Objectives:To evaluate trends in the susceptibility of clinical Enterobacterales and Pseudomonas aeruginosa from the USA to ceftolozane/tazobactam. Methods:The SMART surveillance programme collected 30 658 Enterobacterales and 7454 P. aeruginosa isolates from 37 unique clinical sites in the USA from 2016 to 2024. Nine sites contributed isolates each year. MICs were determined by broth microdilution testing and interpreted using 2025 CLSI breakpoints. Ceftolozane/tazobactam nonsusceptible Enterobacterales were examined for β-lactamase carriage. Results:Overall, 93.9% and 95.8% of clinical isolates of Enterobacterales and P. aeruginosa were susceptible to ceftolozane/tazobactam, respectively. Considering all participating sites, annual percent susceptible values for ceftolozane/tazobactam against Enterobacterales ranged from 95.3% (2018, n = 3657) to 92.0% (2024, n = 3249) with a statistically significant decreasing trend (P < 0.001; Cochran-Armitage test). Limiting analysis solely to the nine clinical sites that participated in each year confirmed this trend [range: 94.5% susceptible (2019, n = 1609) to 91.4% susceptible (2024, n = 1544); P = 0.007]. Including all sites, P. aeruginosa percent susceptible values for ceftolozane/tazobactam remained consistent from 2016 (95.0%) to 2024 (95.0%) [range: 94.5% (2017, n = 991) to 96.9% (2020, n = 817)]. However, considering solely the consistently contributing sites, the rate of ceftolozane/tazobactam susceptibility increased [P = 0.013; range: 91.9% (2017, n = 371) to 96.4% (2024, n = 391)]. The incidence of NDM metallo-β-lactamase and CTX-M ESBLs among ceftolozane/tazobactam nonsusceptible Enterobacterales each exhibited a statistically significant increasing trend. Conclusions:From 2016 to 2024, ceftolozane/tazobactam activity against US P. aeruginosa remained consistently high; however, a trend of marginally decreasing susceptibility to ceftolozane/tazobactam among Enterobacterales was observed, likely associated with increased incidence of NDM- and CTX-M-producers.

Taniborbactam is a novel broad-spectrum β-lactamase inhibitor with inhibitory activity against both serine- and metallo-β-lactamases. Taniborbactam restores the activity of cefepime (FEP) against many difficult to treat organisms, including cephalosporin- and carbapenem-resistant Enterobacterales (EB) and Pseudomonas aeruginosa (PA). The activities of cefepime-taniborbactam (FTB) and comparators were evaluated against nonsusceptible (NS)/resistant (R) clinical isolates of EB and PA collected for the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) program. MICs of FTB (with taniborbactam fixed at 4 µg/mL) and comparators were determined by broth microdilution (CLSI M07Ed12) against EB (n=23,624) and PA (n=9,427) collected from 351 clinical sites in 62 countries from 2018-2023. For FTB, a provisional susceptible breakpoint of ≤16 µg/mL was used for comparative purposes. NS/R phenotypes were based on 2025 CLSI breakpoints (EUCAST breakpoint for meropenem-vaborbactam [MEV] against PA). Multidrug R (MDR) was defined as R to sentinel agents from ≥3 drug classes. Similar percentages (15.7%) of EB isolates were R to FEP and piperacillin-tazobactam (TZP), (Table). FTB had potent activity against all EB (MIC90, 0.25 µg/mL; 99.5% inhibited at ≤16 µg/mL). FTB maintained activity against >90% of meropenem (MEM)-NS, and ceftolozane-tazobactam (CT)-R EB, and >80% of MEV- and ceftazidime-avibactam (CZA)-R isolates. FTB at ≤16 µg/mL inhibited 96.6% of EB identified as MDR. FTB was the most active agent against PA overall (MIC90, 8 µg/mL; 96.2% inhibited at ≤16 µg/mL). Among MEM-NS PA isolates, 87.2% were inhibited by FTB at ≤16 µg/mL compared to 61.0% susceptible to CT. FTB at ≤16 µg/mL inhibited 67.9% of CT-R isolates whereas 18.4% and 22.7% of these isolates were susceptible to CZA and MEV, respectively. Against MDR PA (17.4% of all PA), FTB inhibited 78.8% at ≤16 µg/mL compared to 34.5% susceptible to CT. FTB had potent in vitro activity against worldwide EB and PA, including MDR isolates and isolates R/NS to FEP, TZP, MEM, MEV, CT, and/or CZA. These data support continued development of FTB as a potential treatment option for challenging infections due to resistant Gram-negative pathogens. Mark G Wise, PhD, IHMA: Employee

