MIC ≥2 μg/mL for imipenem (excluded for P. mirabilis, P. penneri, and indole-positive Proteeae) or meropenem (MER), were subjected to genome sequencing and screening of β-lactamase genes. Results In general, CFDC (≥ 99.9% susceptible [S]), imipenem-relebactam (IMR; 99.4-100%S), meropenem-vaborbactam (MEV; 100%S), and ceftazidime-avibactam (CZA; 100%S) were active against carbapenem-susceptible ENT that carried ESBL and/or AmpC genes (Table). CFDC (MIC50/90, 0.5/4 μg/mL; 98.4%S) and CZA (MIC50/90, 1/8 μg/mL; 91.2%S) were the most active agents against carbapenem-nonS isolates, whereas IMR (MIC50/90, 0.25/4 μg/mL; 81.6%S) and MEV (MIC50/90, 0.12/8 μg/mL; 86.4%S) had suboptimal activity. CFDC (MIC50/90, 0.5/2 μg/mL), IMR (MIC50/90, 0.12/0.5 μg/mL), MEV (MIC50/90, 0.03/0.5 μg/mL), and CZA (MIC50/90, 1/2 μg/mL) were active (100%S) against the KPC subset. CFDC (MIC, 0.5-4 μg/mL; 100%S) was also active against ENT carrying MBL genes, whereas CFDC (MIC, 0.5-2 μg/mL; 100%S) and CZA (1-4 μg/mL; 100%S) were active against isolates carrying blaOXA-48-like. Conclusion CFDC activity was consistent, regardless of phenotypes or genotypes, including against isolates carrying carbapenemase genes other than blaKPC, where approved β-lactam/β-lactamase inhibitor combinations showed limited activity. These data reinforce CFDC as an important option for the treatment of infections caused by ENT and resistant subsets. Disclosures 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 John H. Kimbrough, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: 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 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 Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: 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.

Background We used SENTRY Antimicrobial Surveillance Program data to evaluate the prevalence of carbapenemase enzymes in US hospitals and the activity of meropenem-vaborbactam (MEV) and comparators against these isolates. Methods A total of 22,725 Enterobacterales isolates were consecutively collected in 34 US hospitals and susceptibility tested by reference broth microdilution methods. CLSI breakpoints were applied. Carbapenem-resistant Enterobacterales (CRE) isolates, classified by resistance to imipenem or meropenem, were submitted to whole genome sequencing and data analysis for the detection of carbapenemases. Results Overall, 1.0% (222) of the isolates were CRE. A decrease in CRE prevalence was noted in 2020 (0.8%) compared to 2016 (1.2%). blaKPC variants were detected among 174 (78.4% of the CRE) isolates including 95 blaKPC-3, 75 blaKPC-2, and 1 each of blaKPC-4, blaKPC-6, blaKPC-58, and the Ω-loop variant blaKPC-59.blaSME was detected among 7 S. marcescens. Metallo-β-lactamases (MBLs; 4.0% of the CRE) and OXA-48-like (1.8%) were detected among 9 and 4 isolates, respectively: 7 harbored blaNDM-1/-5; 2 isolates carried blaVIM-1; and 4 isolates carried blaOXA-48/-232. MEV (MIC50/90, 0.03/2 mg/L) inhibited 93.2% of the CRE isolates and was the most active agent tested against all isolates. Comparator β-lactam agents had limited activity against these isolates (0 to 5%). Amikacin and tigecycline were the most active comparators and inhibited 78.8% and 95.0% of the CREs, respectively. Ceftazidime-avibactam (CAZ-AVI; MIC50/90, 1/4 mg/L) was tested against 169 (2017-2020) of these isolates, inhibiting 93.5%. Against 181 isolates producing class A serine-carbapenemases, MBV (MIC50/90, 0.03/0.5 mg/L) inhibited 98.9% of all isolates and CAZ-AVI inhibited 99.2% of the 129 isolates collected in 2017-2020. The activity of all agents was limited against MBL producers. Conclusion The occurrence of carbapenemases declined in the study period, but KPC-producing isolates are dominant among CRE from US hospitals. Small numbers of isolates carrying MBLs and/or OXA-48-like enzymes (< 0.1% of overall) were noted. MEV and CAZ-AVI are very active against isolates producing class A serine-carbapenemases. Disclosures 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 Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Cory Hubler, BS, Melinta: Grant/Research Support|Shionogi: 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 Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support.

