SENTRY Antimicrobial Surveillance Program Research Articles

7-Year (2015-21) longitudinal surveillance of lefamulin in vitro activity against bacterial pathogens collected worldwide from patients with respiratory tract infections including pneumonia and characterization of resistance mechanisms.

Lefamulin (Xenleta™), a pleuromutilin antibiotic, was approved for the oral and IV treatment of community-acquired bacterial pneumonia (CABP) in adults in 2019/2020. This study evaluated the in vitro activity of lefamulin and comparators against 19 584 unique bacterial isolates collected from patients with community-acquired respiratory tract infections and hospitalized patients with pneumonia within the global SENTRY Antimicrobial Surveillance Program during 2015-21. Isolates were susceptibility tested by the CLSI broth microdilution method, and resistance mechanisms were investigated in isolates with elevated lefamulin MICs. Lefamulin exhibited potent antibacterial activity against the most common and typical CABP pathogens tested, including Streptococcus pneumoniae [MIC50/90, 0.06/0.25 mg/L; 99.9% susceptible (S)], Staphylococcus aureus (MIC50/90, 0.06/0.12 mg/L; 99.6% S), Haemophilus influenzae (MIC50/90, 0.5/2 mg/L; 99.1% S) and Moraxella catarrhalis (MIC50/90, 0.06/0.12 mg/L; 100.0% S). Potent activity was also observed against the less common pneumonia pathogens: β-haemolytic (MIC50/90 of 0.03/0.06 mg/L) and viridans group Streptococcus spp. (MIC50/90 of 0.06/0.25 mg/L) and Haemophilus parainfluenzae (MIC50/90 of 1/4 mg/L). Lefamulin's activity was not adversely affected by resistance to macrolides, penicillin, tetracyclines, fluoroquinolones and other resistance phenotypes. Non-susceptibility/resistance to lefamulin was rare and primarily determined by ribosomal protection through vga(A) variants in S. aureus, overexpression of AcrAB-TolC efflux pump in H. influenzae or modifications in L3, L4 and 23SrRNA in Streptococcus spp. Based on the coverage of the most important CABP pathogens and lacking cross-resistance, lefamulin may represent a valuable empirical treatment option for ambulatory and hospitalized patients with CABP, particularly in settings with high prevalence of resistance.

2172. Activity of Cefiderocol and Comparator Agents Against Molecularly Characterized Multidrug-resistant Enterobacterales Clinical Isolates from United States Hospitals (2020–2022)

Abstract Background Cefiderocol (CFDC) is a siderophore cephalosporin that hijacks the iron transport system of Gram-negative bacteria 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 US SENTRY Antimicrobial Surveillance Program. Methods 11,884 ENT were collected from 33 sites in the USA in 2020–2022. Susceptibility (S) testing was performed by broth microdilution. CFDC testing utilized iron-depleted media. CLSI breakpoints were used. E. coli, K. pneumoniae, and P. mirabilis with ceftriaxone, ceftazidime, or aztreonam MIC ≥ 2 μg/mL plus any ENT displaying an MIC ≥ 2 μg/mL for imipenem (excluding P. mirabilis, P. penneri, and indole-positive Proteeae) or meropenem (MER) were subjected to genome sequencing and screening of β-lactamase genes. Results CFDC (99.8%S), imipenem-relebactam (IMR; 98.0%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; 97.6%S) and CZA (MIC50/90, 1/8 μg/mL; 91.5%S) were the most active agents against carbapenem-nonS isolates, whereas IMR (MIC50/90, 0.25/4 μg/mL; 81.2%S) and MEV (MIC50/90, 0.12/8 μg/mL; 87.9%S) had suboptimal activity. CFDC (MIC50/90, 0.5/4 μg/mL), IMR (MIC50/90, 0.12/0.5 μg/mL), MEV (MIC50/90, 0.03/1 μg/mL), and CZA (MIC50/90, 1/2 μg/mL) were active (98.7–100%S) against the KPC subset. CFDC (MIC, 2/4 μg/mL; 90.9%S) was also active against ENT carrying MBL genes, whereas CFDC (MIC, 0.5-2 μg/mL; 100%S) and CZA (0.5-4 μg/mL; 100%S) were active against isolates carrying blaOXA-48–like. Conclusion CFDC activity against ENT was consistent, regardless of isolate 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 emphasize 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|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 John H. Kimbrough, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Dee Shortridge, PhD, Melinta: Grant/Research Support|Shionogi: Grant/Research Support 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

2761. Activity of Cefiderocol and Comparator Agents Against Achromobacter and Burkholderia Isolates, Collected During 2020-2022 as Part of SENTRY Antimicrobial Surveillance Program

Abstract Background Achromobacter and Burkholderia species are opportunistic pathogens in individuals with an immunodeficiency, most notably cystic fibrosis. Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria. In this study, the activity of CFDC and comparator agents was determined against isolates of Achromobacter and Burkholderia cepacia species complex, collected in 2020–2022 in Europe and the USA as part of the SENTRY antimicrobial surveillance program. Activity of cefiderocol and comparator agents against Achromobacter and Burkholderia Isolates Methods Minimum inhibitory concentrations (MICs) were determined according to CLSI guidelines against 167 Achromobacter and 160 Burkholderia cepacia species complex isolates, using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparator agents and iron-depleted CAMHB for CFDC. Comparator agents included β-lactam/β-lactamase inhibitor combinations ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam, piperacillin-tazobactam, as well as meropenem, ceftazidime, levofloxacin, amikacin, trimethoprim-sulfamethoxazole, and minocycline. Susceptibility was assessed for agents with CLSI breakpoints. For agents without established CLSI breakpoints, only MIC50, MIC90 and MIC ranges were reported. Results CFDC was the most potent agent tested against Achromobacter, showing MIC50 and MIC90 values of 0.03 and 0.25 µg/mL and all isolates were inhibited at ≤4 µg/mL (Table). Isolates from cystic fibrosis patients (n=15) showed higher MIC50 and MIC90 values for most agents, but CFDC MIC50 and MIC90 values remained low (0.06 and 0.25 µg/mL, respectively). Against Burkholderia cepacia species complex, CFDC was the most potent agent tested, with MIC50 and MIC90 values of 0.06 and 0.5 µg/mL, and 156 out of 160 isolates inhibited at ≤4 µg/mL. None of the comparator agents showed >90% susceptibility against these isolates (Table). Conclusion CFDC showed potent activity against a set of contemporary clinical Achromobacter and Burkholderia cepacia species complex isolates. These in vitro data suggest that CFDC could be an important treatment option for infections caused by these opportunistic pathogens. Disclosures Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: 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 Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee

2790. Activity of Cefiderocol and Comparator Agents Against Pediatric Isolates of Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii-calcoaceticus species complex, and Stenotrophomonas maltophilia from the SENTRY Surveillance Program (2020-2022)

Abstract Background Cefiderocol (CFDC) is a siderophore cephalosporin with broad activity against Gram-negative bacteria including multi-drug resistant isolates. The in vitro activity of CFDC and comparator agents was evaluated against pediatric (0-17 years old) isolates collected in 2020–2022 as part of the SENTRY Antimicrobial Surveillance Program. In vitro Activity of Cefiderocol and Comparator Agents Against Pediatric Isolates Methods 2,249 Enterobacterales (ENT), 707 P. aeruginosa, 194 Acinetobacter baumannii-calcoaceticus complex (ABC) and 220 S. maltophilia from the USA and Europe were tested for susceptibility (%S) by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB). Iron-depleted CAMHB was applied for CFDC. Comparators included newer β-lactam/β-lactamase inhibitor (BL/BLI) combinations ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam (I-R) and meropenem-vaborbactam (MVB) as well as ampicillin/sulbactam (SAM) meropenem (MEM) and colistin (CST). %S was interpreted according to 2023 CLSI & EUCAST breakpoints. Carbapenem non-susceptible (CarbNS) was defined as non-susceptibility to imipenem and MEM. Results All agents displayed >96 %S for ENT while CFDC (MIC50/90, 2/4 mg/L; 91.7 %S) was the most active agent against CarbNS ENT. P. aeruginosa susceptibilities to CFDC and BL/BLI combinations were >97.0%. CFDC was the most potent agent against CarbNS P. aeruginosa with MIC50/90 values of 0.12/0.25 mg/L and 100 %S & 98.5 %S per CLSI & EUCAST breakpoints, respectively. ABC susceptibility to CFDC was >97% per CLSI & EUCAST while the susceptibility for MEM was 87.1% (CLSI & EUCAST) and SAM was 80.9% (CLSI). CFDC (MIC50/90, 0.25/1 mg/L; 95.7 %S) displayed better in vitro potency in CarbNS ABC as compared to SAM (MIC50/90, 32/ >64 mg/L; 17.4 %S CLSI) and CST (MIC50/90, 0.5/ >8 mg/L; 78.3%S EUCAST). Among pediatric S. maltophilia, CFDC was the most active agent with MIC50/90, 0.06/0.25 and 100 %S per CLSI & EUCAST breakpoints. Conclusion CFDC was a highly active β-lactam against contemporary pediatric isolates of Enterobacterales, P. aeruginosa, ABC, and S. maltophilia, including CarbNS subsets for which treatment options are limited. These data suggest CFDC may be a valuable treatment for serious Gram-negative infections in pediatric patients. Disclosures Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Anne Henriksen, PhD, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: 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 Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee

2762. Activity of Cefiderocol and Comparator Agents Against Difficult to Treat Resistance (DTR) Gram-negative Isolates, Collected During 2020-2022 as Part of SENTRY Antimicrobial Surveillance Program

Abstract Background Difficult to Treat Resistant (DTR) Gram-negative isolates show treatment-limiting resistance to all first-line agents; β-lactams and fluoroquinolones. Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with a unique mode of entry into bacteria, showing good activity against Gram-negative bacteria. Here, susceptibility of CFDC and comparator agents was determined against DTR isolates of Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus species complex (ABC). Activity of Cefiderocol and Comparator Agents Against Difficult to Treat Resistance (DTR) Gram-negative Isolates Methods Minimum inhibitory concentrations were determined according to CLSI guidelines against 24,084 Enterobacterales, 7,310 P. aeruginosa, and 2,479 ABC isolates, collected in 2020–2022 in Europe and the USA as part of the SENTRY program, using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparator agents and iron-depleted CAMHB for CFDC. Susceptibility was assessed according to CLSI, EUCAST and FDA breakpoints (BPs). DTR was defined as being non-susceptible, using CLSI BPs, to fluoroquinolones and β-lactams, except for CFDC and β-lactam/β-lactamase inhibitor (BL/BLI) combinations. Results 1.6% (n=387) of the Enterobacterales isolates showed the DTR phenotype, the majority being K. pneumoniae (n=332; 85.8%). The isolates showed high susceptibility to CFDC (95.3% and 81.1% using CLSI/FDA or EUCAST BPs, respectively). Comparator agents, including novel BL/BLI combinations, showed susceptibility of < 80%, except for tigecycline (94.1%, FDA BPs). For P. aeruginosa 4.1% (n=299) showed the DTR phenotype, of which 98.3%, 97.7%, and 89.6% were susceptible to CFDC, according to CLSI, EUCAST and FDA BPs respectively. Colistin was also active (99.7% susceptible, EUCAST BPs) whereas other agents, including novel BL/BLI combinations, had susceptibility of < 65%. Amongst ABC, 47.1% (n=1167) showed the DTR phenotype, and 96.2%, 93.8%, and 89% were susceptible to CFDC according to CLSI, EUCAST and FDA BPs, respectively. Susceptibility to comparator agents was < 40%, except for colistin (81.2%, EUCAST BPs). Conclusion DTR isolates remained susceptible to CFDC, indicative of a low degree of cross resistance with β-lactams, including BL/BLI combinations, and fluoroquinolones. Disclosures Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: 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 Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee

Trends in the susceptibility of U.S. Acinetobacter baumannii-calcoaceticus species complex and Stenotrophomonas maltophilia isolates to minocycline, 2014-2021.

Acinetobacter baumannii-calcoaceticus species complex (ACB) and Stenotrophomonas maltophilia (SM) are opportunistic, non-fermentative organisms that can cause serious hospital-acquired infections in immunocompromised patients. These pathogens are inherently resistant to several common drug classes and often acquire other resistance mechanisms, making them difficult to treat. In this study, we analyzed the susceptibility of 1,029 contemporary ACB and 1,522 SM isolates to minocycline (MIN) and levofloxacin (LEV) as well as meropenem (MER) for ACB and trimethoprim-sulfamethoxazole (TMP/SMX) for SM using the CLSI broth microdilution method. Isolates were collected as a part of the SENTRY Antimicrobial Surveillance Program from 2014 to 2021. Pneumonia in hospitalized patients was the most common infection from which ACB (57.0%) and SM (73.9%) were isolated. MIN had the highest in vitro activity for ACB (86.2%) and SM (99.5%). The activity of ACB and SM to all three agents varied over the period studied. MIN activity to ACB decreased in 2020 (80.6%) but rebounded in 2021 (86.2%). LEV and MER showed an overall trend of increasing susceptibility for ACB, with slightly lower activity in 2020-2021. MIN and TMP/SMX (>98.3% and >93.7%, respectively) activities were stable against SM isolates. LEV activity decreased from 84.3% (2015) to 69.2% (2018). The activity of MIN remained stable and higher than other agents tested for both ACB and SM, pathogens that have limited therapeutic alternatives. These in vitro data suggest that MIN is a useful treatment option for infections caused by ACB or SM.IMPORTANCEAcinetobacter baumannii-calcoaceticus species complex and Stenotrophomonas maltophilia are opportunistic, non-fermentative Gram-negative organisms that can cause serious hospital-acquired infections in immunocompromised patients. These pathogens are inherently resistant to several common drug classes and often acquire other resistance mechanisms, making them difficult to treat. In this study, we analyzed the trends of susceptibility of over 2,500 U.S. bacterial isolates collected from hospitalized patients over an 8-year period to minocycline, which is used to treat infections caused by these pathogens. These in vitro data suggest that minocycline is a useful treatment option for infections caused by Acinetobacter baumannii-calcoaceticus species complex or Stenotrophomonas maltophilia.

Association of health, nutrition, and socioeconomic variables with global antimicrobial resistance: a modelling study

Although antimicrobial use is a key selector for antimicrobial resistance, recent studies have suggested that the ecological context in which antimicrobials are used might provide important factors for the prediction of the emergence and spread of antimicrobial resistance. We used 1547 variables from the World Bank dataset consisting of socioeconomic, developmental, health, and nutritional indicators; data from a global sewage-based study on antimicrobial resistance (abundance of antimicrobial resistance genes [ARGs]); and data on antimicrobial usage computed from the ECDC database and the IQVIA database. We characterised and built models predicting the global resistome at an antimicrobial class level. We used a generalised linear mixed-effects model to estimate the association between antimicrobial usage and ARG abundance in the sewage samples; a multivariate random forest model to build predictive models for each antimicrobial resistance class and to select the most important variables for ARG abundance; logistic regression models to test the association between the predicted country-level antimicrobial resistance abundance and the country-level proportion of clinical resistant bacterial isolates; finite mixture models to investigate geographical heterogeneities in the abundance of ARGs; and multivariate finite mixture models with covariates to investigate the effect of heterogeneity in the association between the most important variables and the observed ARG abundance across the different country subgroups. We compared our predictions with available clinical phenotypic data from the SENTRY Antimicrobial Surveillance Program from eight antimicrobial classes and 12 genera from 56 countries. Using antimicrobial use data from between Jan 1, 2016, and Dec 31, 2019, we found that antimicrobial usage was not significantly associated with the global ARG abundance in sewage (p=0·72; incidence rate ratio 1·02 [95% CI 0·92-1·13]), whereas country-specific World Bank's variables explained a large amount of variation. The importance of the World Bank variables differed between antimicrobial classes and countries. Generally, the estimated global ARG abundance was positively associated with the prevalence of clinical phenotypic resistance, with a strong association for bacterial groups in the human gut. The associations between bacterial groups and ARG abundance were positive and significantly different from zero for the aminoglycosides (three of the four of the taxa tested), β-lactam (all the six microbial groups), fluoroquinolones (seven of nine of the microbial groups), glycopeptide (one microbial group tested), folate pathway antagonists (four of five microbial groups), and tetracycline (two of nine microbial groups). Metagenomic analysis of sewage is a robust approach for the surveillance of antimicrobial resistance in pathogens, especially for bacterial groups associated with the human gut. Additional studies on the associations between important socioeconomic, nutritional, and health factors and antimicrobial resistance should consider the variation in these associations between countries and antimicrobial classes. EU Horizon 2020 and Novo Nordisk Foundation.

Oritavancin in vitro activity against Gram-positive organisms from European medical centers: a 10-year longitudinal overview from the SENTRY Antimicrobial Surveillance Program (2010–2019)

To assess oritavancin in vitro activity against clinically relevant Gram-positive pathogens in European (EU) hospitals, a total of 51,531 consecutive and unique clinical isolates collected in 2010–2019 were evaluated. All isolates were tested by CLSI broth microdilution methods. The key resistance phenotypes differed considerably between Eastern Europe (E-EU) and Western Europe (W-EU), respectively: methicillin-resistant (MR) Staphylococcus aureus 27.7%/22.9%; multidrug resistant (MDR) S. aureus, 19.7%/15.2%; MR coagulase-negative staphylococci, 77.3%/61.9%; vancomycin-resistant enterococci (E. faecium), 44.2%/20.9%; and MDR E. faecium, 63.8%/55.4%. There were no substantive differences in oritavancin minimum inhibitory concentration (MIC) values for the different species/organism groups over time or by EU region. Oritavancin inhibited 99.9% and 99.1% of all S. aureus and coagulase-negative staphylococci at 0.12 mg/L, respectively, and all isolates of E. faecalis and E. faecium at ≤0.5 mg/L. Oritavancin susceptibility rates against β-hemolytic and Viridans group streptococci isolates were 98.1% and 99.4%, respectively. Oritavancin had potent activity in vitro against this contemporary collection of European Gram-positive isolates from 2010 to 2019.

Endemicity of Pseudomonas aeruginosa producing IMP-18 and/or VIM-2 MBLs from the high-risk clone ST111 in Central America.

Pseudomonas aeruginosa is an important cause of serious nosocomial infections. Despite the overall genetic diversity of this species, highly conserved clonal complexes (CCs) have been observed among MDR isolates. Many of these CCs are associated with MBL-producing isolates. To evaluate five P. aeruginosa isolates from Central America that carried IMP-18- and/or VIM-2-encoding genes from the SENTRY Antimicrobial Surveillance Program (2017-2018). Susceptibility testing was performed by broth microdilution (CLSI). WGS was performed using MiSeq (Illumina) and MinION (Oxford Nanopore). Assembled contigs from short and long reads were combined for in silico screening of resistance genes, MLST, core genome (cg)MLST and SNP analysis. The P. aeruginosa isolates were collected in Panama and Mexico from patients with urinary tract infections or pneumonia. Isolates were categorized as XDR (CLSI/EUCAST). All isolates belonged to ST111 but carried different combinations of resistance-encoding genes. Transposon-associated MBL genes, blaIMP-18 and/or blaVIM-2, were chromosomally located. blaIMP-18 was detected in an In1666 integron whereas blaVIM-2 was embedded in an In59-like integron. Isolates were closely related based on cgMLST (average allele distance 2-34) and SNP analysis (5-423 different SNPs). MBL-producing ST111 P. aeruginosa have become endemic in Panama and may have spread to Mexico via clonal dissemination. Recombination events are apparent in the evolution of this CC. Surveillance is warranted to track the expansion and movement of this clone.

Correction to: In vitro activity of sulopenem and comparator agents against Enterobacterales and anaerobic clinical isolates collected during the SENTRY Antimicrobial Surveillance Program

Correction to: <i>In vitro</i> activity of sulopenem and comparator agents against Enterobacterales and anaerobic clinical isolates collected during the SENTRY Antimicrobial Surveillance Program

In vitro activity of sulopenem and comparator agents against Enterobacterales and anaerobic clinical isolates collected during the SENTRY Antimicrobial Aurveillance Program.

Physicians must leverage several factors when making antibiotic therapy decisions, including route of administration and duration of therapy. Oral administration provides several potential advantages including increased accessibility, prevention of hospitalizations and earlier discharges. Sulopenem-a broad-spectrum, synthetic penem β-lactam agent-uniquely possesses both oral and IV formulations along with noted stability among antimicrobial-resistant subsets. This study evaluated the in vitro activity of sulopenem and comparator agents against contemporary Enterobacterales and anaerobic clinical isolates predominantly from patients with bloodstream, intra-abdominal and urinary tract infections. A contemporary collection of 1647 Enterobacterales and 559 anaerobic isolates was assembled from medical centres in Europe and the USA. Isolates were susceptibility tested using the CLSI reference methods: broth microdilution for Enterobacterales and agar dilution for anaerobes. Sulopenem demonstrated potent in vitro antimicrobial activity (MIC50/90, 0.03/0.25 mg/L) against Enterobacterales isolates regardless of infection type, inhibiting 99.2% of isolates at ≤1 mg/L. This activity was conserved against resistant phenotypes including ESBL-phenotype Escherichia coli (MIC50/90, 0.03/0.06 mg/L) and ESBL-phenotype Klebsiella pneumoniae (MIC50/90, 0.06/1 mg/L). Sulopenem maintained activity against ciprofloxacin-, nitrofurantoin- and trimethoprim/sulfamethoxazole-non-susceptible subsets (MIC50/90, 0.03-0.06/0.12-0.5 mg/L). Against anaerobic isolates, sulopenem (98.9% inhibited at ≤4 mg/L) and meropenem [98.4% susceptible (CLSI)] were the most active compounds tested. The potent in vitro activity of sulopenem against this large collection of recent Enterobacterales and anaerobic clinical isolates from multiple infection types supports its further clinical evaluation in the treatment of intra-abdominal and urinary tract infections.