The novel β-lactamase inhibitor, taniborbactam, is notable for its broad-spectrum inhibitory activity including the ability to inhibit serine-, and NDM- and VIM-type metallo-β-lactamases (MBLs). Taniborbactam potentiates cefepime against cephalosporin- and carbapenem-resistant (R) Enterobacterales (EB) and Pseudomonas aeruginosa (PA). The activities of cefepime-taniborbactam (FTB) and comparators were evaluated against a large global collection of clinical isolates of EB and PA with defined β-lactamase carriage. MICs of FTB (taniborbactam fixed at 4 µg/mL) and comparators were determined using the CLSI reference method against EB (n=23,624) and PA (n=9,427) collected from 351 clinical laboratories in 62 countries from 2018-2023 and interpreted with CLSI 2025 breakpoints. For FTB, a provisional susceptible MIC breakpoint of ≤16 µg/mL was used for comparative purposes. Organisms with FTB MIC ≥16 µg/mL, those R to meropenem, and approximately 25% of EB susceptible to meropenem, but with ceftazidime or cefepime MIC ≥2 µg/mL, were screened for acquired β-lactamases by either PCR or WGS. FTB was the only agent with activity against NDM-harboring EB (Table 1; 76.0% inhibited at ≤16 µg/mL). 94.4% of VIM-carrying EB were inhibited by FTB, 50 percentage points higher than meropenem-vaborbactam. FTB also exhibited potent activity versus KPC-, OXA-48-like-, ESBL- and AmpC-harboring isolates, with >98% of each group inhibited at ≤16 µg/mL. FTB at ≤16 µg/mL inhibited 88.9% of the carbapenemase-carrying meropenem-R EB and 93.5% of those without a carbapenemase. Against PA, FTB was the sole agent with activity versus isolates carrying VIM-type MBLs (78.9% inhibited at ≤16 µg/mL) and displayed high levels of activity against isolates carrying ESBLs, inhibiting >92% of the population of VEB-, GES- and PER- carriers (Table 2). FTB at ≤16 µg/ml inhibited 94.1% of meropenem-R PA isolates without a detected carbapenemase. Taniborbactam greatly enhanced cefepime in vitro activity against both EB and PA carrying serine- and metallo-β-lactamases. These findings support the continued development of FTB as a potential new therapeutic agent for use against β-lactamase-harboring Gram-negative pathogens. Mark G Wise, PhD, IHMA: Employee

Aztreonam-avibactam (ATM-AVI) is a β-lactam/β-lactamase inhibitor combination to treat infections caused by Gram-negative organisms, particularly those carrying metallo-β-lactamases (MBLs) and other β-lactamases. Aztreonam is stable to hydrolysis by MBLs and avibactam inhibits Class A, C, and some Class D enzymes. We examined ATM-AVI activity against Enterobacterales isolates producing one or more carbapenemase and the frequency of co-production of carbapenemases among isolates collected as a part of the ATLAS global surveillance program (2019-2023). 88,196 isolates from 226 medical centers in 56 countries (excluding mainland China, Canada, and the USA) were collected and tested for susceptibility using the broth microdilution method according to CLSI guidelines. Analysis was performed with CLSI 2024 breakpoints. Isolates testing with meropenem MIC values >1 µg/mL or Escherichia coli, Klebsiella pneumoniae, K. oxytoca, or Proteus mirabilis isolates testing with ceftazidime and/or aztreonam MIC values >2 µg/mL were screened for β-lactamase genes by PCR, which were sequenced when identified. One or more carbapenemase gene was identified in 7312 isolates. In 2019, 10% of carbapenemase-positive isolates carried two carbapenemase genes, which increased to 21% by 2023 (Figure 1). Among isolates carrying two carbapenemase genes, the blaNDM+blaOXA-48-like genotype accounted for 84%, while blaNDM+blaKPC (7%), blaVIM+blaKPC (5%) and blaNDM+blaGES (2%) were the other most common genotypes (Figure 2). ATM-AVI was active in vitro against (genotype, percent susceptible): Single-carbapenemase positive, 97.7%; multiple-carbapenemase-positive, 98.1%; blaNDM+blaOXA-48-like, 98.0%; blaNDM+blaKPC, 98.8%; blaVIM+blaKPC, 98.1%, and blaNDM+blaGES, 100% (Table 1). Enterobacterales isolates that produce multiple carbapenemases are on the rise. While the NDM+OXA-48-like combination is still dominant, a plethora of combinations has been observed. While these organisms present complex resistance patterns, ATM-AVI demonstrated potent in vitro activity against them. Katherine Perez, PhD, Pfizer: Stocks/Bonds (Public Company)

Aztreonam-avibactam (ATM-AVI) is a β-lactam/β-lactamase inhibitor combination to treat infections caused by Gram-negative organisms, particularly those carrying metallo-β-lactamases (MBLs) and other β-lactamases. Aztreonam is stable to hydrolysis by MBLs and avibactam inhibits Class A, C, and some Class D enzymes. We compared the in vitro activities of ATM-AVI and cefiderocol (FDC) against MBL-producing Enterobacterales collected as a part of the ATLAS program (2021-2022). 40,256 isolates from 208 medical centers in 56 countries (excluding Canada and the USA) were collected and tested for susceptibility using the broth microdilution method according to CLSI guidelines. EUCAST 2025 breakpoints were used for ATM-AVI and CLSI 2025 for FDC. Isolates testing with meropenem MIC values >1 µg/mL or Escherichia coli, Klebsiella pneumoniae, K. oxytoca, or Proteus mirabilis isolates testing with ceftazidime and/or aztreonam MIC values >2 µg/mL were screened for β-lactamase genes by PCR, which were sequenced when identified. WGS was used to characterize isolates collected in China. 1,024 isolates carried an MBL. Isolates carried variants of NDM (916), VIM (70), IMP (33), or a combination of these (5). ATM-AVI was active against more isolates producing MBLs of each family than FDC: NDM, 95.5% ATM-AVI-S, 85.9% FDC-S; VIM, 100% ATM-AVI-S, 92.9% FDC-S; IMP, 100% ATM-AVI-S, 97.0% FDC-S (Figure 1). Isolates that carried NDM as the sole MBL carried NDM-1 (449), NDM-5 (398), NDM-7 (31), or others (22). For isolates carrying NDM ATM-AVI was active against more isolates that carried each variant than FDC: NDM-1, 98.7% ATM-AVI-S, 81.5% FDC-S; NDM-5, 91.7% ATM-AVI-S, 91.0 FDC-S; NDM-7, 93.5% ATM-AVI-S, 87.1% FDC-S. ATM-AVI demonstrated a higher rate of in vitro potency than cefiderocol against isolates that carried MBLs of any family, including all of the most frequently identified variants of NDM. Katherine Perez, PhD, Pfizer: Stocks/Bonds (Public Company)

