CIRCE Study Highlights Cefiderocol’s Activity Against Highly Resistant Gram-Negative Infections

Emerging real-world evidence from the CIRCE study is shedding new light on the clinical utility of cefiderocol in tackling some of the most challenging antimicrobial-resistant infections. In patients with metallo-beta-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE), the study reported a 68% clinical cure rate at day 14 and an 83% survival rate at day 28—encouraging outcomes in a population historically associated with high mortality and few effective treatment options.

Contagion spoke Christine M. Slover, PharmD, executive medical director, Anti-Infectives, Shionogi, about the about the study’s data as well as the threat of carbapenem-resistant Enterobacterales and how it is vital to strengthen antimicrobial stewardship while accelerating the development of novel, targeted therapies to address rising resistance.

Contagion: The CIRCE study reported a 68% clinical cure rate at day 14 and 83% survival at day 28. How do these outcomes compare to existing treatment options for MBL-producing Enterobacterales infections?

Slover: The CIRCE study provides critical real-world data on cefiderocol, showing a 68% clinical cure rate at day 14 and an 83% survival rate at day 28 for patients with metallo-beta-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) infections. These outcomes are promising, especially given that these infections have limited treatment options.¹

Infections caused by MBL-producing Enterobacterales are associated with high mortality rates, which have been reported to be in the range of about 20-60%.² However, it is important to note that the CIRCE study was not designed to directly compare cefiderocol with other treatments.

Contagion: Given that metallo-beta-lactamase–producing pathogens can inactivate most beta-lactam antibiotics, what makes cefiderocol’s mechanism of action particularly effective against these highly resistant organisms?

Slover: Cefiderocol is a siderophore cephalosporin antibiotic that can circumvent the major mechanisms of carbapenem resistance by entering cells via active transport and passive diffusion, overcoming efflux pump-up regulation and being stable against all classes of beta-lactamases. Cefiderocol works by binding to iron, an essential nutrient for bacteria, and then exploiting the bacteria’s natural iron transport system to cross the bacterial outer membrane. Once inside the bacterial cell, cefiderocol acts like other beta-lactam antibiotics by binding to penicillin-binding proteins (PBPs), mainly PBP3, which disrupts cell wall synthesis and leads to bacterial death.³

Cefiderocol is stable against breakdown by most beta-lactamases of clinical interest including class A, C, D, serine beta-lactamases and class B metallo-beta-lactamases (MBLs) due to its design and particularly the configuration of side chains on the molecule.^3-5

Cefiderocol is one of the few agents with activity against Gram-negative isolates carrying MBLs.⁶ In data from the SENTRY Surveillance study, cefiderocol showed potent activity against carbapenem-nonsusceptible Enterobacterales and in the subsets carrying MBL genes, including New Delhi Metallo-β-Lactamase.⁷ In this study, the activity of cefiderocol and comparator agents were assessed against MBL-carrying Enterobacterales collected in the SENTRY Antimicrobial Surveillance Program samples from patients hospitalized in 35 medical centers in the US and 42 sites in Europe, including Turkey and Israel, during 2020–2023.⁷

Contagion: With nearly one-third of patients in the study being immunosuppressed and over a quarter in intensive care, what do these results suggest about cefiderocol’s role in treating critically ill populations?

Slover:The CIRCE study population included a substantial number of critically ill patients: at baseline, 29% of patients were immunosuppressed and more than one quarter of patients (27%) were in the intensive care unit. 13% of patients had septic shock at baseline.¹

At day 14 after cefiderocol initiation, 68% of patients achieved overall clinical cure and 82% achieved clinical response in this critically ill population. These results contribute to the growing body of real-world evidence supporting cefiderocol in treating patients with serious infections caused by multidrug-resistant Gram-negative pathogens, where effective treatment options are limited.¹

Contagion: The study found no new safety signals beyond cefiderocol’s established profile. How important is this finding when introducing newer antibiotics into real-world clinical practice?

Slover: Data from the clinical development program demonstrated the efficacy and safety of cefiderocol to treat difficult-to-treat Gram-negative infections.⁸ However, as pathogens continuously evolve, surveillance and real-world evidence can improve our understanding of how cefiderocol performs in clinical settings.Real-world evidence studies provide data on the safety and effectiveness of medications across different pathogens, regions, infection types and patient populations.

Contagion: Considering the World Health Organization classifies carbapenem-resistant Enterobacterales as a critical priority threat, how do these findings influence future strategies for antimicrobial stewardship and drug development?

Slover: The most frequent pathogens identified among patients in the CIRCE study were carbapenem-resistant Klebsiella Pneumoniae and Enterobacter spp, which are both identified as priority pathogens by the World Health Organization.¹ The new data from CIRCE contributes to the growing body of real-world evidence demonstrating the effectiveness of cefiderocol in treating patients infected with resistant pathogens, including those categorized as Critical Priority by the World Health Organization, for which effective treatments are urgently needed to help address the global burden of antimicrobial resistance.⁹

Our efforts to address antimicrobial resistance (AMR) have been recognized by Access to Medicine Foundationand Shionogi & Co., Ltd. was recently ranked 2nd among large R&D companies in the Antimicrobial Resistance Benchmark Report. This recognition reflects the impact of our commitment to research new drugs, responsibly manufacture existing medicines, improve access and advance stewardship initiatives.

References

1. Boán, J., Aguado, J. M., Soriano-Cuesta, C., Martínez-Sagasti, F., Vidart, N., Hidalgo-Tenorio, C., Sequera, S., Garcia, L., Longshaw, C., & González Calvo, A. J. (2026, April 17–21). Real-world efficacy of cefiderocol for treatment of infections caused by metallo-beta-lactamase-producing Enterobacterales in Spain [Conference poster]. ESCMID Global 2026, Munich, Germany.

2. Kanj, S. S., Kantecki, M., Arhin, F. F., & Gheorghe, M. (2025). Epidemiology and outcomes associated with MBL-producing Enterobacterales: A systematic literature review. International journal of antimicrobial agents, 65(4), 107449. https://doi.org/10.1016/j.ijantimicag.2025.107449

3.Wu JY, Srinivas P, Pogue JM. Cefiderocol: a novel agent for the management of multidrug-resistant Gram-negative organisms. Infectious diseases and therapy. 2020 Mar;9(1):17-40. DOI: 10.1007/s40121-020-00286-6.

4.Soriano, A., & Mensa, J. (2022). Mechanism of action of cefiderocol. Revista Española de Quimioterapia, 35(Suppl 2), 16–19. https://doi.org/10.37201/req/s02.02.2022

5.Kazmierczak KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and metallo-β-lactamase-producing isolates (SIDERO-WT-2014 Study). Int J Antimicrob Agents.2019;53(2):177-184.

6. Boudewijn L.M. DeJonge, et al. Activity of Cefiderocol and Comparator Agents Against Metallo-β-Lactamase Carrying Acinetobacter baumannii-calcoaceticus Complex Isolates Collected in the SENTRY Antimicrobial Surveillance Program. Poster presented at IDWeek 2025.

7. Mendes RE, Kimbrough JH, Beekman D, Maher JM, Sader HS, Castanheira M. Cefiderocol activity against clinical Enterobacterales isolates carrying metallo-β-lactamase genes in United States and European Hospitals (2020–2023) [P-1363]. Poster presented at IDWeek 2024; 16-19 October, 2024; Los Angeles, CA

8. Fetroja^® Prescribing information. Available at: https://www.shionogi.com/content/dam/shionogi/si/products/pdf/fetroja.pdf. Accessed April 2026.

9. World Health Organization. (2023, November 21). Antimicrobial resistance.https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance.