An FDA advisory committee has raised concerns regarding the potential for antibiotic resistance and inappropriate use of sulopenem etzadroxil/probenecid (sulopenem), a novel oral antibiotic intended for the treatment of uncomplicated urinary tract infections (uUTIs) in adult women. The Antimicrobial Drugs Advisory Committee reviewed the risks and benefits of sulopenem, with discussions likely influencing the FDA's final decision on its approval, targeted for October 25.
Concerns Over Resistance and Off-Label Use
A significant concern among FDA advisors is the potential for the development of antimicrobial resistance with sulopenem, which shares similar in vitro activity against targeted species as carbapenems. Carbapenems are typically reserved for severe bacterial infections, and the committee fears that widespread use of sulopenem could compromise their effectiveness. Jalal Sheikh, PhD, from the FDA, noted sulopenem is likely to share resistance to the same organisms as carbapenems.
Appropriate Patient Selection
Committee members, including Roger Lewis, MD, PhD, of the David Geffen School of Medicine at UCLA, emphasized the importance of identifying a subset of patients who would genuinely benefit from sulopenem, ideally those with culture-demonstrated resistance to first-line agents. The committee noted that most uUTIs are treated empirically, which carries the risk of selecting the wrong antibiotic and increasing resistance. Michael Green, MD, MPH, of the UPMC Children's Hospital of Pittsburgh, highlighted the growing problem of carbapenem resistance and the lack of new drug classes to replace them.
Clinical Trial Data and Labeling Considerations
Iterum Therapeutics, the drugmaker, has proposed that the indication for sulopenem should be limited to uUTIs caused by designated susceptible microorganisms in women 18 years and older. However, advisors suggested modifications to the drug's labeling, such as a limitations-of-use statement restricting its use to patients with resistant organisms or those who have failed first-line therapy, or a boxed warning about the risk of off-label use. Data from previous NDA applications showed sulopenem had a better overall response rate compared with ciprofloxacin in the micro-MITTR population with ciprofloxacin-resistant pathogens but was inferior in the micro-MITTS population. New trial data showed sulopenem was noninferior to amoxicillin/clavulanate for overall response in patients with susceptibility to amoxicillin/clavulanate (61.7% vs 55%; 6.7% difference, 95% CI 0.3-13.0) and for clinical success (77.3% vs 76.7%; 0.6% difference, 95% CI -4.8 to 6.1). Sulopenem was superior in achieving microbiologic success (75.2% vs 66.7%; 8.5% difference, 95% CI 2.6-14.3).
Mitigation Strategies
Acting Committee Chairperson Lindsey Baden, MD, of Brigham and Women's Hospital, suggested that risk mitigation should center on timely identification of patients at highest risk, along with postmarketing surveillance and mechanisms for ongoing regulatory review to refine the label and optimize the drug's use.
