FDA OKs cefiderocol for complicated urinary tract infections

Drugs for urinary tract infection
Drugs for urinary tract infection

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The US Food and Drug Administration (FDA) has approved a new antibiotic for patients with severe urinary tract infections and few other treatment options.

The agency announced late yesterday that is has approved cefiderocol for the treatment of complicated urinary tract infections (cUTIs), including kidney infections, caused by gram-negative bacteria in patients with limited or no other treatment options. FDA approval was based on the results of a multinational randomized phase 2 clinical trial that evaluated the safety and efficacy of the drug in patients with cUTI versus a comparator antibiotic (imipenem-cilastatin).

The results of the trial showed that symptoms were resolved and bacteria eradicated 7 days after treatment in 72.6% of patients (183 of 252) administered cefiderocol, compared with 54.6% of patients (65 of 119) in the imipenem-cilastatin arm. Clinical response rates (resolution of symptoms alone) were similar between the two groups.

Novel mechanism of action

"Today's approval provides an additional treatment option for patients with cUTIs who have limited or no alternative treatment options," John Farley, MD, MPH, acting director of the Office of Infectious Diseases in the FDA's Center for Drug Evaluation and Research, said in a press release.

"A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections, like cUTIs. This approval represents another step forward in the FDA's overall efforts to ensure safe and effective antimicrobial drugs are available to patients for treating infections."

Developed by Japanese drug maker Shionogi & Co, of Osaka, cefiderocol is a cephalosporin antibiotic with a novel method of penetrating the tough outer membrane of gram-negative bacteria, including multidrug-resistant (MDR) strains. Attached to the drug's main molecule is a siderophore, a compound secreted by bacteria to seek out iron—which bacteria need for survival—and transport it across cell membranes. Cefiderocol is also able to overcome other resistance mechanisms used by gram-negative bacteria to evade antibiotics.

Cefiderocol was designated as a Qualified Infectious Disease Product (QIDP) by the FDA, a designation given to antibacterial or antifungal products that treat serious or life-threatening infections and address unmet medical needs. QIDPs are eligible to be fast-tracked for FDA approval, and they receive priority review. The FDA's Antimicrobial Drugs Advisory Committee recommended cefiderocol for approval in a 14-2 vote last month.

Approval comes with warning

The FDA statement also noted, however, that labeling for cefiderocol, which will be sold under the brand name Fetroja, will come with a warning about higher all-cause mortality found in patients with highly drug-resistant infections who were treated with the drug in another clinical trial.

The warning is based on a phase 3 study comparing cefidericol against the best available therapy in patients with cUTIs, hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), and bloodstream infections or sepsis caused by carbapenem-resistant bacteria. An independent adjudication committee found that, among the patients with HABP/VABP, bloodstream infections, and sepsis, a greater percentage in the cefiderocol arm had infection-related death with treatment failure than in the control arm (15.8% vs 8.2%).

"The safety and efficacy of Fetroja has not been established for the treatment of these types of infections," the FDA said.

The cause of the increase in mortality among those patients has not been established, but concerns about the findings led some members of the Antimicrobial Drugs Advisory Committee to recommend a boxed warning.

Effect against metallo-beta-lactamases

Neil Clancy, MD, an associate professor of medicine and director of the mycology program at the University of Pittsburgh, says that infections caused by highly resistant pathogens like carbapenem-resistant Enterobacteriaceae (CRE), along with non-fermenting bacteria like Acinetobacter baumannii and Pseudomonas aeruginosa, are where cefidericol will especially be needed.

"The urinary tract indication…is ultimately not where this is going to fit in to the armamentarium," said Clancy, who consulted with Shionogi on cefiderocol.

While several new CRE antibiotics have been approved in recent years, Clancy explained that cefiderocol is different because it has shown the ability, in laboratory and animal studies, to overcome carbapenem resistance caused by metallo-beta-lactamase enyzmes like NDM (New Delhi metallo-beta-lactamase), which are carried on mobile genes that can be shared among different species of bacteria. Bacteria carrying NDM and other metallo-beta-lactamase genes have become a significant source of severe and deadly multidrug-resistant infections in India and have begun spreading to other countries.

Most other CRE antibiotics are directed mainly against Klebsiella pneumoniae carbapenemase (KPC)-carrying Enterobacteriaceae—which are more common in the United States—and don't cover metallo-beta-lactamases.

"We've not seen, as yet, a massive influx into this country of metallo-beta-lactamases, but they predominate in many other parts of the world, so that's a legitimate hole in what we have right now," Clancy said.

Because Shionogi hasn't yet been able to show that cefiderocol is better than currently available drugs in treating patients with these types of highly resistant and difficult-to-treat infections (the cUTI trial did not include patients with carbapenem-resistant infections), Clancy said it will be up to clinicians to figure out how the drug should be used.

"The crucial piece of data that this really offers something against those multidrug-resistant infections, those data aren't there," he said. "I'm happy it got approved, but we'll have to see where it ends up going."

The most common adverse reactions observed in patients treated with cefiderocol in the cUTI trial included diarrhea, constipation, nausea, vomiting, and infusion-site reactions. The FDA said the antibiotic should not be used in patients who have a known history of severe hypersensitivity to beta-lactam antibiotics.

See also:

Nov 12 FDA press release

Nov 12 Shionogi & Co. press release

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