1711. In Vitro Activity of Cefiderocol Against US Achromobacter spp. and Burkholderia spp. Clinical Isolates from the SENTRY Surveillance Program 2020-2021

Abstract Background Infections caused by Achromobacter spp. and Burkholderia spp. have limited clinical treatment options due to the intrinsic resistance of these non-fermenters to several antimicrobial agents. These pathogens are known to cause severe nosocomial infections such as bloodstream infections and pneumonia in immunocompromised patients. Cefiderocol (CFDC) is a siderophore cephalosporin antibiotic approved in the US and Europe, with potent activity against Gram-negative bacteria including carbapenem-resistant strains. We evaluated the in vitro activity of CFDC and comparator agents against Achromobacter spp. and Burkholderia spp. clinical isolates, collected from hospitalized patients in US medical centers as part of the SENTRY Antimicrobial Surveillance Program. Methods Susceptibility testing for CFDC and comparators were performed by broth microdilution according to the CLSI guidance. CFDC was tested in iron-depleted cation-adjusted Mueller Hinton broth. The susceptibilities of CFDC and comparators against a total of 78 strains of Achromobacter spp. and a total of 99 strains of Burkholderia spp. isolated in the US between 2020 to 2021 were analyzed. CLSI breakpoints were used where available. Isolate identification was provided by the submitting site and confirmed at JMI Laboratories using MALDI-TOF. Results The minimum inhibitory concentration (MIC) range, MIC50/90, and susceptible rate for CFDC and comparators for Achromobacter spp. and Burkholderia spp. are shown in the Table 1 and 2, respectively. CFDC inhibited the growth of all 78 Achromobacter spp. isolates tested at ≤4 µg/mL and showed MIC90 of 0.5 μg/mL. CFDC inhibited the growth of 96% (95/99) of Burkholderia spp. isolates tested at ≤4 µg/mL and showed MIC90 of 1 μg/mL. There were 4 strains with high CFDC MIC (≥16 µg/mL), 3 of which were Burkholderia gladioli and 1 was Burkholderia multivorans. Table 1Activity of cefiderocol and comparator antimicrobial agents tested against 78 Achromobacter spp. isolates collected from medical centers in the US during 2020 and 2021Table 2Activity of cefiderocol and comparator antimicrobial agents tested against 99 Burkholderia spp. isolates collected from medical centers in the US during 2020 and 2021 Conclusion CFDC demonstrated potent in vitro activity against Achromobacter spp. and Burkholderia spp. collected in the US between 2020 and 2021, indicating that CFDC has high potential for treating infections caused by these pathogens. Disclosures Miki Takemura, n/a, Shionogi: Employee Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Christine M. Slover, PharmD, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi: Employee Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Yoshinori Yamano, PhD, Shionogi: Employee.

1677. In vitro Activity of SPR206 and Comparator Compounds against Enterobacterales Isolates Responsible for Infections in United States Hospitals

Abstract Background SPR206 is a next generation polymyxin under clinical development to treat infections, such as pneumonia, bloodstream, and urinary tract infections caused by Gram-negative (GN) multidrug-resistant (MDR) pathogens. The in vitro activity of SPR206 and comparators was 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 Enterobacterales (ENT) from US hospitals. Methods A total of 1,614 ENT recovered from clinical samples during the SENTRY Program for 2021 were included in the study. Isolates were collected from medical centers in all 9 US Census Divisions and centrally tested for susceptibility using the CLSI broth microdilution method and interpretations. Results E. coli (EC; 425) and K. pneumoniae (KP; 425) were the most common pathogens included in this surveillance study, followed by E. cloacae (215), Citrobacter spp. (120), K. oxytoca (110), S. marcescens (104), K. aerogenes (65), P. mirabilis (60), M. morganii (60), and other 11 species (30). Overall, SPR206 and colistin (COL) had MIC50 of 0.06 and 0.25 mg/L against all ENT, respectively. Indole-positive Proteae, Proteus species and Serratia spp., which are intrinsically resistant to COL (MIC values, ≥8 mg/L), also had an elevated MIC for SPR206 (MIC, ≥8 mg/L). Excluding these organisms, SPR206 (MIC50/90, 0.06/0.12 mg/L) and meropenem (MIC50/90, 0.03/0.06 mg/L) showed the lowest MIC against this ENT subset, followed by COL (MIC50/90, 0.25/0.25 mg/L) and ceftazidime-avibactam (MIC50/90, 0.12/0.5 mg/L). SPR206 (MIC50/90, 0.06/0.12 mg/L) had MIC 2- to 4-fold lower than COL (MIC50/90, 0.25/0.25 mg/L) against EC and KP. Finally, SPR206 (MIC50/90, 0.06/0.25 mg/L) showed the lowest MIC against MDR and extremely drug-resistant (XDR) isolates. Conclusion SPR206 was consistently more potent than COL against ENT pathogens causing various infections in US hospitals. SPR206 remained active against the MDR and XDR subsets, where limited intravenous options were available. These SPR206 data, combined with its favorable safety and tolerability profiles in Phase 1 studies, support the continued clinical advancement and development of SPR206. 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.

