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

Objectives: The intent of this study was to report reference in vitro antimicrobial susceptibility testing results for funobactam (formerly XNW4107) in combination with imipenem against recent, worldwide clinical isolates of Gram-negative bacilli. Methods: MICs for imipenem in combination with a fixed concentration of funobactam (8 mg/L), and seven comparator agents, were determined using the reference CLSI M07 broth microdilution method for 4003 clinical isolates of Gram-negative bacilli (2008 Enterobacterales, 999 Acinetobacter baumannii, and 996 Pseudomonas aeruginosa) collected from 211 unique clinical laboratory sites in 54 countries as part of industry-sponsored antimicrobial surveillance studies in 2021 and 2022. MICs were interpreted by 2026 CLSI M100 breakpoints. Most isolates with imipenem-funobactam MICs of ≥4 mg/L (95.4%) underwent whole genome sequencing to identify acquired β-lactamase gene carriage. Results: MIC90 values for imipenem-funobactam were 2 mg/L for all 2008 isolates of Enterobacterales, and 1, 0.5, and 0.5 mg/L, respectively, for metallo-β-lactamase (MBL)-negative Enterobacterales (n = 1969), non-Morganellaceae Enterobacterales (NME) (n = 1752), and MBL-negative NME (n = 1718) isolate subsets. MIC90 values for imipenem-funobactam and imipenem alone were identical or within one doubling dilution for all 14 species of Enterobacterales tested except Klebsiella pneumoniae, Citrobacter freundii, and Enterobacter bugandensis which showed differences of 32-fold (imipenem-funobactam MIC90, 0.5 mg/L; imipenem MIC90, 16 mg/L), 8-fold (0.25 mg/L; 2 mg/L), and 4-fold (0.25 mg/L; 1 mg/L), respectively. Both for all A. baumannii isolates (n = 999) and for MBL-negative isolates (n = 962), the imipenem-funobactam MIC90 value (4 mg/L) was 32-fold lower than for imipenem alone (128 mg/L). Both for all P. aeruginosa (n = 996) isolates and MBL-negative isolates (n = 962), we observed a 4-fold difference in potency between imipenem-funobactam (MIC90, 4 mg/L) and imipenem alone (MIC90, 16 mg/L). Isolates carrying MBL demonstrated the highest MICs for imipenem-funobactam. Conclusions: Imipenem-funobactam demonstrated potent in vitro activity against most carbapenem-resistant isolates of A. baumannii, K. pneumoniae, NME and many isolates of carbapenem-resistant P. aeruginosa. Continued development of imipenem-funobactam is warranted.

Ceftolozane/tazobactam (C/T) is an antipseudomonal cephalosporin combined with a β-lactamase inhibitor approved by FDA for complicated urinary tract and intraabdominal infections in adults and children, and hospital-acquired/ventilator-associated bacterial pneumonia in adults. We evaluated annual trends in the antimicrobial activity of C/T against Enterobacterales (EB) and Pseudomonas aeruginosa (PA) isolates collected in the United States from 2016-2023 for the global SMART surveillance program. From 2016-2023, 35 unique clinical laboratories in the US collected 250 consecutive, aerobic or facultative, Gram-negative pathogens per year from patients with intraabdominal, urinary tract, lower respiratory tract, and starting in 2018, bloodstream infections. Not all sites participated each year. MICs were determined using CLSI broth microdilution and interpreted with 2025 CLSI breakpoints. Trends in annual susceptibility percentages were assessed for statistical significance using the Cochran-Armitage test for trend (XLSTAT 2024.2.2.1422). A p-value ≤0.001 was considered significant. Against EB, the annual susceptibility percentage to C/T ranged from 95.3% (2018) to 92.2% (2023) with a statistically significant decreasing trend (p=0.001) over the 8-year time frame (Fig. 1). Susceptibility to meropenem was consistently >98% each year, while susceptibility percentages to cefepime were approximately 5 percentage points less than C/T each year, with cefepime also exhibiting a significant decreasing trend in susceptibility (p< 0.0001). Against PA, C/T inhibited ≥94.5% of the population each year, approximately 16-20 percentage points higher than meropenem (Fig. 2). Susceptibility of PA to cefepime and piperacillin/tazobactam was also consistently lower than C/T, with both agents exhibiting a trend of increasing activity over the studied time range (p< 0.0001). C/T maintained consistently high levels of antimicrobial activity against PA in the United States from 2016-2023, while a trend of slightly decreasing activity levels was observed against EB. Nevertheless, C/T inhibited a considerably higher percentage of EB isolates than cefepime and piperacillin/tazobactam each year. All Authors: No reported disclosures

