As antibiotic resistance continues to rise globally, reviewers at a recent FDA meeting raised concerns about the potential risks of providing an oral antibiotic for uncomplicated urinary tract infections (uUTIs).

On September 9, the FDA’s Antimicrobial Drugs Advisory Committee (AMDAC) examined Iterum Therapeutics’s antibiotic oral sulopenem. Iterum’s drug, which is sulopenem etzadroxil combined with probenecid in a bilayer tablet, is a thiopenem antibiotic. If approved, it could become the first oral penem available in the US to treat uUTIs.

This was not the first time Iterum’s sulopenem reached the regulator. In July 2021, the FDA issued a complete response letter rejecting Iterum’s antibiotic due to insufficient evidence of effectiveness in the Phase III uUTI 301 (NCT03354598) and 310 (NCT05584657) trials. In the former study, oral sulopenem demonstrated efficacy in the ciprofloxacin-resistant patient cohort, but it was not effective in the ciprofloxacin-susceptible population, primarily due to microbiologic failure. Similarly, in the 310 study, Iterum’s sulopenem established efficacy in patients who were Augmentin (amoxicillin/clavulanate)-susceptible, but results were inconclusive in the Augmentin-resistant population due to the small sample size.

Furthermore, neither study recruited patients with uUTI due to resistant bacteria such as extended-spectrum β-lactamases (ESBL)-producers or those who failed first-line treatment.

After FDA feedback, Iterum initiated the Phase III REASSURE clinical trial in October 2022, which formed the basis of an NDA resubmission in April 2024. In the trial, oral sulopenem was effective in 61.7% of patients compared to 55% of patients on Augmentin. The FDA has set a prescription drug user fee act (PDUFA) date of October 25, by which it will assess the company’s new drug application (NDA) for oral sulopenem.

However, years of antibiotic overuse have made the employment of new and effective antimicrobials a Catch-22 situation. While new drugs are needed to combat resistance, widespread or indiscriminate use of these improved therapies could also lead to newly resistant organisms.

Very few companies are currently developing new antibiotics for patients, and this is an essential step in tackling the resistance problem, so Iterum’s new antibiotic is very welcome, says Vicky Bennett, a PhD researcher at the University of Bath, UK, focusing on antibiotic resistance. The availability of both intravenous and oral formulations will allow patients to access treatments outside of the hospital, allowing earlier hospital discharge, says Dr. Lars Bjerrum, a professor at the University of Copenhagen, Denmark.

However, Bjerrum adds that it is a “major concern” that the drug may be administered orally and “heavily misused”. The World Health Organization’s (WHO) Global Priority Pathogen List of resistant bacteria lists several bacteria targeted by sulopenem, including carbapenem-resistant gram-negative bacteria. If approved, the way in which this antimicrobial drug is used remains key to the development of new and innovative antimicrobial drugs.

Risk-benefit assessment challenging

uUTIs are bacterial infections in the bladder and lower urinary tract in non-pregnant individuals who do not have other conditions that could increase the risk of complications. In the US, uUTIs are the most prevalent bacterial infections in the ambulatory setting.

The AMDAC members acknowledged that while there are multiple FDA-approved oral antibacterial drugs for the treatment of uUTIs, there are limited options. This was partly due to adverse reactions limiting the choices and rising antimicrobial resistance to first-line antibacterial drugs, including ESBL-producing bacteria.

Carbapenem therapy is the primary treatment option for uUTIs caused by ESBL producers, but current options are delivered intravenously. Other first-line alternatives include oral nitrofurantoin, TMP-SMX, fosfomycin, and pivmecillinam, which may become ineffective in the future due to their overuse contributing to resistance.

A shorter course or lower dose of the drug, which could be possible given Phase III results, may lead to a higher risk of developing bacterial resistance, says Bjerrum. Additionally, with oral administration, there are concerns surrounding a potential influence on other bacteria in the gastrointestinal system, adds Bjerrum.

Bjerrum explains that a leading cause of the rise in antibiotic resistance related to uUTIs is the empirical treatment of the disease, where patients are given a course of treatment that may not be specific to their case. While Danish guidelines now prevent the prescription of critical antibiotics without a patient susceptibility test, this remains a challenge, he adds.

With oral sulopenem, several AMDAC members said the drug’s label and dosage would need to be specified for responsible prescription. “The positioning comes down to only using it [oral sulopenem] when it is really needed,” says Hazel Parker, an honorary clinical senior research fellow at the University of Exeter, UK, researching antibiotic prescribing practices in the UK. “For example, this can be based on culture results that show resistance to other treatment options. Pack sizes that mirror treatment courses could also be beneficial,” says Parker. The drug’s label will likely have warnings surrounding the potential of antibiotic resistance, adds Bennett.

In a 13 September press release, Corey Fishman, Iterum’s CEO, said he agreed that “the appropriate use of oral sulopenem by treating physicians is critical to limiting antimicrobial resistance”.

At the AdCom, Dr. Angela Kopack, an AMDAC member, discussed the potential addition of a section on the label specifying use limitations, which would include any uncertainties about the risk-benefit profile and have clear outlines of which patients should have access to the therapy. The positioning of this information on the drug’s label would also need to be assessed by the FDA.

A push towards antibiotic stewardship

When the WHO released its “bacterial priority pathogens list” released in May 2024, the organization underscored the need for public-private cooperation in efforts to curb antibiotic resistance. Parker highlights Merck’s antibiotic stewardship efforts as a good example for the pharmaceutical industry to follow in tackling the antimicrobial resistance problem, given its support of the Study for Monitoring Antimicrobial Resistance Trends (SMART) initiative, researches molecular epidemiology.

Iterum could potentially take on stewardship efforts through its post-marketing surveillance, suggests Bjerrum. Studies that last for at least one year, examining the gastrointestinal tract could help evaluate the impact of the oral antibiotic’s impact on resistant strains. However, despite public interest in such studies, there is much less participation in such research on the industry side, explains Bennett.

Dr. Lindsey R. Baden, the acting AMDAC chairperson, says all available post-marketing surveillance tools will be essential for the antibiotic’s use as this is a dynamic problem. On stewardship programs, several members envisioned a mechanism for regulatory review of new data from post-marketing studies to further refine the label and design education and optimization of its use.

During the AdCom, Iterum suggested that prior authorizations by insurance companies could limit the misuse of the drug upon approval. However, Jia Ahmad, a research fellow at Public Citizen’s Health Research Group, rebutted Iterum’s suggestion, saying, “This strategy, even in combination with language in the labeling of the drug and communications with prescribers, is insufficient to mitigate the risk of increasing antimicrobial resistance. Furthermore, judicious regulation that would prevent overutilization or inappropriate use of this drug is the purview of the FDA, not insurance companies.” She suggested that future post-market studies could measure the frequency of oral sulopenem’s off-label use and uUTI infections that could be treated with other drugs.