Background Limited therapeutic options are currently available for oral treatment of complicated urinary tract infections (cUTIs) caused by resistant Enterobacterales (ENT). Ceftibuten (CTB) is an oral cephalosporin active against ENT approved by the US FDA in 1995. Avibactam (AVI) is a potent inhibitor of extended-spectrum β-lactamases (ESBLs), serine carbapenemases, and AmpC that can be administered orally. We evaluated the in vitro activity of CTB-AVI against ENT causing cUTI. Methods 3,216 isolates (1/patient) were consecutively collected from patients with cUTI in 72 hospitals from 25 countries in 2021 then susceptibility (S) tested by CLSI broth microdilution. Isolates were mainly from the US (n=1,584; 29 centers) and Europe (n=1,411; 33 centers in 18 countries), but included E. coli isolates from Latin America (LATAM; n=121; 6 centers in 5 countries) and Japan (n=100). A proposed CTB-AVI breakpoint (≤ 2 mg/L) and the current CLSI breakpoint for CTB (≤ 8 mg/L) were applied for comparison. Results The most active agents against ENT were CTB-AVI (99.1%/99.6% inhibited at ≤ 2/≤ 8 mg/L), ceftazidime (CAZ)-AVI (99.6%S), amikacin (AMK; 99.1%S), and meropenem (MEM; 98.2%S; Table). CTB-AVI was 4-fold more potent than CAZ-AVI based on MIC50/90 values. The most active oral agents were CTB (89.3%S; 82.9% inhibited at ≤ 2 mg/L), levofloxacin (LEV; 75.4%S), and trimethoprim-sulfamethoxazole (TMP-SMX; 73.4%S). Only CTB-AVI, CAZ-AVI, MEM, and AMK were active against >90% of ESBL-phenotype isolates; only CTB-AVI, CAZ-AVI, and AMK were active against > 70% of CRE isolates. CRE rates were 1.8%/1.9% in US/EU; CTB-AVI inhibited 79.3%/81.5% of CRE isolates from US/EU at ≤ 8 mg/L (75.9%/77.8% at ≤ 2 mg/L). The second most active oral agent against CRE was TMP-SMX (24.6%S). Only 17 isolates (0.5%) showed CTB-AVI MICs ≥8 mg/L; these were from the US (n=9; 0.6% of US isolates), EU (n=6; 0.4%), and LATAM (n=2; 1.7%). Among these 17 isolates, 23.5% were MEM-S, 41.2% were TMP-SMX-S, and 82.4% were AMK-S. Conclusion CTB-AVI was highly active against a large collection of contemporary ENT isolated from patients with cUTIs and exhibited a similar spectrum to CAZ-AVI. CTB-AVI may represent a valuable option for oral treatment of cUTI caused by resistant ENT. 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 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, 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 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.

Background Staphylococcus argenteus (SAR) is a novel species within the S. aureus (SAU) complex. SAR has been misidentified as SAU but has been increasingly reported worldwide as a pathogen. This study evaluated the prevalence of SAR causing bloodstream infection (BSI) in US centers, and the phenotypic, genotypic, and clinical outcomes associated with SAR BSI. Methods 785 SAU (326/459 MRSA/MSSA) from blood cultures (BC) of patients in 31 sites located in all 9 US Census Divisions during the SENTRY Antimicrobial Surveillance Program for 2019 were included. Isolates were screened for SAR by multiplex PCR. Isolates were subjected to MALDI-TOF and susceptibility (S) testing using the CLSI method. Isolates were subjected to genome sequencing, followed by DNA analysis. Results 0.4% (3/785) SAR were detected and originated from Milwaukee (12 yo female; patient 1), Houston (64 yo male; patient 2), and Seattle (21 yo male; patient 3). Patient 1 had a SAR recovered from BC 10 days after admission, but additional clinical information was not available. Patient 2 had end-stage renal disease and was admitted due to MRSA bacteremia/endocarditis, along with septic embolism in the lungs and brain. SAR grew from BC on day 4 and vancomycin was prescribed; the patient died on day 24. Patient 3 presented fever and chills in the 24 hours pre-admission, with a medical history significant for catheter-associated BSI. SAR was cultured from BC upon admission, and the patient received linezolid (5 days), but BCs remained positive. The central line was removed, and BCs cleared thereafter. MALDI-TOF generated highest scores for SAR for all 3 strains, but scores ≥2.0 were also obtained for SAU and S. schweitzeri. SAR (ST2198) from patient 1 was S to all agents tested, as were the other 2 strains (ST2250 and ST1223), except for oxacillin. The latter 2 strains carried SCCmec type IV(2B) and a dfrG was also detected in the ST2250 lineage strain. All 3 strains carried multiple virulence genes. Conclusion Low prevalence of SAR causing BSI was observed in US hospitals in 2019; however, SAR can clearly cause invasive infections. ST2250 has predominantly been detected in the USA and Canada, but this study showed distinct lineages causing BSI, including strains carrying mecA and various virulence genes. Disclosures Rafael Mendes, BS, JMI Laboratory: Grant/Research Support Lalitagauri M. Deshpande, PhD, Melinta: Grant/Research Support|Pfizer: 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 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.