The β-lactamase inhibitor, avibactam, has potent inhibitory activity against Class A, Class C, and certain Class D serine β-lactamases. This study evaluated the in vitro activity of ceftazidime-avibactam (CZA) and comparators against clinical isolates of Pseudomonas aeruginosa collected for the ATLAS global surveillance program in 2019-2023 stratified by source of infection and ward. 32,105 isolates of P. aeruginosa collected from 264 medical centers in 58 countries as part of the ATLAS program from 2019-2023 (excluding North America) for which the patient location was either a general ward (n=21,430) or an ICU (n=10,675) and infection source was specified were evaluated. Infection sources included BSI (bloodstream infection), IAI (intra-abdominal infection), RTI (respiratory tract infection), SSTI (skin and soft tissue infection) and UTI (urinary tract infection). Susceptibility testing was performed by broth microdilution following the CLSI standard method and analyzed using CLSI 2024 breakpoints. Results are shown in Table 1. CZA (86.2% S) and amikacin (87.2% S) were the most active agents tested against isolates from ICUs. Against isolates from general wards, CZA (91.4% S) and amikacin (91.3% S) were the most active agents. Activity of CZA ranged from 81.7% S to 87.4% S across infection sources from ICU isolates, and 87.0% S to 92.6% S for isolates from general wards. For all agents tested, %S was higher in general wards compared to ICUs by 4.1 (amikacin) to 12.3 (meropenem) percentage points. CZA is active against all groupings of P. aeruginosa regardless of patient location or infection source. These data suggest CZA remains an excellent therapeutic choice to consider against P. aeruginosa. Katherine Perez, PhD, Pfizer: Stocks/Bonds (Public Company) Paurus Irani, MD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds (Private Company)

ObjectivesTo investigate the in vitro susceptibility of recent clinical Enterobacterales and Pseudomonas aeruginosa isolates collected in the Arabian Gulf region to ceftolozane/tazobactam, imipenem/relebactam, and comparator antimicrobial agents.MethodsFrom 2020 to 2024, two clinical laboratories in Kuwait and one each in Qatar, the United Arab Emirates, and Oman (participated in 2022–2024 only) collected up to 250 consecutive Gram-negative isolates per year from patients with bloodstream, intra-abdominal, lower respiratory tract, and urinary tract infections. MICs were determined by CLSI broth microdilution and interpreted with 2025 EUCAST breakpoints. Most imipenem, imipenem/relebactam, and ceftolozane/tazobactam non-susceptible isolates were interrogated for their acquired β-lactamase content.ResultsCeftolozane/tazobactam was active against 85.6% of the Enterobacterales (n = 3,603), including 92.0% of ESBL-positive, non-CRE (non-carbapenem-resistant Enterobacterales) phenotype Escherichia coli and 91.6% of ESBL-positive, non-CRE phenotype Klebsiella pneumoniae, but was poorly active against MDR (multiple-drug resistant) isolates (21.6% susceptible). In total, 90.6% of non-Morganellaceae Enterobacterales (n = 3,421) were imipenem/relebactam-susceptible, including 95.6% of the E. coli and 80.7% of the K. pneumoniae. Pseudomonas aeruginosa isolates (n = 1,347) were highly susceptible to both ceftolozane/tazobactam and imipenem/relebactam, with 91.2% and 89.0% inhibited, respectively. Both ceftolozane/tazobactam and imipenem/relebactam retained activity against ≥70% of cefepime-resistant, ceftazidime-resistant, and piperacillin/tazobactam-resistant P. aeruginosa. Ceftolozane/tazobactam inhibited the greatest percentage of meropenem-resistant P. aeruginosa (66.9%) among comparator β-lactam antimicrobials. Molecular characterization showed that the majority of both the imipenem/relebactam- and ceftolozane/tazobactam-resistant Enterobacterales harbored the NDM metallo-β-lactamase (MBL). Most of the imipenem/relebactam-resistant P. aeruginosa characterized did not possess acquired β-lactamases, while the majority of those resistant to ceftolozane/tazobactam carried a variety of acquired enzymes, including MBLs (IMP, VIM, NDM) and ESBLs (VEB, GES).ConclusionRecent clinical isolates of Enterobacterales collected in the Arabian Gulf region were highly susceptible to imipenem/relebactam, while both imipenem/relebactam and ceftolozane/tazobactam exhibited excellent activity against P. aeruginosa. However, the incidence of MBLs in the region remains a significant concern for future therapeutic strategies.