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.

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

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 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

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.

Abstract Background Hospital ward and patient age are factors that can guide in the selection of empiric therapy. Imipenem/relebactam (IMR) is a combination of imipenem with the β-lactamase inhibitor relebactam, an inhibitor of class A and C β-lactamases. Ceftolozane/tazobactam (C/T) combines ceftolozane, an anti-pseudomonal cephalosporin, with tazobactam. We evaluated the activity of IMR, C/T and comparators against isolates of non-Morganellaceae Enterobacterales (NME) and Pseudomonas aeruginosa that were collected in the United States as part of the SMART surveillance program from 2020 to 2022 with data stratified by hospital ward (ICU versus general wards), and by patient age (< 60 and ≥60 years old). Methods In 2020-2022, 26 clinical labs in the US each collected up to 250 consecutive Gram-negative pathogens per year. MICs were determined using CLSI broth microdilution and interpreted with 2024 CLSI breakpoints. Multi-drug resistance (MDR) was defined as resistance to ≥3 sentinel agents (amikacin, aztreonam, cefepime, ceftazidime [Enterobacterales only], colistin, imipenem, levofloxacin, and piperacillin/tazobactam). Difficult-to-treat resistance (DTR) was defined as non-susceptibility to all β-lactams (including aztreonam, ceftazidime, cefepime, imipenem, meropenem, piperacillin-tazobactam), and fluoroquinolones (levofloxacin). Results Susceptibility to commonly used β-lactams was lower among isolates from ICU patients compared to those in non-ICU wards, but no clear pattern was linked to patient age. Against the NME, IMR was among the most active agents inhibiting >98% of the isolates in all strata (Table). Meropenem, ceftazidime/avibactam and amikacin also inhibited >98% of the isolates. IMR retained activity against the MDR NME, as >96.9% of the isolates were susceptible. Against P. aeruginosa, C/T was the first or second (after amikacin) most active agent versus isolates in all strata, with >95% susceptible. C/T remained active against ≥77% of MDR and ≥72% of DTR isolates, 7-30 percentage points higher than ceftazidime/avibactam. Conclusion IMR is an important treatment option for patients with infections caused by NME, while C/T is an excellent choice against P. aeruginosa, regardless of patient age or treatment in the ICU. Disclosures Daniel F. Sahm, PhD, Pfizer, Inc.: Advisor/Consultant

