ECCMID 2023: Shionogi Announces Real-World Evidence Demonstrating the Efficacy of Fetcroja® / Fetroja® (cefiderocol) Against Some of the Most Difficult-to-Treat Gram-Negative Bacterial Pathogens

A retrospective chart review interim analysis demonstrated that cefiderocol achieved clinical cure in 65% and 60% of patients with Pseudomonas aeruginosa and Acinetobacter baumannii respectively, the majority of whom were severely ill with comorbidities.

OSAKA, Japan, APRIL 17, 2023 - Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.; hereafter "Shionogi") announces key data for Fetcroja^® (cefiderocol), an innovative siderophore cephalosporin, to be presented at the 33^rd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), April 15-18, 2023, including new real-world evidence demonstrating its efficacy against some of the most difficult-to-treat Gram-negative bacterial infections.

In Europe, cefiderocol is commercially available under the brand name Fetcroja^® for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.¹ In the US, cefiderocol is available under the brand name Fetroja^® and is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia (HABP/VABP) and complicated urinary tract infections (cUTIs) caused by certain susceptible Gram-negative microorganisms.²

Interim results are emerging from PROVE (Retrospective Cefiderocol Chart Review), an ongoing international, retrospective study of the real-world use of cefiderocol for Gram-negative infections across EU and US sites.^3,4 The study includes 194 patients with Pseudomonas aeruginosa infections treated with cefiderocol (123 from the US and 71 from the EU). These were generally seriously ill patients, many requiring mechanical ventilation and/or vasopressor support. The interim results show that cefiderocol achieved clinical cure in 65% of these patients, and 81% of patients were alive within 30 days of starting cefiderocol treatment. The patients principally had respiratory tract and bloodstream infections. Cefiderocol was initiated for a documented pathogen in the majority of cases (77%), and as monotherapy in 57% of patients. 

Also in the study were 98 patients with Acinetobacter baumannii infections (71 from US and 27 from the EU).  The patients had respiratory infection and bacteraemia as the most common infections. High levels of organ support were required in these patients, with 45% receiving mechanical ventilation and 30% requiring vasopressor support. Cefiderocol achieved clinical cure in 60% of patients, and 76% of patients were alive within 30-days of starting treatment. Cefiderocol was targeted as first treatment or as salvage therapy in 93% of patients, and as monotherapy in 41% of patients.

“These interim results from PROVE build on a growing body of real-world evidence across Europe and the US demonstrating the efficacy of cefiderocol in treating patients with life-threatening infections, such as Acinetobacter baumannii and Pseudomonas aeruginosa, the majority of whom are very sick with multiple comorbidities,” commented Prof. Dr. Dominic Wichmann, Consultant in department of Intensive Care Medicine, University of Hamburg-Eppendorf. “These are pathogens that fall into the World Health Organization’s critical priority list, for which effective treatments are urgently needed.”

Antimicrobial resistance (AMR) is a major health burden which urgently needs to be addressed. Globally, in 2019, there were 1.27 million deaths attributable to bacterial AMR.⁵ Infections caused by carbapenem-resistant Gram-negative bacteria are often associated with a high mortality rate.⁶ If no action is taken, antimicrobial resistance is predicted to kill 10 million people every year by 2050, at a cumulative cost to global economic output of 100 trillion USD.⁷

Cefiderocol is a siderophore cephalosporin antibiotic with an innovative mechanism for penetrating the outer cell membrane of Gram-negative pathogens by acting as a siderophore. In addition to entering cells by passive diffusion through porin channels, cefiderocol binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters, which function to incorporate this essential nutrient for bacteria.⁸ These mechanisms allow cefiderocol to achieve higher concentrations in the periplasmic space where it can bind to penicillin-binding proteins and inhibit cell wall synthesis in the bacterial cells.⁹ Cefiderocol has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases.^10,11 Data from multinational surveillance studies for cefiderocol demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant A. baumannii, P. aeruginosa, Enterobacterales, and S. maltophilia.¹² The clinical significance of the in vitro data is unknown. Cefiderocol has no clinically relevant activity against Gram-positive or anaerobic bacteria.

In Europe, cefiderocol is commercially available under the brand name Fetcroja^® for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.

Fetroja^® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.

SHIONOGI Website Inquiry Form : https://www.shionogi.com/global/en/contact.html

¹ FETCROJA SMPC. Available at: https://www.ema.europa.eu/en/documents/product-information/fetcroja-epar-product-information_en.pdf

Last accessed March 2023

² Fetroja FDA prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209445s002lbl.pdf

Last accessed March 2023

³ Larcher R, et al. Real-world use of cefiderocol in the EU and US for Pseudomonas aeruginosa: interim data from the PROVE

study. ECCMID abstract P2274

⁴ Timsit JF, et al. Real-world use of cefiderocol in the EU and US for Acinetobacter baumannii: interim data from the PROVE

study. ECCMID abstract P2272

⁵ Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis.

Lancet 2022; 399: 629–55

⁶ Perez F, et al. ‘Carbapenem-Resistant Enterobacteriaceae: A Menace to our Most Vulnerable Patients’. Cleve Clin J Med. Apr

2013; 80(4): 225–33

⁷ O’Neill. The Review on antimicrobial resistance. 2016. Available at: https://amr

review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf Last accessed March 2023

⁸ Ito A, Nishikawa T., Masumoto S, et al. Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for

Antibacterial Activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016;60(12):7396-7401

⁹ Tillotson GS. Trojan Horse Antibiotics—A Novel Way to Circumvent Gram-Negative Bacterial Resistance? Infectious

Diseases: Research and Treatment. 2016;9:45-52 doi:10.4137/IDRT.S3156

¹⁰ K Kazmierczak 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). ). International Journal of Antimicrobial Agents, 2019; 53(2) 177-184

¹¹ A Ito et al. In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative

Bacteria. Antimicrobial Agents and Chemotherapy, 2018, 62:e01454-17.

¹² M Hackel, M Tsuji, Y Yamano, et al. In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, Against a Recent

Collection of Clinically Relevant Gram-Negative Bacilli from North America and Europe, Including Carbapenem Non-

Susceptible Isolates: The SIDERO-WT-2014 Study. Antimicrobial Agents Chemotherapy. 2017;61(9)

¹³ Antimicrobial Resistance Benchmark 2021.

https://accesstomedicinefoundation.org/medialibrary/resources/61ee760d03810_Antimicrobial%20Resistance%20Benchmark%20report%202021.pdf Last accessed March 2023