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The US FDA has approved a novel injectable antibiotic combination of the fourth-generation cephalosporin drug cefepime and zidebactam (Zaynich, Wockhardt) for the treatment of complicated urinary tract infections (UTIs) including pyelonephritis, Wockhardt reported.

“Multidrug-resistant bacterial infections are a substantial burden for patients and the healthcare system, as patients with these infections typically require longer, more intensive care, and are at increased risk of life-threatening complications,” explained Keith Kaye, MD, MPH, professor of medicine and division chief for infectious diseases at Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, in a Wockhardt press statement.

“There is an ongoing need for new antibiotics to combat these drug-resistant pathogens, and we are pleased that this approval means patients will soon have an exciting unique option,” he said.

Complicated UTIs result in as many as 600,000 hospitalizations in the US annually, and the infections — associated with significant morbidity and mortality — are increasingly caused by multidrug-resistant bacteria.

The cefepime-zidebactam combination has shown a synergistic effect in treating gram-negative resistant infections. Cefepime primarily targets penicillin-binding protein-3 (PBP3) and PBP1a/b in Enterobacterales , and PBP3 in other gram-negative bacterial pathogens, while zidebactam, a non-beta-lactam antibacterial and beta-lactamase inhibitor, selectively inhibits PBP2, according to Wockhardt.

“This synergy occurs even in the presence of beta-lactamases, including metallo-beta-lactamases, which are not inhibited by zidebactam, and other non-enzymatic cefepime resistance mechanisms, such as hyper-efflux and downregulation of outer membrane porin channels,” the company reported in their press statement.

In the phase 3 ENHANCE-1 trial— which was, in part, a basis for the FDA approval — 529 patients at 44 global sites who were hospitalized with a diagnosis of complicated UTI or acute pyelonephritis were randomized to the cefepime-zidebactam combination or the broad-spectrum carbapenem antibiotic meropenem.

In each group, patients were treated for 7-10 days with adjustments in dose based on renal function. 

For the primary endpoint of achieving a composite clinical cure and microbiological response rate at the test-of-cure visit at day 17 (± 2 days), the cefepime-zidebactam combination showed significantly greater improvement, with 89.0% of patients reaching the endpoint vs 68.4% in the meropenem group, representing a treatment difference 20.6%. 

The results were consistent in all analyzed subgroups, including older adults and those with renal-insufficiency, obesity, and cefepime-resistant uropathogens.

The combination therapy was generally well-tolerated.

The cefepime-zidebactam combination is indicated specifically for the treatment of complicated UTIs including pyelonephritis that are caused by susceptible microorganisms including Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae complex, and Pseudomonas aeruginosa.

Kaye noted, however, potentially important uses of the combination beyond the specific indications.

“While this new antibiotic does not currently have an FDA indication for treatment outside of the urinary tract, it might be used off label to treat infections occurring outside of the urinary tract due to resistant gram-negative bacteria for which there are limited treatment options — including bloodstream infection, intra-abdominal infection, and pneumonia,” he told Medscape Medical News.

Ultimately, “ this is an exciting innovative antibiotic that has unique, broad activity against many of the highly resistant strains of gram-negative pathogens — including some of which are resistant to most, and in some cases all, other safe and effective antibiotic options,” Kaye said.

The ENHANCE-1 trial was sponsored by Wockhardt. Kaye is a paid consultant for Wockhardt.