1676. Activity of SPR206 and Comparator Agents Against Pseudomonas aeruginosa and Acinetobacter baumannii Causing Infections in United States Hospitals

Abstract 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 &amp;gt;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.

1715. In Vitro Antibacterial Activity of Cefiderocol against Difficult-to-treat Resistant (DTR) Gram-negative Pathogens in United States from SENTRY Antimicrobial Surveillance Program in 2020/2021

Abstract Background Difficult-to-treat resistant (DTR) isolates are defined as resistance to all first-line high-efficacy, low-toxicity antibiotics (penicillins, cephalosporins, carbapenems and quinolones), leaving physicians with limited treatment options. Cefiderocol (CFDC) is a siderophore cephalosporin with activity against a wide variety of Gram-negative bacteria, including carbapenem-resistant Enterobacterales and non-fermenters. We evaluated the in vitro activity of cefiderocol against DTR isolates collected in United States as part of SENTRY surveillance program in 2020 and 2021. In vitro susceptibility of cefiderocol and comparator agents to DTR isolates Methods Susceptibility testing was performed by broth microdilution according to CLSI guidelines. All antibiotics were tested in cation-adjusted Mueller-Hinton broth (CAMHB) except for CFDC, for which iron-depleted CAMHB was used. Susceptibility rate (%) was determined according to CLSI breakpoints, and DTR pathogens were defined as being resistant to cefepime, ceftazidime ceftriaxone (only for Enterobacterales), imipenem, meropenem, ciprofloxacin and levofloxacin according to CLSI/FDA breakpoints. Results Among a total of 8,328 Enterobacterales, 2,241 Pseudomonas aeruginosa, and 586 Acinetobacter calcoaceticus-baumannii complex (ACB) clinical isolates from the United States, 50 Enterobacterales (0.6%), 36 P. aeruginosa (1.6%) and 114 ACB (19.5%) isolates showed a DTR phenotype, respectively. CFDC demonstrated its potent in vitro activity against these DTR isolates with MIC90 of ≤4 μg/mL with a susceptibility rate of ≥92% except for DTR ACB based on FDA breakpoint (75.4%). In contrast, MIC90s of β-lactam/β-lactamase inhibitor combination drugs showed lower activity (Table). Conclusion Cefiderocol demonstrated potent in vitro activity against DTR isolates of Enterobacterales, P. aeruginosa and ACB, indicating cefiderocol has high potential for treating infections caused by these difficult-to-treat strains. Disclosures Yoshinori Yamano, PhD, Shionogi: Employee Miki Takemura, n/a, Shionogi: Employee Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Christine M. Slover, PharmD, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi: Employee Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant.

2036. Dual VIM-producing Proteus mirabilis, Including a Novel VIM-75, Among Elderly Patients in a Medical Center from Hungary: Report from the 2020 SENTRY Antimicrobial Surveillance Program

