Antibiotic Resistance in the Context of UTI Treatment Developments
Jeff Freiberg, MD, PhD review on key trials and challenges from 2024 in the fight against antibiotic resistance in complicated and uncomplictaed UTIs, including cefepime-taniborbactam and gepotidacin.
Clinical science in infectious diseases (ID) saw significant progress in 2024, with multiple clinical trials of new antibiotics and infection prevention strategies. The year also brought public health challenges, including outbreaks of antimicrobial resistance, and more, highlighting the continued need for research and clinical interventions.1
At IDWeek 2024, experts gathered to review these developments and ongoing challenges. The What's Hot in ID Clinical Science session highlighted key trials and trends from the past year. While many studies were considered, this review focuses on findings that may influence future clinical practice.1
Antibiotic resistance, due to resistant gram-negative organisms, has become a concern in the treatment of UTIs. Over the past year, recurrent UTIs, often treated with antibiotics, have led to increased resistance, making these infections harder to manage. This issue has spurred clinical trials aimed at identifying new antibiotics and alternative treatments for uncomplicated and complicated UTIs.1
In our interview with Jeff Freiberg, MD, PhD, assistant professor at Vanderbilt University Medical Center and expert in infectious diseases, he explained the impact of antibiotic resistance on UTI treatment. “Part of the problem with antibiotic resistance is driven by resistant, gram-negative organisms, and one of the places we commonly encounter these is in urinary tract infections,” Freiberg noted. “We see a pattern where people with recurrent UTIs are treated repeatedly over time, which leads to increasing resistance. This makes it a critical area for exploring new treatment options.”
One of the developments in this area was the trial of cefepime-taniborbactam, a combination of a fourth-generation cephalosporin and a new beta-lactamase inhibitor. The trial, which focused on complicated UTIs, found that the combination was superior to meropenem, a commonly used antibiotic, in terms of microbiological success. While both treatments showed similar clinical success, the cefepime-taniborbactam combination achieved better microbiological outcomes.2
Despite the promising results, the FDA rejected the application for approval, citing concerns related to the manufacturing process rather than the drug's efficacy. Freiberg elaborated “The data was very promising, and there were no concerns about efficacy,” he said. “But until the manufacturing concerns are addressed, we are left in a position where it’s unclear when or if we’ll see this drug as an FDA-approved option.”
Another antibiotic, gepotidacin, first-in-class DNA replication inhibitor. Unlike fluoroquinolones, which target DNA replication differently, gepotidacin binds to alternative sites, making it potentially less susceptible to the development of resistance. This novel mechanism has sparked significant interest in treating uncomplicated UTIs.
Gepotidacin was studied in two trials, the EAGLE-2 and EAGLE-3 studies, both of which compared the drug to nitrofurantoin and trimethoprim-sulfamethoxazole—common oral antibiotics for UTIs. The results were encouraging, with one study finding gepotidacin non-inferior to nitrofurantoin, while the other demonstrated its superiority. These findings suggest that gepotidacin could become an important new oral treatment for uncomplicated UTIs.1
Freiberg highlighted the significance of these findings, “gepotidacin represents an exciting new option for treating uncomplicated UTIs, particularly because it binds in a different way than fluoroquinolones, potentially reducing the risk of resistance development. The results from the EAGLE-2 and EAGLE-3 studies are very promising, and this could offer an important alternative to current treatments.”
“With antibiotic resistance on the rise, we need new treatments now more than ever,” Freiberg said. “The clinical data for drugs like cefepime-taniborbactam and gepotidacin is very encouraging, but we still face hurdles in terms of approval and availability. The medical community must continue to push for innovative treatments to combat resistant infections.”
Another advancement in the realm of UTIs from 2024 was the FDA approval of oral sulopenem (Orlynvah) from Iterum Therapeutics for treating uncomplicated urinary tract infections (uUTIs) in adult women. The approval followed results from the SURE 1 and REASSURE trials, which showed the drug's effectiveness against Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. In the SURE 1 trial, sulopenem demonstrated better results than ciprofloxacin for fluoroquinolone-resistant infections, while in the REASSURE trial, it outperformed amoxicillin/clavulanate. The approval addresses the need for treatment options for resistant infections, with post-market monitoring recommended.3
