FDA Approves Antibiotic Combination for Complicated UTIs

The FDA approved the combination of cefepime and enmetazobactam (Exblifep) for the treatment of adult patients with complicated urinary tract infections, including pyelonephritis.

The agency’s decision was based on data from the phase III ALLIUM trial in which the β-lactam/β-lactamase inhibitor combination demonstrated superiority over piperacillin/tazobactam.

Clinical efficacy was shown for Pseudomonas aeruginosa and among Enterobacterales species for Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae complex, the FDA noted.

In ALLIUM, 1,041 patients with complicated urinary tract infection or acute pyelonephritis were randomized (mean age 54.7 years, 55% women) and 1,034 received at least one dose of the study drug.

The proportion of patients infected with gram-negative pathogens who achieved clinical cure and microbiological eradication at the test-of-cure visit was 79.1% in the cefepime/enmetazobactam group compared with 58.9% in the piperacillin/tazobactam group, a difference that met the trial’s prespecified criteria for non-inferiority and superiority.

In the 20.9% (142/678) of patients with an extended-spectrum β-lactamase (ESBL)-producing baseline pathogen, 73.7% of patients in the cefepime/enmetazobactam group and 51.5% of those in the piperacillin/tazobactam group achieved the composite outcome.

“Antimicrobial resistance mediated by ESBLs is a critical clinical challenge and there is a substantial need for novel antibiotics that enable us to effectively treat resistant infections,” said Keith Kaye MD, MPH, of Rutgers University in New Brunswick, New Jersey, and the study’s lead author, in a press release that accompanied the publication of ALLIUM’s results.

“Cefepime/enmetazobactam has shown improved efficacy compared to a standard of care treatment with a good safety profile,” he added. “It has the potential to become a replacement for piperacillin/tazobactam and an alternative to the use of carbapenems.”

Treatment-emergent adverse events (TEAEs) were observed in 50% of patients treated with cefepime/enmetazobactam and 44% of those treated with piperacillin/tazobactam, with most mild to moderate in severity (89.9% vs 88.6%, respectively).

Rates of drug-related TEAEs were 19.8% and 14.5%, respectively, and treatment-emergent serious adverse events were 4.3% and 3.7%.

The most common TEAEs were elevations of liver function parameters, including alanine aminotransferase (11.4% vs 11.6%), aspartate aminotransferase (9.1% vs 8.9%), and blood bilirubin (5.8% vs 3.9%).

Of those who received cefepime/enmetazobactam, 1.7% failed to complete therapy due to adverse events versus 0.8% of those who received piperacillin/tazobactam.

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