Ceftazidime is a third-generation cephalosporin that is available in combination with the diazabicyclooctane β-lactamase inhibitor avibactam for the treatment of complicated intra-abdominal infections, complicated urinary tract infections, and hospital/ventilator-acquired bacterial pneumonia caused by susceptible Gram-negative pathogens. Here we show the in vitro activity of ceftazidime-avibactam (CAZ-AVI) against Enterobacterales collected in Latin America for the ATLAS surveillance program (2019-2023), stratified by β-lactamase carriage. 14,792 isolates from 37 medical centers in 10 countries were collected and tested for susceptibility using the broth microdilution method according to CLSI guidelines. Analysis was performed with CLSI 2025 breakpoints. Isolates testing with meropenem MIC values >1 µg/mL or a subset of Escherichia coli, Klebsiella pneumoniae, K. oxytoca, or Proteus mirabilis isolates testing with ceftazidime and/or aztreonam MIC values >2 µg/mL were screened for β-lactamase genes by PCR, which were sequenced when identified. Isolates that carried metallo-β-lactamases (MBLs) were not susceptible to CAZ-AVI or meropenem (MEM) and were comprised mostly of NDM- (95%) or VIM-producers (3%) (Table 1 and Figure 1). Of isolates with serine-carbapenemases, 99.3% were susceptible to CAZ-AVI, while only 6.4% were susceptible to MEM. KPC was the sole carbapenemase identified in 94% of these isolates, with OXA-48 in 5%. Of 91 isolates carrying AmpC and no carbapenemase, 97.8% were susceptible to CAZ-AVI and 96.7% were susceptible to MEM. These isolates primarily carried variants of CMY (74%) or DHA (20%). Of isolates that carried an ESBL and no carbapenemase or AmpC, 99.7% were susceptible to CAZ-AVI and 93.3% were susceptible to MEM. The majority of these isolates carried a variant of CTX-M and no other family of ESBL (96%). Ceftazidime-avibactam retained potent in vitro activity against isolates that carry β-lactamases other than MBLs in this collection of molecularly characterized Enterobacterales isolates collected in Latin America from 2019-2023. Katherine Perez, PhD, Pfizer: Stocks/Bonds (Public Company) Paurus Irani, MD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds (Private Company)

Abstract Background Imipenem/relebactam (IMR) combines imipenem with the β-lactamase inhibitor relebactam, an inhibitor of class A and C β-lactamases. We assessed the activity of IMR and comparators against Pseudomonas aeruginosa collected in 9 countries in the Asia/Pacific region as part of the global SMART surveillance program, with a focus on the increased antimicrobial activity brought by the addition of relebactam to imipenem for those organisms interpreted as “intermediate” by 2024 CLSI criteria (MIC = 4 µg/mL) to imipenem alone. Methods From 2018-2022, 50 clinical laboratories in nine countries in Asia/Pacific (Australia, Hong Kong, Malaysia, New Zealand, Philippines, South Korea, Taiwan, Thailand, and Vietnam) each collected up to 250 consecutive, aerobic or facultative, Gram-negative pathogens per year from patients with bloodstream, intraabdominal, lower respiratory tract, and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted with 2024 CLSI breakpoints. Most isolates that were imipenem or ceftolozane/tazobactam-nonsusceptible (NS) were screened for β-lactamases. Results IMR demonstrated excellent antimicrobial activity against isolates from most countries, inhibiting >80% of the isolates from each country except Vietnam (63.2% susceptible; Table). Ceftolozane/tazobactam and amikacin showed similar levels of activity. Limiting the analysis to isolates that tested “intermediate” to imipenem (MIC = 4 µg/mL) revealed that the addition of relebactam rendered >96% of the organisms from each country susceptible, ranging from 100% (Australia, New Zealand and South Korea) to 96.3% (Vietnam). Most imipenem-I P. aeruginosa examined molecularly (727/740; 98.2%) did not carry an acquired β-lactamase. As relebactam itself does not possess antibacterial activity, this suggests that the increased antimicrobial activity attributable to its addition is likely a result of its inhibitory activity on the intrinsic AmpC (blaPDC) in this species. Conclusion IMR showed potent activity against clinical P. aeruginosa collected in Asia/Pacific. The addition of relebactam to imipenem was responsible for the inhibition of >96% of isolates that were “intermediate” to imipenem alone. Disclosures Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Abstract Background Gepotidacin (GEP) is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial that inhibits bacterial DNA replication by a unique mechanism of action, distinct binding site, and provides a well-balanced inhibition (for most uncomplicated urinary tract infection (uUTI) uropathogens and N. gonorrhoeae)) of two different Type II topoisomerase enzymes. We present the activity of GEP against molecularly characterized N. gonorrhoeae isolates collected from patients in Australia, India, and the United States from 2018-2021 as part of a GEP global gonococcal surveillance study. Methods N. gonorrhoeae isolates were tested for susceptibility to GEP and comparator agents by CLSI agar dilution method and analyzed using CLSI 2024 breakpoints. Isolates that met predefined selection criteria, which included GEP MIC values >1 µg/mL or nonsusceptible or resistant (R) to select comparators, were characterized by whole genome sequencing. Results A total 711 N. gonorrhoeae isolates were collected and of these 341 (48%) were characterized. The GEP MICs for both populations of isolates