Cefiderocol calms cUTI

OSAKA, Japan & FLORHAM PARK, N.J.—Shionogi & Co., Ltd. reported yesterday that The Lancet Infectious Diseases has published clinical results from the pivotal randomized controlled trial evaluating cefiderocol for the treatment of complicated urinary tract infection (cUTI) in patients at risk of multidrug-resistant Gram-negative infections.

The paper, entitled “Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative pathogens: a phase 2, randomised, double-blind, non-inferiority trial,” was published October 25th.

Results from the study demonstrated that treatment with cefiderocol met non-inferiority versus imipenem/cilastatin (IPM/CS) in patients with cUTI at test of cure (TOC). In the study, 73 percent (183/252) of patients in the cefiderocol group met the primary endpoint (combination of clinical response and microbiological response at TOC) versus 55 percent (65/119) in the IPM/CS group, with an adjusted treatment difference of 18.58 percent. These results in a post-hoc analysis showed that cefiderocol was superior to IPM/CS. The study enrolled 452 patients with cUTI and patients were randomly assigned 2:1 to cefiderocol and IPM/CS with a median duration of treatment of nine days for both groups.

The microbiologic response rate at TOC for the cefiderocol group was 73 percent (184/252) versus 56 percent (67/119) in the IPM/CS group, with the difference between groups at TOC at 17.25 percent. Although the study was designed to determine non-inferiority, the findings showed that cefiderocol resulted in clinically meaningful microbiological eradication rates and outperformed IPM/CS. Additionally, cefiderocol exhibited a safety profile consistent with that of other cephalosporins.

Cefiderocol is a siderophore cephalosporin with a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens, including MDR strains. 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. This mechanism allows cefiderocol to achieve higher concentrations in the periplasmic space where it can then bind to receptors and inhibit cell wall synthesis in the bacterial cells.

Cefiderocol can also enter cells by passive diffusion through porin channels and is stable against all known classes of beta-lactamases, including both the metallo- and serine-β-lactamases. Data from global surveillance studies for cefiderocol demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii, P. aeruginosa, Enterobacteriaceae, and S. maltophilia. Cefiderocol has poor in vitro activity against Gram-positive or anaerobic bacteria.

Currently in clinical development, cefiderocol has two Phase III studies ongoing and enrolling patients with carbapenem-resistant pathogens at various infection sites (CREDIBLE-CR) and a HAP/VAP/HCAP clinical trial (APEKS-NP). The company plans to submit a New Drug Application to the U.S. Food and Drug Administration late in the year, followed by a marketing authorization application to the European Medicines Agency and other countries.

“The data presented in The Lancet Infectious Diseases shows the potential of cefiderocol, particularly in a complicated patient population with comorbidities and at greater risk of multidrug-resistant infection with difficult to treat Gram-negative bacteria,” said Dr. Tsutae “Den” Nagata, Chief Medical Officer, Shionogi. “Once approved, cefiderocol will be an important, new antibiotic option for providers caring for these very sick patients who may have very limited treatment options.”