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.

Background SPR206 is a next generation polymyxin being developed to treat serious infections caused by Gram-negative (GN) multidrug-resistant (MDR) pathogens. The in vitro activity of SPR206 and comparators were monitored against GN pathogens causing infection in US and European hospitals during 2021 as part of the SENTRY Antimicrobial Surveillance Program. This study reports the activity of SPR206 against A. baumannii-calcoaceticus species complex (ACB) and P. aeruginosa (PSA) recovered from patients hospitalized in the USA. Methods A total of 238 ACB and 450 PSA recovered from clinical samples during the SENTRY Program for 2021 were included in the study. Isolates were collected from sites in all 9 US Census Divisions and centrally tested for susceptibility by CLSI broth microdilution method and interpretations. Results A total of 34.9% (83/238) and 14.7% (35/238) ACB displayed an MDR or XDR phenotype, whereas 17.8% (80/450) and 8.0% (36/450) PSA had these phenotypes, respectively. Overall, SPR206 had MIC50/90 of 0.12/0.5 mg/L against all ACB, whereas colistin (COL) had MIC50/90 results of 0.5/1 mg/L. SPR206 and COL inhibited, respectively, 98.0% and 97.0% of ACB at MIC of ≤2 mg/L. Other agents tested against ACB showed MIC90 of >16 mg/L. SPR206 remained active against the MDR (MIC50/90, 0.12/1 mg/L) and XDR (MIC50/90, 0.12/0.25 mg/L) subsets of ACB, as did COL (MIC50/90, 0.5/1 mg/L). MIC50, MIC90, and MIC100 of 0.25 mg/L, 0.25 mg/L, and 2 mg/L were obtained for SPR206 against all PSA, respectively. COL (MIC50/90, 1/1 mg/L), ceftazidime-avibactam (MIC50/90, 2/8 mg/L; 94.9% susceptible), and ceftolozane-tazobactam (MIC50/90, 0.5/2 mg/L; 96.9% susceptible) were active against PSA. SPR206 (MIC50/90, 0.25/0.5 mg/L) and COL (MIC50/90, 1/1 mg/L) remained active against the MDR and XDR PSA subsets. Conclusion SPR206 showed potent in vitro activity against these recent collections of ACB and PSA from the USA. SPR206 potency was consistently greater than clinically available in-class and other comparator agents. These results, and favorable safety and tolerability profiles of SPR206 in Phase 1 studies, support the clinical development of SPR206 for the usually difficult-to-treat infections caused by these pathogens and their resistant subsets. Disclosures 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 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 SJ Ryan Arends, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Shionogi: Grant/Research Support Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds 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.

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.