Objectives To assess the in vitro antimicrobial activity of ceftolozane/tazobactam, imipenem/relebactam and comparator agents against clinical isolates of Gram-negative bacilli collected in Israel from 2018 to 2022.Methods Six clinical laboratories each 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 2024 EUCAST breakpoints. Acquired beta-lactamase gene carriage was investigated for most ceftolozane/tazobactam- and imipenem/relebactam-resistant isolates.Results Among the full collection of Enterobacterales (n = 4420), 95.1% were susceptible to ceftolozane/tazobactam, including 95.3% of putative AmpC/ESBL-positive, non-carbapenem-resistant Enterobacterales (CRE) phenotype Escherichia coli and 86.6% of AmpC/ESBL-positive, non-CRE phenotype Klebsiella pneumoniae. Overall, 99.8% of non-Morganellaceae Enterobacterales (n = 3723) were imipenem/relebactam susceptible including 98% of the MDR isolates. Most Pseudomonas aeruginosa isolates (n = 1182) were inhibited by ceftolozane/tazobactam (93.9% susceptible) and imipenem/relebactam (94.7%). Imipenem/relebactam retained activity against >= 78% of cefepime-resistant, ceftazidime-resistant, and piperacillin/tazobactam-resistant P. aeruginosa, while ceftolozane/tazobactam inhibited the greatest percentage of meropenem-resistant P. aeruginosa (67.4%) among comparator beta-lactam antimicrobials. Molecular characterization showed the majority of imipenem/relebactam-resistant Enterobacterales harboured a metallo-beta-lactamase, while half of the ceftolozane/tazobactam-resistant Enterobacterales carried an acquired ESBL or AmpC. Most of the imipenem/relebactam- and ceftolozane/tazobactam-resistant P. aeruginosa characterized did not possess acquired beta-lactamases.Conclusions Recent clinical isolates of Enterobacterales and P. aeruginosa collected in Israel were highly susceptible to ceftolozane/tazobactam and imipenem/relebactam.

ABSTRACTOxacillinases (OXA)-48-like β-lactamases are one of the most common resistance determinants among carbapenem-resistant Enterobacterales reported globally. Moreover, there is no standard treatment available against organisms producing OXA-48-like enzymes, and they are sometimes difficult to detect, making treatment challenging. The objective of this study was to evaluate the distribution and antimicrobial susceptibility of blaOXA-48-like Enterobacterales isolates against ceftazidime–avibactam (CAZ-AVI) and a panel of comparators collected worldwide from 2016 to 2020 as a part of the Antimicrobial Testing Leadership and Surveillance program. Among all the Enterobacterales isolates collected, 1.8% (1,690/94,052) carried blaOXA-48-like, and a majority of those were identified as K. pneumoniae (86.5%, 1,462/1,690). Among all the blaOXA-48-like isolates, 88.9% (1,502/1,690) were extended-spectrum β-lactamase (ESBL)-positive, 20.7% (350/1,690) were metallo-β-lactamase (MBL)-positive, and 8.9% (150/1,690) were ESBL- and MBL-negative. There were 10 different variants of the OXA-48-like family of enzymes detected, with the major variant being blaOXA-48 (50.2%, 848/1,690), blaOXA-232 (29.3%, 496/1,690), and blaOXA-181 (18.0%, 304/1,690). Overall, all the blaOXA-48-like isolates showed a susceptibility of 78.6% to CAZ-AVI. Importantly, high susceptibility to CAZ-AVI was shown by all the blaOXA-48 type, MBL-negative isolates (n = 1,380, ≥99.0%), and all the MBL-negative isolates (n = 1,300, ≥97.6%) of the major variants (blaOXA-48, blaOXA-232, and blaOXA-181) studied. Among the comparator agents, all isolates showed good susceptibility to only tigecycline (>95.0%) and colistin (>78.6%). Considering the limited treatment options available, CAZ-AVI could be considered as a potential treatment option against blaOXA-48-like Enterobacterales. However, routine surveillance and appropriate stewardship strategies for these organisms may help identify emerging resistance mechanisms and effective treatment of infections.IMPORTANCEResistance to carbapenems among Enterobacterales is often due to the production of enzymes that are members of the oxacillinases (OXA)-48-like family. These organisms can also be resistant to other classes of drugs and are difficult to identify and treat. This study evaluated the activity of the drug ceftazidime–avibactam (CAZ-AVI) and other comparator agents against a global collection of Enterobacterales that produce OXA-48-like enzymes. CAZ-AVI was active against blaOXA-48-like Enterobacterales, and only colistin and tigecycline were similarly active among the comparator agents, highlighting the limited treatment options against these organisms. Continued surveillance of the distribution of these OXA 48-like producing Enterobacterales and monitoring of resistance patterns along with the implementation of antimicrobial stewardship measures to guide antibiotic use and appropriate treatment are necessary to avoid drug resistance among these organisms.

