Mark G. Wise

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.

To evaluate trends in the susceptibility of clinical Enterobacterales and Pseudomonas aeruginosa from the USA to ceftolozane/tazobactam. 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. 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. 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.

Objectives: To 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. Methods: From 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. Results: Ceftolozane/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). Conclusion: Recent 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.

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 (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.

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 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.

Taniborbactam is a boronate-based β-lactamase inhibitor in clinical development in combination with cefepime. 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. β-Lactamase genes were identified in additional meropenem-resistant isolates by PCR/Sanger sequencing. 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. 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.

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. 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 β-lactamase gene carriage was investigated for most ceftolozane/tazobactam- and imipenem/relebactam-resistant isolates. 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 β-lactam antimicrobials. Molecular characterization showed the majority of imipenem/relebactam-resistant Enterobacterales harboured a metallo-β-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 β-lactamases. Recent clinical isolates of Enterobacterales and P. aeruginosa collected in Israel were highly susceptible to ceftolozane/tazobactam and imipenem/relebactam.

To evaluate the in vitro susceptibility of recent Gram-negative pathogens collected in South Korean medical centres to imipenem/relebactam and comparator agents. From 2018 to 2021, six hospitals in South Korea each collected up to 250 consecutive, aerobic or facultative Gram-negative pathogens per year from patients with bloodstream, intra-abdominal, lower respiratory tract and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted by 2023 CLSI breakpoints. Most isolates that were imipenem/relebactam, imipenem or ceftolozane/tazobactam non-susceptible were screened for β-lactamase genes by PCR or WGS. Of all non-Morganellaceae Enterobacterales (NME) isolates (n = 4100), 98.8% were imipenem/relebactam susceptible. Most NME were also susceptible to imipenem alone (94.7%) and meropenem (97.3%); percent susceptible values for non-carbapenem β-lactam comparators were lower (68%–80%). Imipenem/relebactam retained activity against 96.4%, 70.8% and 70.6% of MDR, difficult-to-treat resistant (DTR) and meropenem-non-susceptible NME, respectively, and inhibited 93.1% of KPC-carrying and 95.5% of ESBL-carrying NME. Of imipenem/relebactam-resistant NME, 21/25 (84.0%) carried an MBL or an OXA-48-like carbapenemase. Of all Pseudomonas aeruginosa isolates (n = 738), 82.8% were imipenem/relebactam susceptible; percent susceptible values for all β-lactam comparators, including carbapenems (imipenem, meropenem) were 61.5%–74.7%. Less than 20% of MDR and DTR isolates, and 41% of meropenem-non-susceptible P. aeruginosa isolates were imipenem/relebactam susceptible. Of imipenem/relebactam-resistant P. aeruginosa isolates, 61.6% carried an MBL and 37.0% did not possess any acquired β-lactamase genes. Based on in vitro data, imipenem/relebactam, if licensed in South Korea, may be a viable treatment option for many hospitalized patients infected with common Gram-negative pathogens including NME exhibiting MDR, DTR and carbapenem resistance and many β-lactam-resistant phenotypes of P. aeruginosa.