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An FDA advisory committee raised concerns on Monday about the potential for antibiotic resistance with and inappropriate use of a novel oral antibiotic for the treatment of uncomplicated urinary tract infections (uUTIs).

During the , members of the Antimicrobial Drugs Advisory Committee reviewed two topics: 1) the overall risks and benefits of sulopenem etzadroxil/probenecid (sulopenem) for the treatment of uUTIs in adult women, and 2) considerations that would be important to convey to medical providers to ensure appropriate use of the drug.

The committee did not vote, but the discussion will likely influence the FDA's final decision on sulopenem's approval, which has a target date of October 25.

As previously detailed, the FDA rejected oral sulopenem in 2021 for uUTI, based on mixed data from a phase III trial, and recommended that drugmaker Iterum Therapeutics conduct an additional trial. After completing another phase III trial, Iterum resubmitted a new drug application (NDA) in April.

Potential for the development of antimicrobial resistance with sulopenem, as well as closely related carbapenems, was a major concern among FDA advisors. Carbapenems are typically reserved for severe or life-threatening bacterial infections.

Penems have slight molecular differences from carbapenems, said Jalal Sheikh, PhD, the FDA's clinical microbiology reviewer. However, sulopenem demonstrates similar in vitro activity against most targeted species as carbapenems. Importantly, sulopenem is likely to share resistance to the same organisms as carbapenems, Sheikh said.

Iterum proposed that the indication for the antibiotic should be for the treatment of uUTI caused by designated susceptible microorganisms in women 18 years of age and older.

However, FDA advisors pointed out that most uUTIs are treated empirically, without performing culture and sensitivity testing. The practice carries the risk of choosing the wrong antibiotic and increasing chances for resistance, they said.

"With that wording and that interpretation, which may or may not have been intended by the sponsor, I would not support a positive benefit-risk for that broad class," said committee member Roger Lewis, MD, PhD, of the David Geffen School of Medicine at the University of California Los Angeles.

"It seems to me that the considerations that balance the benefit-risk in the positive direction rely on identifying a subset of patients who have a low probability of successful clinical cure with accepted first-line agents," Lewis added. "That population is ideally defined by a culture that demonstrates resistance to accepted first-line agents. But as I mentioned earlier, in my clinical practice, that's rarely the setting in which I find myself."

Other committee members voiced similar concerns that Iterum had not attempted to identify patient characteristics that could help clinicians decide who would most benefit from sulopenem. For example, the phase III clinical trials did not analyze efficacy data based on menopausal status or number of recurrent UTIs.

"So, in my mind, an acceptable positive benefit-risk ratio would require wording that restricts the use to a population at substantially higher risk of treatment failure with currently available first-line oral agents," Lewis said.

Committee member Michael Green, MD, MPH, of the UPMC Children's Hospital of Pittsburgh, noted that "carbapenem resistance is a thing and it's far worse now than it was 10 years ago."

"And now we don't have the next class of drugs after the penems and carbapenem," he emphasized. "I've taken care of patients even last week that had no drugs that could be used. In the back of all of our minds is what happens if [sulopenem] gets broadly used in the community and we no longer have a benefit of carbapenems and no new class really evolving to take its place."

Acting Committee Chairperson Lindsey Baden, MD, of Brigham and Women's Hospital in Boston, noted that "overall, I have the sense from the committee that there are certain circumstances where this agent may be beneficial to our patients. There is a high risk of off-label use and significant community risks to amplification of resistance, particularly [carbapenem-resistant Enterobacterales] infections."

"There's individual risk to that amplification, not just community [risk]," he pointed out. "Risk mitigation is likely to center on a timely identification of who's at highest risk."

Tools such as postmarketing surveillance and mechanisms for ongoing regulatory review would be necessary "to be able to further refine the label and the education, and the optimization of its use," he added.

Advisors proposed that modifications to the candidate drug's labeling might be warranted. Two strategies could be the inclusion of a limitations-of-use statement indicating that sulopenem should be used only in patients with resistant organisms or those who have failed a first-line therapy, or a boxed warning about the risk of off-label use.

Data from the previous NDA application showed the drug had a better overall response rate compared with ciprofloxacin in the microbiological modified intent-to-treat-resistant (micro-MITTR) population with ciprofloxacin-resistant pathogens. However, it was inferior to ciprofloxacin in the microbiological modified intent-to-treat-susceptible (micro-MITTS) population with ciprofloxacin-susceptible baseline pathogens.

The new trial data that Iterum submitted revealed that in patients with susceptibility to amoxicillin/clavulanate (micro-MITTS), oral sulopenem was noninferior to amoxicillin/clavulanate for overall response -- defined as a composite of clinical success and microbiologic eradication -- at day 12 (61.7% vs 55%; 6.7% difference, 95% CI 0.3-13.0). The drug was also noninferior to amoxicillin/clavulanate for clinical success (77.3% vs 76.7%; 0.6% difference, 95% CI -4.8 to 6.1) in the micro-MITTS group.

Sulopenem did prove to be superior to its comparator in achieving microbiologic success (75.2% vs 66.7%; 8.5% difference, 95% CI 2.6-14.3).

However, no conclusions could be drawn from the trial's results for sulopenem use in patients resistant to amoxicillin/clavulanate (micro-MITTR), because of the small number of patients in that group.

Asymptomatic bacteriuria at day 5 and at day 12 did not predict clinical failure at day 12 or day 28.

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