Background: Imipenem/relebactam (IMR) was approved for patient use in Taiwan in 2023. We evaluated the in vitro susceptibility of recent Gram -negative pathogens collected in Taiwan hospitals to IMR and comparators with a focus on carbapenem-resistant and KPC-carrying non-Morganellaceae Enterobacterales (NME), and carbapenem-resistant Pseudomonas aeruginosa (CRPA). Methods: From 2018 to 2021, eight hospitals in Taiwan 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 Clinical Laboratory Standards Institute (CLSI) broth microdilution. Most isolates that were IMR-, imipenem-, or ceftolozane/tazobactam-nonsusceptible were screened for B-lactamase genes by PCR or whole-genome sequencing. Results: Ninety-eight percent of NME (n = 5063) and 94% of P. aeruginosa (n = 1518) isolates were IMR-susceptible. Percent susceptible values for non-carbapenem B-lactam comparators, including piperacillin/tazobactam, were 68-79% for NME isolates, while percent susceptible values for all B-lactam comparators, including meropenem, were 73-81% for P. aeruginosa. IMR retained activity against 93% of multidrug-resistant (MDR) NME and 70% of MDR P. aeruginosa. Sixty-five percent of carbapenem-resistant NME and 81% of KPC-positive NME (n = 80) were IMR-susceptible. IMR inhibited 70% of CRPA (n = 287). Fifty percent of IMRnonsusceptible NME tested for B-lactamase carriage had an MBL or OXA-48-like enzyme, whereas most (95%) IMR-nonsusceptible P. aeruginosa examined did not carry acquired B-lactamase genes. Conclusion: Based on our in vitro data, IMR may be a useful option for the treatment of hos- pitalized patients in Taiwan with infections caused by common Gram-negative pathogens, including carbapenem-resistant NME, KPC-positive NME, and CRPA. Copyright 2023, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/).

Objectives To report trends in carbapenem resistance and difficult-to-treat resistance (DTR) among clinical isolates of Gram-negative priority pathogens collected by the ATLAS global surveillance program from 2018 to 2022. Methods Reference broth microdilution testing was performed in a central laboratory for 79,214 Enterobacterales, 30,504 Pseudomonas aeruginosa, and 13,500 Acinetobacter baumannii-calcoaceticus complex isolates collected by a constant set of 157 medical centres in 49 countries in Asia Pacific (APAC), Europe (EUR), Latin America (LATAM), Middle East-Africa (MEA), and North America (NA) regions. MICs were interpreted by 2023 CLSI M100 breakpoints. β-lactamase genes were identified for meropenem-nonsusceptible (MIC ≥2 mg/L) Enterobacterales isolates. Results Carbapenem-resistant Enterobacterales (CRE) detection increased (P <0.05) in APAC, EUR, LATAM, and MEA regions and decreased in NA, while annual DTR percentages increased in all five regions. Carbapenem-resistant P. aeruginosa (CRPA; decreased in MEA region) and carbapenem-resistant A. baumannii-calcoaceticus complex (CRAB; decreased in MEA region and increased in EUR) remained relatively stable over time in all regions, although notably, annual percentages of CRAB and DTR A. baumannii-calcoaceticus complex isolates were consistently >25 percentage points lower in NA than in other regions. For all regions except NA, the majority of changes in CRE percentages could be attributed to hospital-acquired infections. Among meropenem-nonsusceptible Enterobacterales, KPC was the most frequent carbapenemase in NA and EUR each year. NDM was the most prevalent carbapenemase detected in 2022 in other global regions. Conclusion CRE, CRPA, CRAB, and DTR rates vary among global regions over time highlighting the need for continuing surveillance to inform treatment strategies and antimicrobial stewardship.