ranged from ≤0.06 to 2 µg/mL; MIC90 of 1 µg/mL (Table 1). Of 324 ciprofloxacin-R isolates, 105 (32.4%) had a mutation of D86N in ParC; this mutation was associated with a GEP MIC90 of 2 µg/mL (range= 0.25-2 µg/mL). Isolates with this mutation also carried mutations in the quinolone-resistance determining region (QRDR) of GyrA as well as mutation(s) suggesting the upregulation of the MtrCDE efflux pump. When categorizing isolates by QRDR mutation, ParC D86N was the only mutation associated with a GEP MIC90 >1 µg/mL. A myriad of resistance mechanisms relevant to penicillin, azithromycin, and tetracycline, were identified among the characterized isolates, against which GEP MIC90s ranged from 1-2 µg/mL (Table 2). Conclusion GEP demonstrated potent in vitro activity against N. gonorrhoeae isolates, including those that were not susceptible to comparator agents. GEP’s MIC90 value relative to all isolates, and those with other QRDR mutations in this study, was one dilution higher (2 versus 1 µg/mL) against isolates that carried ParC D86N, which is known to be important for GEP binding. Disclosures Mark Estabrook, MS, Pfizer, Inc.: Advisor/Consultant Renuka Kapoor, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Didem Torumkuney, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Henry Li, MS in Biotechnology, Pfizer, Inc.: Advisor/Consultant Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Abstract Background The spread of antimicrobial resistance among clinically isolated Enterobacterales (Eba) is a threat to public health. Aztreonam (ATM) is a monobactam stable against hydrolysis by metallo-β-lactamases (MBLs) and avibactam (AVI) inhibits class A, class C, and some class D serine β-lactamases. ATM-AVI is being developed for use against infections caused by drug-resistant Eba, especially those co-producing MBLs and other β-lactamases. This study evaluated the in vitro activity of ATM-AVI and comparators against Eba collected in 2018-2022 from pediatric and adult patients as part of the ATLAS global surveillance program. Methods 87621 Eba isolates were collected from patients in 226 medical centers in 57 countries in Europe, Latin America, Asia/Pacific (excluding mainland China), and Middle East/Africa. Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2024 breakpoints. PCR and sequencing were used to identify β-lactamase genes among all isolates testing with meropenem MIC >1 µg/mL, and a randomly sampled subset of approximately 80% of Escherichia coli, Klebsiella spp. and Proteus mirabilis testing with ATM or ceftazidime MIC >1 µg/mL. Results MIC90 values for ATM-AVI of 0.12 µg/mL (pediatric isolates) and 0.25 µg/mL (adult isolates) were observed. Against all Eba isolates, ≤8 µg/mL of ATM-AVI inhibited 99.9% of both pediatric and adult isolates, whereas only 66.3% (pediatric) and 71.4% (adult) of these isolates were susceptible to ATM alone (table). Among isolates that screened positive for an MBL, MIC90 values for ATM-AVI were 0.5 µg/mL (pediatric) and 2 µg/mL (adult) and ATM-AVI inhibited 100% (pediatric) and 98.6% (adult) at concentrations ≤8 µg/ml. In contrast, only 14.5% (pediatric) and 17.2% (adult) of MBL-positive isolates were susceptible to ATM without AVI. Conclusion Based on MIC90 values, ATM-AVI demonstrated potent in vitro activity against Eba isolated both from pediatric and adult patients. Avibactam’s ability to potentiate aztreonam against MBL-positive Enterobacterales isolates warrants its continued development. Disclosures Mark Estabrook, MS, Pfizer, Inc.: Advisor/Consultant Julie Dickson, BS, Pfizer, Inc.: Advisor/Consultant Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

OBJECTIVES:To evaluate the in vitro susceptibility of recent Gram-negative pathogens collected from pediatric patients to imipenem/relebactam (IMI/REL) and comparator agents. METHODS:From 2018 to 2022 254 hospitals in 62 countries collected Enterobacterales or Pseudomonas aeruginosa isolates from patients <18 years old as part of the SMART global surveillance program. Minimum inhibitory concentrations (MIC)s were determined using CLSI broth microdilution and interpreted with 2024 CLSI breakpoints. Most isolates non-susceptible to IMI/REL were queried for their acquired β-lactamase content. RESULTS:Overall, 96.8% of all non-Morganellaceae Enterobacterales (NME) isolates from pediatric patients (n = 12 060) were IMI/REL-susceptible. Most NME were also susceptible to imipenem alone (93.9%), meropenem (96.0%), and ertapenem (94.4%); isolates were less susceptible to piperacillin/tazobactam (82.8%), cefepime (76.3%), and ceftazidime (74.4%). Non-Morganellaceae Enterobacterales collected in Asia were the least susceptible to IMI/REL (91.6%), while those from Australia/New Zealand were the most (99.3%). Imipenem/relebactam was equally potent against NME isolates regardless of infection source, hospital ward, age, and length of hospitalization. In total, 90.8% of all Pseudomonas aeruginosa isolates (n = 3046) were IMI/REL-susceptible; ceftolozane/tazobactam also inhibited >90% of the P. aeruginosa. Regionally, P. aeruginosa isolates from Eastern Europe were least susceptible to IMI/REL. Molecular characterization revealed that, globally, most resistance to IMI/REL among the NME could be attributed to the presence of NDM-type metallo-β-lactamases, while no acquired β-lactamases were detected in approximately half the IMI/REL non-susceptible P. aeruginosa examined. CONCLUSION:Based on in vitro data, IMI/REL represents a good therapeutic option for most hospitalized pediatric patients infected with common Gram-negative pathogens.