Background CRE isolates are considered a threat to human health. Until recently, the treatment options for CRE were limited. New BL/BLIs, such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MVB), and imipenem-relebactam (IMI-REL), are active against most of these isolates, but these agents display some variation in activity. In this study, we evaluated the activity of these new BL/BLIs and comparator agents against CRE isolates collected in US hospitals. Methods A total of 27,834 Enterobacterales isolates were collected in 74 US hospitals and susceptibility tested by reference broth microdilution methods. CLSI breakpoints were applied. CRE isolates resistant to imipenem or meropenem were submitted to whole genome sequencing and data analysis for the detection of β-lactamases. Results CRE comprised 0.9% (261) of the isolates. An increase in CRE prevalence was noted in 2021 (1.1%) compared to 2019 (0.8%) and 2020 (0.9%; p=0.06). This increase was noted in isolates from bloodstream infections and among patients hospitalized with pneumonia; a slight decrease was observed among urinary tract infections. Among the CREs, an increase in E. cloacae, K. aerogenes, and less common Enterobacterales species was observed. CRE isolates included 8 species in 2019/2020 and 12 species in 2021. Most CRE isolates produced KPC enzymes, mainly KPC-2 and KPC-3, but a decline was noted over time, from 73.8% in 2019 to 67. 5% in 2020 and 54.1% in 2021. Conversely, MBLs increased from 3.8% in 2019 to 18.4% in 2021. MBLs were mainly NDM-1/-5, but also IMP-27 and IMP-4. OXA-48-like enzymes without NDM were detected among 8 isolates. Overall, CAZ-AVI inhibited 86.6% of CRE isolates. When comparing the activity of 3 new BL/BLIs tested against 2021 isolates, CAZ-AVI was active against 78.6% of the CRE isolates whereas MVB inhibited 76.5% and IMI-REL inhibited 73.3%. Conclusion An increase in CREs driven by an increase in MBL-producing isolates was noted in 2021. This increase is worrisome since there are no effective therapeutic options against MBL producers. CAZ-AVI was the most active agent against CREs, but the increase in MBLs should be closely monitored. New therapies against these isolates are urgently needed. Disclosures 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 Timothy Doyle, MS, AbbVie: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: 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 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.

Background Coagulase-negative staphylococci (CoNS) is a common organism group implicated in catheter-related bloodstream infection (BSI) and infective endocarditis. Prompt appropriate antimicrobial therapy is crucial for suspected or confirmed invasive infections. The in vitro activity of oritavancin (ORI) and comparators was evaluated against CoNS causing BSI in US medical centers. Methods 587 CoNS isolates (1/patient) were consecutively collected in 30 US centers in 2017-2019. Bacterial identification was performed by MALDI-TOF, and susceptibility testing using CLSI broth microdilution methodology in a central laboratory. CLSI breakpoints were applied for comparators and the ORI susceptible (S) breakpoint for S. aureus (≤0.12 mg/L) was used for in vitro comparison only. Results The most common species were S. epidermidis (Sepi; 62.4%; 366), followed by S. hominis (Shom; 13.1%; 77), S. capitis (Scap; 7.3%; 43), S. lugdunensis (Slug; 5.1%; 30), and S. haemolyticus (Shae; 4.3%; 25). 12 other species represented < 10 (1.5%) isolates each. Overall, 59.1% of isolates were methicillin-resistant (MR), with the highest rate in Sepi (73.2%), followed by Shae (68.0%), Shom (46.8%), and Scap (30.2%). No MR isolates were detected in Slug. ORI (MIC50/90, 0.06/0.12 mg/L) inhibited 96.1% of CoNS at ≤0.12 mg/L. Linezolid (LZD; MIC50/90, 1/1 mg/L; 96.4%S), daptomycin (DAP; MIC50/90, 0.25/0.5 mg/L; 100%S), and vancomycin (VAN; MIC50/90, 1/2 mg/L; 100%S) were also active against CoNS. ORI displayed similar MIC50 (0.03-0.06 mg/L) and MIC90 (0.12-0.25 mg/L) values against Sepi, Shom, Scap, and Shae, and inhibited 96.0%, 96.1%, 97.7%, and 84.0% of these isolates at ≤0.12 mg/L, respectively. All Slug isolates were inhibited by ORI at ≤0.015 mg/L. ORI inhibited 94.8% of all MRCoNS at ≤0.12 mg/L, and 95.5%, 94.4%, 92.3%, and 82.4% of MR Sepi, Shom, Scap, and Shae species, respectively. VAN, DAP, and LZD inhibited 100.0%, 100.0%, and 93.9% of MRCoNS isolates at their susceptible breakpoints, respectively. Conclusion ORI was highly active and inhibited ≥96% of all CoNS and individual species ( >10 isolates) at ≤0.12 mg/L, regardless of methicillin profile, except for Shae. VAN, DAP, and LZD were also active against CoNS causing BSI in US medical centres. Disclosures Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support 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 Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: 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.