BACKGROUND Aztreonam-avibactam (ATM-AVI) is a combination of aztreonam, notable for its stability to metallo-β-lactamases (MBLs), and avibactam, an inhibitor of class A, class C and some class D β-lactamases that inactivate aztreonam and are frequently co-carried with MBLs. ATM-AVI was recently approved in EU for treatment of adult patients with complicated intra-abdominal infections, hospital- and ventilator-associated pneumonia, and complicated urinary tract infections. This study evaluated the activity of ATM-AVI and comparators against Enterobacterales collected in six Middle Eastern countries from various infection sources, including lower respiratory tract infections (LRTI), urinary tract infections (UTI), intra-abdominal infections (IAI), skin and soft tissue infections (SSTI) and bloodstream infections (BSI). METHODS From 2018-2022, 6,326 non-duplicate Enterobacterales were collected from 17 hospitals in Israel, Jordan, Kuwait, Qatar, Saudi Arabia and Turkey for which infection source was specified. Susceptibility testing was performed by broth microdilution and interpreted using 2024 EUCAST breakpoints. RESULTS ATM-AVI showed excellent in vitro activity against isolates from all infection sources as evidenced by low MIC90 values (0.25 mg/L for BSI, IAI and LRTI isolates; 0.12 mg/L for SSTI and UTI isolates). Overall, ≥99.4% of the population from each infection type was susceptible to ATM-AVI. Among comparators, meropenem (88.0% - 94.4% susceptible) and amikacin (88.1% - 94.5%) were also active. The addition of AVI to ATM increased the susceptibility rate by >35 percentage points for each infection source over ATM alone. CONCLUSIONS ATM-AVI was the most potent agent examined regardless of infection source and offers promise for use against multidrug-resistant Enterobacterales, including MBL-carriers.

Objectives: Taniborbactam is a boronate-based beta-lactamase inhibitor in clinical development in combination with cefepime. Methods: Cefepime-taniborbactam and comparator broth microdilution MICs were determined for patient isolates of Enterobacterales (n = 20 725) and Pseudomonas aeruginosa (n = 7919) collected in 59 countries from 2018 to 2022. Taniborbactam was tested at a fixed concentration of 4 mg/L. Isolates with cefepime-taniborbactam MICs >= 16 mg/L underwent WGS. beta-Lactamase genes were identified in additional meropenem-resistant isolates by PCR/Sanger sequencing. Results: Taniborbactam reduced the cefepime MIC90 value for all Enterobacterales from >16 to 0.25 mg/L (>64-fold). At <= 16 mg/L, cefepime-taniborbactam inhibited 99.5% of all Enterobacterales isolates; >95% of isolates with MDR and ceftolozane-tazobactam-resistant phenotypes; >= 89% of isolates with meropenem-resistant and difficult-to-treat-resistant (DTR) phenotypes; >80% of isolates with meropenem-vaborbactam-resistant and ceftazidime-avibactam-resistant phenotypes; 100% of KPC-positive, 99% of OXA-48-like-positive, 99% of ESBL-positive, 97% of acquired AmpC-positive, 95% of VIM-positive and 76% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value from 32 to 8 mg/L (4-fold). At <= 16 mg/L, cefepime-taniborbactam inhibited 96.5% of all P. aeruginosa isolates; 85% of meropenem-resistant phenotype isolates; 80% of isolates with MDR and meropenem-vaborbactam-resistant phenotypes; >70% of isolates with DTR, ceftazidime-avibactam-resistant and ceftolozane-tazobactam-resistant phenotypes; and 82% of VIM-positive isolates. Multiple potential mechanisms of resistance, including carriage of IMP, or alterations in PBP3 (ftsI), porins (decreased permeability) and efflux (up-regulation) were present in most isolates with cefepime-taniborbactam MICs >= 16 mg/L. Conclusions: Cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa, and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM MBLs.