Abstract Background Enterobacterales with multidrug-resistance (MDR) or difficult-to-treat resistance (DTR) present clinicians with limited treatment options. Imipenem/relebactam (IMR) is a combination of imipenem with relebactam, a β-lactamase inhibitor of class A and C β-lactamases. We examined the activity of IMR and comparators against isolates of non-Morganellaceae Enterobacterales that were the etiological agents of bloodstream and respiratory infections in the United States. Methods In 2020-2022, 26 clinical labs in the U.S. participated in the global SMART surveillance program each collecting up to 250 consecutive gram-negative pathogens per year. Only isolates from patients with bloodstream and respiratory tract infections were included in this study. MICs were determined using CLSI broth microdilution and interpreted with 2024 CLSI breakpoints. MDR was defined as resistance to ≥3 sentinel agents (amikacin, aztreonam, cefepime, ceftazidime, colistin, imipenem, levofloxacin, and piperacillin/tazobactam). DTR phenotypes were defined by isolates nonsusceptible (intermediate or resistant) to all β-lactams (including aztreonam, ceftazidime, cefepime, imipenem, meropenem, piperacillin-tazobactam), as well as fluoroquinolones (levofloxacin). Results Among 4,763 collected NME isolates, 575 (12.1%) were MDR and 33 (0.7%) were DTR. Escherichia coli (n=1695) and Klebsiella pneumoniae (n=958) were the most common species collected and their MDR rate was 12.2% and 13.5%, respectively, while their DTR rate was 0.1% and 1.8%, respectively. Against the full collection, IMR and meropenem were the most active agents, each inhibiting 98.7% of the population (Figure). Ertapenem, amikacin and imipenem alone were also active, inhibiting >93%. IMR retained its activity versus the MDR subset, as 97.0 were interpreted as susceptible, the highest percentage among comparator drugs. IMR also showed activity against the challenging DTR subsets with 81.8% susceptible, approximately 30 percentage points higher than amikacin. Conclusion Based on these in vitro data, IMR appears to be an excellent therapeutic choice for use against NME infections from blood and respiratory tract sources, including those identified as MDR and DTR. Disclosures Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Abstract Background Ceftazidime-avibactam (CAZ-AVI) is a β-lactam/β-lactamase inhibitor combination approved to treat infections caused by Gram-negative organisms. Notably, CAZ-AVI has activity against Enterobacterales producing Class A, C, and D β-lactamases, but not Class B metallo-β-lactamases (MBLs). The in vitro activity of CAZ-AVI and comparator agents against clinical Enterobacterales isolates producing one or more β-lactamase collected as a part of the ATLAS global surveillance program (2018-2022) was evaluated. Methods 89,316 isolates from 228 medical centers in 57 countries (excluding mainland China, Canada, and the USA) were collected and tested for susceptibility using the broth microdilution method according to CLSI guidelines. Analysis was performed with CLSI 2024 breakpoints. Isolates testing with meropenem MIC values >1 µg/mL or Escherichia coli, Klebsiella pneumoniae, K. oxytoca, or Proteus mirabilis isolates testing with ceftazidime and/or aztreonam MIC values >2 µg/mL were screened for β-lactamase genes by PCR, which were sequenced when identified. Results One or more extended-spectrum β-lactamase (ESBL), acquired AmpC, serine-carbapenemase, or MBL was identified among 17,348/18,798 isolates characterized. Against isolates producing ESBLs (51.1%), susceptibility to CAZ-AVI was similar if the isolate carried one ESBL (99.4%) or two ESBLs (98.4%). Against acquired AmpC-producing isolates (5.9%), CAZ-AVI susceptibility was similar if the isolates co-carried 0, 1, or 2 ESBLs (98.9%, 97.1%, and 100% susceptible, respectively). Against isolates carrying serine-carbapenemases (18.6%), CAZ-AVI activity was similar regardless of co-carriage of acquired AmpC and/or one or more ESBLs (95.5-100% susceptible). CAZ-AVI was not active against isolates that carried an MBL (16.6%), regardless of other enzyme carriage (0-2.9% susceptible). Conclusion These results highlight that the number of distinct β-lactamases have little association with susceptibility to CAZ-AVI, while the type of β-lactamase (MBL or non-MBL) has a greater association. Disclosures Mark Estabrook, MS, Pfizer, Inc.: Advisor/Consultant Henry Li, MS in Biotechnology, Pfizer, Inc.: Advisor/Consultant Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Abstract Background Taniborbactam is a novel β-lactamase inhibitor that inhibits serine-β-lactamases and NDM & VIM (but not IMP) metallo-β-lactamases, restoring the activity of cefepime against most isolates of Enterobacterales and P. aeruginosa carrying these enzymes. This study examined the in vitro activity of cefepime-taniborbactam (FTB) against recent clinical isolates from the US, focusing on genotypically-characterized carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant P. aeruginosa (CRPA). Methods From 2018-2022, as part of the GEARS program, 4,932 Enterobacterales and 1,508 P. aeruginosa isolates were collected from 42 hospitals in the US. MICs of cefepime-taniborbactam and comparators were determined by CLSI reference broth microdilution and interpreted using 2024 CLSI breakpoints. CRE was defined by resistance to meropenem; CRPA was defined by resistance to meropenem and/or imipenem. Isolates with cefepime-taniborbactam MIC ≥16 µg/mL were characterized by whole genome sequencing. Isolates resistant to meropenem were screened for acquired β-lactamases by PCR. Results 95.9% of the 73 CRE isolates were inhibited by ≤16 µg/mL FTB (Fig. 1). Most CRE (55/73; 75.3%) produced a carbapenemase (40 KPC, 7 NDM, 2 VIM, 2 OXA-48-like, 2 KPC+OXA-48, 1 IMP, and 1 VIM+OXA-48); 96.4% were inhibited by ≤16 µg/mL FTB and the most active comparator was meropenem-vaborbactam (80.0% susceptible). At ≤16 µg/mL, FTB inhibited 92.0% of all CRPA (n=386) and 87.2% of meropenem-resistant CRPA (n=226) (Fig. 2). Among meropenem-resistant CRPA, 6 isolates (2.7%) carried a carbapenemase (2 IMP, 1 IMP+VIM, 1 VIM, 1 GES, 1 NDM). FTB at ≤16 µg/mL inhibited 88.6% of meropenem-resistant, carbapenemase-negative P. aeruginosa and 2/3 non-IMP carbapenemase-positive isolates. Conclusion FTB at ≤16 µg/mL inhibited >94% of CRE isolates collected in the US, regardless of carbapenemase carriage. Similarly potent activity was observed for cefepime-taniborbactam against meropenem-resistant CRPA isolates, most of which lacked a carbapenemase. Upon approval, cefepime-taniborbactam could be an important option for use against CRE and CRPA, as currently available therapies have limited activity. Disclosures Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Abstract Background Cefepime-taniborbactam (FTB) is an investigational β-lactam/β-lactamase inhibitor combination with activity against most isolates of carbapenem-resistant and multidrug-resistant (MDR) Enterobacterales and P. aeruginosa. We evaluated the activity of FTB and comparators against clinical isolates of Enterobacterales and P. aeruginosa from the US and assessed FTB cross-resistance to ceftazidime-avibactam (CZA) and ceftolozane-tazobactam (CT) in resistant subsets. Methods MICs were determined by CLSI reference broth microdilution against Enterobacterales (n=4,932) and P. aeruginosa (n=1,508) collected in the US in 2018-2022. Phenotypes were based on 2024 CLSI breakpoints. A provisional FTB susceptible breakpoint of ≤16 µg/mL was used for comparative purposes. An MDR phenotype was defined as resistance to ≥1 agent from ≥3 drug classes. Results Among Enterobacterales, 1.8% of isolates were nonsusceptible to meropenem (MEM; Table 1). FTB was the most active agent, inhibiting 96.7% of MEM-nonsusceptible Enterobacterales isolates at ≤16 µg/mL whereas 80.4% were susceptible to CZA and 87.0% were susceptible to meropenem-vaborbactam (MEV). Among P. aeruginosa, 11.9% of isolates were MDR (Table 1). FTB was the most active agent, inhibiting 82.2% of MDR P. aeruginosa isolates at ≤16 µg/mL whereas 56.1% were susceptible to CT and 63.9% were susceptible to CZA (Table 1). Among MEM-nonsusceptible Enterobacterales, 80.2% were susceptible to both FTB and CZA, 16.5% were susceptible to FTB but not to CZA, 1.1% were susceptible to CZA but not to FTB, and 2.2% were nonsusceptible to both agents (Table 2A). Among MDR P. aeruginosa, 54.4% were susceptible to both FTB and CT, 27.8% were susceptible to FTB but not to CT, 1.7% were susceptible to CT but not to FTB, and 16.1% were nonsusceptible to both agents (Table 2B). Conclusion FTB was active in vitro against recent clinical isolates of Enterobacterales and P. aeruginosa from the US including most isolates resistant to CZA and CT in key resistant subsets. These data support continued development of FTB as a potential treatment option for patients with challenging infections due to carbapenem-resistant Enterobacterales and MDR P. aeruginosa. Disclosures Greg Moeck, PhD, Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Stocks/Bonds (Private Company) Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication through a distinct binding site and unique mechanism of action, providing well-balanced inhibition of two different type II topoisomerase enzymes for most uropathogens. Phase III clinical trials, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), showed gepotidacin to be non-inferior and superior, respectively, to nitrofurantoin for the treatment of patients with uncomplicated urinary tract infections (uUTIs). To better define gepotidacin in vitro activity against pathogens that commonly cause UTIs, CLSI broth microdilution MICs were determined for gepotidacin and seven comparator agents, and agar dilution MICs were determined for fosfomycin, against 4,000 predominantly UTI isolates of Enterobacterales (3,250), Enterococcus faecalis (500), and Staphylococcus saprophyticus (250) collected globally from 2012 to 2020. Gepotidacin MIC90s against the Enterobacterales species tested were 4 µg/mL for Escherichia coli (1,000) and Klebsiella oxytoca (250), 8 µg/mL for Citrobacter spp. (250) and Klebsiella aerogenes (250), 16 µg/mL for Proteus mirabilis (250) and Providencia rettgeri (250), and 32 µg/mL for Enterobacter cloacae (500) and Klebsiella pneumoniae (500). Against the gram-positive species, gepotidacin MIC90s were 0.12 µg/mL and 4 µg/mL for S. saprophyticus (250) and E. faecalis (500), respectively. Gepotidacin MIC90s for ciprofloxacin not susceptible isolates ranged from 4 µg/mL for E. coli (352) to 128 µg/mL for P. rettgeri (48). Gepotidacin MIC90s for presumptive extended spectrum beta-laactamase (ESBL)-positive E. coli (228) and K. pneumoniae (145) were 8 µg/mL and 32 µg/mL, respectively. Gepotidacin was bactericidal (minimum bactericidal concentration [MBC]/MIC ratio ≤4) against 94% (47/50) of isolates tested.