Background Patients undergoing hematologic, oncologic, and/or transplant treatment are at risk for infections. Appropriate antimicrobial management is crucial for patients with suspected or confirmed bloodstream infections (BSI). We evaluated the in vitro activity of oritavancin (ORI) and comparators against Gram-positive (GP) isolates causing BSI in patients from hematology/oncology and transplant units (HTU) in US medical centers. Methods 1,217 isolates (1/patient) were consecutively collected from HTU patients in 33 US hospitals during 2010-2019. Isolates were identified by MALDI-TOF and/or standard microbiological testing methods, and susceptibility (S) tested by CLSI reference broth microdilution in a central laboratory. CLSI breakpoints were applied. Results Enterococcus spp. (overall, 36.1%; E. faecium [EFM], 20.2%; E. faecalis [EF], 14.3%) and S. aureus (SA, 35.7%; 36.4% methicillin-resistant [MRSA]) were the most common organism groups, followed by coagulase-negative Staphylococcus (CoNS; 11.8%; 76.4% MR), Viridans group streptococci (VHS; 9.6%), and beta-haemolytic streptococci (BHS; 3.5%). ORI inhibited 96.7%/98.9% of EFM/EF at ≤0.12mg/L (S breakpoint for vancomycin [VAN]-S EF). Ampicillin (100.0%S), linezolid (LZD; 100.0%S), daptomycin (DAP; 98.3%S), and VAN (97.1%S) were also active against EF. Only ORI (96.7%S) and LZD (100.0%S) remained active against EFM. A VRE phenotype and elevated daptomycin MIC (2-4 mg/L) were noted in 72.8% and 55.3% of EFM, with ORI inhibiting 95.5% and 95.6% of these isolates at ≤0.12mg/L, respectively. ORI displayed equivalent MIC50/90 (0.03/0.06 mg/L) values against MSSA (99.3%S) and MRSA (99.4%S). ORI inhibited 95.5% of MRCoNS at ≤0.12mg/L (SA breakpoint). VAN, DAP, and LZD remained active against MRSA and MRCoNS. ORI was also active against BHS (MIC50/90, 0.03/0.25 mg/L; 95.2%S) and VGS (MIC50/90, 0.015/0.25 mg/L; 96.6%S) as was VAN (100.0%), DAP (100.0%), and LZD (100.0%/99.1%S, respectively). Conclusion VRE EFM, MRCoNS, and MRSA rates were generally high in BSI GP isolates recovered from patients in HTU. ORI was highly active and inhibited > 95% of isolates at MIC of ≤ 0.12mg/L from this unique collection, including R subsets such as VAN-R EFM, EFM displaying elevated DAP MIC (2-4 mg/L), MRSA, and MRCoNS. Disclosures Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: 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 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.

Background Aztreonam-avibactam (ATM-AVI) is being developed to treat infections caused by Gram-negative bacteria. We evaluated the in vitro activities of ATM-AVI and comparators against a global (ex-US) collection of carbapenem-resistant Enterobacterales (CRE), including ceftazidime-avibactam (CAZ-AVI) resistant (R) isolates. Methods 24,924 isolates were consecutively collected (1/patient) from 69 medical centers in 36 countries in 2019-2021. Isolates were susceptibility tested by CLSI broth microdilution and CRE isolates (n=1,098; 4.4%) were further evaluated. CRE isolates were from Europe (EU; n=681), Latin America (LATAM; n=240) and Asia-Pacific region (APAC; n=177). An ATM-AVI PK/PD breakpoint of ≤8 mg/L was applied for comparison. CRE isolates from 2019-2020 were screened for carbapenemase (CPE) genes by whole genome sequencing (WGS). Susceptibility results were stratified by geography and CPE gene. Results ATM-AVI inhibited 99.6% of CREs at ≤ 8 mg/L (MIC50/90, 0.25/0.5 mg/L), including 98.9% (345/349) of CAZ-AVI-R isolates (Table). ATM-AVI activity was consistent across geographic regions (98.9-100.0% inhibited at ≤8 mg/L), but susceptibility to comparators varied markedly. Susceptibility rates for CAZ-AVI, meropenem-vaborbactam and imipenem-relebactam were 73.6%, 59.1% and 55.5% in EU, 74.1%, 78.3% and 68.0% in LATAM, and 38.6%, 39.8% and 31.4% in APAC, respectively. The most active comparator was tigecycline (MIC50/90, 0.5/2 mg/L; 93.4% susceptible [S]). ATM-AVI retained activity against isolates non-S to colistin (99.7% inhibited at ≤ 8 mg/L) or tigecycline (98.6% inhibited at ≤8 mg/L). A CPE gene was identified in 608 of 692 isolates (87.9%) submitted to WGS. The most common CPEs were KPC (40.9% of CREs), NDM (26.9%), and OXA-48-like (20.1%); 37 isolates (5.3%) had > 1 CPE gene. ATM-AVI inhibited 100.0% of CPE-producers at ≤ 8 mg/L independent of CPE type or geography, whereas current available β-lactamase inhibitors combinations exhibited limited activity against isolates producing MBL or OXA-48-like. Conclusion ATM-AVI activity was not adversely affected by clinically relevant CPEs. Our results support the development of ATM-AVI to treat infections caused by CRE, including MBL producers. 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 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 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.

Although a large part of the genome is transcribed, only 1.9% has a protein-coding potential; most of the transcripts are non-coding RNAs such as snRNAs, tRNAs, and rRNAs that participate in mRNA processing and translation. In addition, there are small RNAs with a regulatory role, such as siRNAs, miRNAs, and piRNAs. Finally, the long non-coding RNAs (lncRNAs) are transcripts of more than 200 bp that can positively and negatively regulate gene expression (both in cis and trans), serve as a scaffold for protein recruitment, and control nuclear architecture, among other functions. An essential process regulated by lncRNAs is genome stability. LncRNAs regulate genes associated with DNA repair and chromosome segregation; they are also directly involved in the maintenance of telomeres and have recently been associated with the activity of the centromeres. In cancer, many alterations in lncRNAs have been found to promote genomic instability, which is a hallmark of cancer and is associated with resistance to chemotherapy. In this review, we analyze the most recent findings of lncRNA alterations in cancer, their relevance in genomic instability, and their impact on the resistance of tumor cells to anticancer therapy.

Recently, porphyrin units have been attached to graphene nanoribbons (Por-GNR) enabling a multitude of possible structures. Here we report first principles calculations of two prototypical, experimentally feasible, Por-GNR hybrids, one of which displays a small band gap relevant for its use as electrode in a device. Embedding a Fe atom in the porphyrin causes spin polarization with a spin ground state $S=1$. We employ density functional theory and nonequilibrium Green's function transport calculations to examine a 2-terminal setup involving one Fe-Por-GNR between two metal-free, small band gap, Por-GNR electrodes. The coupling between the Fe-$d$ and GNR band states results in a Fano anti-resonance feature in the spin transport close to the Fermi energy. This feature makes transport highly sensitive to the Fe spin state. We demonstrate how mechanical strain or chemical adsorption on the Fe give rise to a spin-crossover to $S=1$ and $S=0$, respectively, directly reflected in a change in transport. Our theoretical results provide a clue for the on-surface synthesis of Por-GNRs hybrids, which can open a new avenue for carbon-based spintronics and chemical sensing.

We present a joint experimental and theoretical study of parametric resonance of spin wave eigenmodes in Ni$_{80}$Fe$_{20}$/Pt bilayer nanowires. Using electrically detected magnetic resonance, we measure the spectrum of spin wave eigenmodes in transversely magnetized nanowires and study parametric excitation of these eigenmodes by a microwave magnetic field. We also develop an analytical theory of spin wave eigenmodes and their parametric excitation in the nanowire geometry that takes into account magnetic dilution at the nanowire edges. We measure tuning of the parametric resonance threshold by antidamping spin Hall torque from a direct current for the edge and bulk eigenmodes, which allows us to independently evaluate frequency, damping and ellipticity of the modes. We find good agreement between theory and experiment for parametric resonance of the bulk eigenmodes but significant discrepancies arise for the edge modes. The data reveals that ellipticity of the edge modes is significantly lower than expected, which can be attributed to strong modification of magnetism at the nanowire edges. Our work demonstrates that parametric resonance of spin wave eigenmodes is a sensitive probe of magnetic properties at edges of thin-film nanomagnets., Comment: 24 pages, 9 figures