FDA OKs New Antibiotic for Complicated Urinary Tract Infections

Officials with the FDA have granted approval to cefiderocol (Fetroja, Shionogi & Co), a new antibacterial drug to treat adults with complicated urinary tract infections (cUTIs), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options, according to a press release.¹

Cefiderocol previously received Priority Review and the FDA’s Qualified Infectious Disease Product designation, which is given to antibacterial and antifungal drug products intended to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now title of the FDA Safety and Innovation Act.¹

Last month, the FDA’s Antimicrobial Drugs Advisory Committee voted 14 to 2 to recommend approval of the antibiotic, finding that Shionogi provided substantial evidence about the efficacy and sufficient evidence of the safety of cefiderocol.²

The approval comes after the CDC released a new report addressing the threat of antibiotic resistance in the United States, in which more than 2.8 million antibiotic-resistant infections occur each year. The World Health Organization and the CDC have identified carbapenem-resistant strains of Enterobacteriaceae, P. aeruginosa, and A. baumannii as the top priority in the research and development of new antibiotics.³

Cefiderocol, a cephalosporin antibiotic, has a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens by acting as a siderophore, according to Shionogi. Cefiderocol also binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters, allowing it to achieve higher concentrations in the periplasmic space where it can attach to penicillin-binding proteins and inhibit cell wall synthesis in the bacterial cells.³

Cefiderocol demonstrated safety and efficacy in the APEKS-cUTI study, which included 448 patients with cUTIs. The study compared cefiderocol versus imipenem/cilastin (IPM/CS).³

According to the data, among the patients who received cefiderocol, 72.6% had resolution of symptoms and eradication of the bacteria approximately 7 days after completing treatment, compared with 54.6% in patients who received IPM/CS. The study also showed similar clinical response rates between both treatment groups.³

In a trial with critically ill patients with multi-drug resistant Gram-negative bacterial infections, higher all-cause mortality rates were seen in patients treated with cefiderocol versus those treated with other antibiotics. Labeling for cefiderocol includes a warning for this risk. Although the cause of mortality has not been established, some of the deaths were a result of worsening or complications of infection, or underlying co-morbidities. This higher all-cause mortality was observed in patients with hospital-acquired/ventilator-associated pneumonia, bloodstream infections, or sepsis; types of infections for which cefiderocol’s safety and efficacy has not been established, according to the FDA.¹

“In the pivotal study, cefiderocol achieved a higher response rate compared to imipenem/cilastatin,” George H. Karam, MD, MACP, Pauly Garvey Manship Chair of Medicine at the Louisiana State University School of Medicine, said in a statement.³ “With today’s approval of cefiderocol, the infectious disease community now has a new type of antibiotic with a unique mechanism of cell entry to add to their toolkit to assist in the complexity of treating highly resistant pathogens that are occurring with increasing frequency in life-threatening infections.”

Serious adverse events were reported for 4.7% of patients who received cefiderocol and 8.1% of patients who received IPM/CS. The most common adverse reactions observed in the trial with cefiderocol included diarrhea, constipation, nausea, vomiting, elevations in liver tests, rash, infusion site reactions, candidiasis, cough, headache, and hypokalemia.¹

Cefiderocol is also being evaluated in patients with nosocomial pneumonia (NP) in the phase 3 APEKS-NP clinical trial. The study met its primary endpoint of non-inferiority compared with high-dose meropenem in all-cause mortality at 14 days after initiation of the study drug.⁴

Shionogi expects to make cefiderocol commercially available in early 2020, according to the release.³

References

• FDA approves new antibacterial drug to treat complicated urinary tract infections as part of ongoing efforts to address antimicrobial resistance [news release]. FDA’s website. https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug-treat-complicated-urinary-tract-infections-part-ongoing-efforts. Accessed November 15, 2019.
• US FDA Advisory Committee Recommends Approval of Cefiderocol for Treatment of Complicated Urinary Tract Infections [news release]. Shionogi’s website. https://www.shionogi.com/u-s-fda-advisory-committee-recommends-approval-of-cefiderocol-for-treatment-of-complicated-urinary-tract-infections/. Accessed November 15, 2019.
• FETROJA (cefiderocol) Approved by the FDA for Treatment of Complicatd Urinary Tract Infections (cUTI) in Adult Patients with Limited or No Alternative Treatment Options [news release]. Shionogi’s website. http://www.shionogi.co.jp/en/company/news/2019/pmrltj0000004e8d-att/e_191115.pdf. Accessed November 15, 2019.
• Shionogi Reports Positive Results from Cefiderocol Phase III Study in Adults with Pneumonia Caused by Gram-negative Pathogens [news release]. Shionogi’s website. https://www.shionogi.com/shionogi-reports-positive-results-from-cefiderocol-phase-iii-study-in-adults-with-pneumonia-caused-by-gram-negative-pathogens/. Accessed November 15, 2019.