Abstract Background Aztreonam-avibactam (ATM-AVI) is a β-lactam/β-lactamase inhibitor combination to treat infections caused by Gram-negative organisms, particularly those carrying metallo-β-lactamases (MBLs) and other β-lactamases. Aztreonam is stable to hydrolysis by MBLs and avibactam inhibits Class A, C, and some Class D enzymes. We examined ATM-AVI activity against Enterobacterales isolates producing one or more β-lactamase collected as a part of the ATLAS global surveillance program (2018-2022). Methods 88,750 isolates from 227 medical centers in 57 countries (excluding mainland China, Canada, and the USA) were collected and tested for susceptibility using the broth microdilution method according to CLSI guidelines. Analysis was performed with CLSI 2024 breakpoints. Isolates testing with meropenem MIC values >1 µg/mL or Escherichia coli, Klebsiella pneumoniae, K. oxytoca, or Proteus mirabilis isolates testing with ceftazidime and/or aztreonam MIC values >2 µg/mL were screened for β-lactamase genes by PCR, which were sequenced when identified. Results One or more extended-spectrum β-lactamase (ESBL), serine-carbapenemase, MBL, or acquired AmpC was identified among 17,013/18,408 isolates characterized. Among isolates carrying one or two ESBLs (51.4%), 99.9-100% tested with ATM-AVI MICs ≤8 µg/mL (MIC90 values of 0.12 and 0.5 µg/mL, respectively). Among isolates with a serine-carbapenemase and one or more ESBL (18.3%), 99.9-100% tested with ATM-AVI MICs ≤8 µg/mL (MIC90 values of 0.5-1 µg/mL). MBL-positive isolates with or without serine-carbapenemases and/or ESBLs (13.7%) demonstrated MICs ≤8 µg/mL among 98.3-100% of isolates in each category (MIC90 values of 0.5-1 µg/mL). Isolates carrying acquired AmpC as well as any combination of additional β-lactamases (9%) tested with ATM-AVI MICs ≤8 µg/mL among 93.6-100% of each population (MIC90 values of 0.5-8 µg/mL). Conclusion ATM-AVI demonstrated potent in vitro activity against Enterobacterales isolates regardless of the number of β-lactamases carried. Slightly reduced potency was observed in populations that carried acquired AmpC. This may be expected as some variants of AmpC with extended-spectrum activity are known to increase ATM-AVI MICs. Disclosures Mark Estabrook, MS, Pfizer, Inc.: Advisor/Consultant Henry Li, MS in Biotechnology, Pfizer, Inc.: Advisor/Consultant Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Abstract Background The proliferation of carbapenemases in many geographies has compromised the effectiveness of the carbapenem class of antimicrobials and constitutes a major clinical problem. However, carbapenems paired with β-lactamase inhibitors, like imipenem/relebactam (IMR), can restore their activity against isolates carrying some types of carbapenemases. We evaluated trends in carbapenemase and co-carbapenemase production among Enterobacterales collected as part of the SMART surveillance program in Latin America. Methods In 2018-2022, 47 clinical labs in 11 countries in Latin America (Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Mexico, Panama, Peru, Puerto Rico, Venezuela) each collected up to 250 consecutive Gram-negative pathogens per year from patients with bloodstream, intraabdominal, respiratory tract, and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted with 2024 CLSI breakpoints. Most imipenem (IPM) nonsusceptible non-Morganellaceae Enterobacterales and ceftolozane/tazobactam (C/T) nonsusceptible Enterobacterales were screened for β-lactamases genes. Results Of the 29,419 Enterobacterales collected, 6669 tested non-susceptible to IPM or C/T; of these, 4474 (67.1%) were characterized molecularly. KPC was the most frequently observed carbapenemase each year, ranging from 40.8% of the characterized isolates in 2021 to 31.1% in 2022, exhibiting an overall slight decreasing trend (Fig. 1). In contrast, the rate of NDM detection increased annually, ranging from 2.0% of the characterized isolates in 2018 to 20.8% in 2022. Rates of detection of other carbapenemases, including OXA-48-like, VIM, IMP and GES remained low and relatively stable over the studied time frame. Detection of carbapenemase co-carriers peaked in 2021 (3.5%), with isolates harboring NDM & KPC the most common genotype (Fig. 2). Conclusion KPC was the most commonly encountered carbapenemase among Enterobacterales in Latin America from 2018-2022, suggesting agents that retain potency against KPC-carrying Enterobacterales, like IMR, remain appropriate therapies. However, the increasing trend of NDM detection in this region is of concern as it severely limits treatment options. Disclosures Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Objectives: To describe annual trends in the susceptibility of clinical isolates of Pseudomonas aeruginosa from Latin America to ceftolozane/tazobactam. Methods: The Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program collected 10,188 P. aeruginosa isolates from 57 unique clinical sites in 12 Latin American countries from 2016 to 2024. MICs were determined by reference broth microdilution testing and interpreted using 2025 CLSI M100 breakpoints. Results: Overall, 86.3% of clinical isolates of P. aeruginosa collected in Latin America were susceptible to ceftolozane/tazobactam, including 45.5% of multidrug-resistant (MDR) isolates. From 2016 to 2024, annual percent susceptible values for ceftolozane/tazobactam ranged from 84.9% (2016, n = 779) to 89.2% (2023, n = 1144), with a statistically significant linear trend for increasing susceptibility (p = 0.024; Cochran–Armitage test for trend). However, limiting analysis solely to the 14 clinical sites, from six countries, that participated in each of the nine years (n = 4565) indicated that the annual percent susceptible values for ceftolozane/tazobactam remained unchanged from 2016 (82.6%) to 2024 (83.9%) (p = 0.367; percent susceptible value range, 82.6 to 89.1%). Every year, from 2016 to 2024, all P. aeruginosa isolates from pediatric patients (<18 years of age) were consistently more susceptible to ceftolozane/tazobactam than those from adult patients (90.3 to 95.0%/year versus 83.3 to 88.6%/year, respectively). Significant variation (p < 0.05) in annual ceftolozane/tazobactam percent susceptible values was not observed for isolates from blood, intra-abdominal, and respiratory tract sources, while isolates from urine showed a trend of increasing ceftolozane/tazobactam susceptibility from 73.1% (2018, n = 145) to 90.6% (2023, n = 117) (p < 0.0001). Among individual countries that participated each year, P. aeruginosa isolates from all except Guatemala displayed stable or increasing rates of susceptibility to ceftolozane/tazobactam. Conclusions: Since it was first tested by the SMART program in 2016, and for 8 years thereafter, the in vitro activity of ceftolozane/tazobactam has remained consistent against clinical isolates of P. aeruginosa from the Latin American region (overall, 86.3% susceptible), with limited resistance development restricted to specific clinical sites.