Abstract Background Nonsusceptibility of Proteus mirabilis to imipenem allows this pathogen evade surveillance for carbapenemases. Metallo-beta-lactamases of the VIM family are widespread among Enterobacterales in Europe. We identified an outbreak of P. mirabilis carrying 2 VIM enzymes among elderly patients from a medical center in Hungary. Methods A total of 16 P. mirabilis isolates were received from Hungary during 2020 as part of the SENTRY Antimicrobial Surveillance Program. Isolates were susceptibility tested by the CLSI reference broth microdilution method. Carbapenem-nonsusceptible isolates were submitted to whole genome sequencing, screened for resistance mechanisms, and evaluated for core genome multi-locus sequence typing (cgMLST). Results Among the 16 P. mirabilis isolates from Hungary, 5 carbapenem-nonsusceptible, multidrug-resistant isolates (3 from urinary tract infections and 1 each from bloodstream infection and pneumonia) were identified from patients 66-92 years old. Four of these 5 isolates were listed as community acquired. All isolates were resistant to ceftriaxone (MIC, &amp;gt; 8 mg/L), cefepime (16- &amp;gt; 32), imipenem ( &amp;gt; 8), gentamicin ( &amp;gt; 16), levofloxacin (16- &amp;gt; 32), nitrofurantoin ( &amp;gt; 64), trimethoprim/sulfamethoxazole ( &amp;gt; 4), and plazomicin ( &amp;gt; 128), but susceptible to meropenem (0.25-0.5) and ertapenem (0.03-0.25). Isolates carried blaVIM-4 and blaVIM-75 on a class 1 integron within IS26 and separated by aac(6’)-IIc. IS26 was located on a compound plasmid carrying other resistance-encoding genes, including armA. The integron structure is identical to the blaVIM-4 and blaVIM-1-carrying integron described from a Vibrio cholerae isolated from a seagull in France in 2015 (KR262557). blaVIM-75 is a single amino acid variant (Q60R) of blaVIM-1. All isolates carried mutations in the QRDR (gyrA_S83I, parC_S84I). Based on cgMLST analysis, these 5 P. mirabilis isolates were highly similar, with only 7-19 SNPs detected. Conclusion The outbreak of multidrug-resistant P. mirabilis isolates carrying blaVIM-4 and blaVIM-75 in a Hungarian medical center is a cause of concern. Surveillance should be performed to understand the spread of and treatment options for infections caused by carbapenem-nonsusceptible P. mirabilis. Disclosures Lalitagauri M. Deshpande, PhD, Melinta: Grant/Research Support|Pfizer: Grant/Research Support Katalin Burián, MD, JMI Laboratories: Grant/Research Support Ilona Dóczi Csányi, MD, JMI Laboratories: 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.

645. Trends in the Susceptibility of US Acinetobacter baumannii-calcoaceticus Species Complex and Stenotrophomonas maltophilia Isolates to Minocycline, 2014-2021

Abstract Background Acinetobacter baumannii-calcoaceticus species complex (ACB) and Stenotrophomonas maltophilia (SM) are opportunistic, non-fermentative organisms that can cause serious hospital-acquired infections in immunocompromised patients. These pathogens are inherently resistant to several common drug classes and often acquire other resistance mechanisms, making them difficult to treat. In this study, we analyzed the susceptibility of contemporary ACB and SM isolates to minocycline (MIN), levofloxacin (LEV), meropenem (MER) for ACB, and trimethoprim-sulfamethoxazole (T/S) for SM. Isolates were collected as a part of the SENTRY Antimicrobial Surveillance Program from 2014-2021. Susceptibilities of SM and ACB to MIN and comparators, 2014-2021 Methods Isolates were collected from hospitalized patients in 35 US medical centers. Hospitals submitted 1 isolate per patient per infection episode that met local criteria for being the likely causative pathogen. Identification was performed by the submitting laboratory and confirmed by JMI Laboratories with matrix-assisted laser desorption ionization-time of flight mass spectrometry or other standard methods as required. Isolates were tested for susceptibility (S) to MIN and comparators using the CLSI broth microdilution method. All infection types were included in the analysis. CLSI (2022) breakpoints were applied. Results A total of 1,029 ACB and 1,520 SM were tested. Pneumonia in hospitalized patients was the most common infection from which ACB (57.0%) and SM (73.9%) were isolated. The %S of the agents tested against the organisms in this study are shown in the table. MIN had the highest %S for ACB (86.2%S) and SM (99.5%S). The %S of ACB and SM to all 3 agents varied over the period studied. MIN %S to ACB decreased in 2020 (80.6%) but rebounded in 2021 (86.2%). LEV and MER showed an overall trend of increasing S for ACB, with slightly lower %S in 2020-2021. SM had stable %S to MIN and T/S ( &amp;gt;98.3% and &amp;gt;93.7%, respectively). LEV varied from 84.3%S (2015) to 69.2%S (2018). Conclusion %S to MIN remained stable and higher than other agents tested for both ACB and SM, pathogens which have limited therapeutic alternatives. ACB showed &amp;lt; 6% decrease in %S to all 3 agents in 2020-2021. These in vitro data suggest that MIN is a useful treatment option for infections caused by ACB or SM. Disclosures Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: 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 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.

1675. Activity of Gepotidacin Against Escherichia coli Isolates from Community-acquired Urinary Tract Infections Collected Between 2019-2021 in the United States

Abstract 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.

641. Activity of Gepotidacin Tested Against Molecularly Characterized Escherichia coli Isolates Resistant to Commonly Used Oral Therapies for UTI in the US (2019-2020)

Abstract 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.

643. Cefiderocol In vitro Activity Against Molecularly Characterized Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus complex Clinical Isolates Causing Infection in United States Hospitals (2020-2021)

Abstract 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 (&amp;lt; 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.