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FDA Reviewers Voice Concerns Over Novel UTI Treatment

Ahead of an Antimicrobial Drugs Advisory Committee meeting on Monday, FDA reviewers voiced ongoing concerns about the benefits versus risks of a novel oral antibiotic for the treatment of uncomplicated urinary tract infections (uUTIs), including its potential for inappropriate use.

The drug in question -- sulopenem etzadroxil/probenecid (sulopenem) -- is a penem antibiotic with in vitro activity against gram-positive, gram-negative, and anaerobic organisms including Enterobacterales species that encode extended-spectrum β-lactamases (ESBLs) and AmpC-type β-lactamases.

Based on mixed data from phase III trial outcomes, the FDA rejected the antibiotic in 2021 and recommended that Iterum Therapeutics conduct an additional trial.

After completing another phase III trial, Iterum resubmitted a new drug application (NDA) in April of this year. Iterum is seeking approval for sulopenem etzadroxil/probenecid as treatment for uUTI in adult women caused by susceptible organisms.

New antibiotics are needed for the treatment of uUTIs. Currently, oral first-line treatment of uUTIs include nitrofurantoin, trimethoprim-sulfamethoxazole, fosfomycin, and pivmecillinam (Pivya). Alternate drugs include amoxicillin or oral cephalosporins. However, drug-resistant uUTI may require treatment with IV antibiotics, the FDA pointed out.

"While there are multiple FDA-approved oral antibacterial drugs for the treatment of uUTI, treatment options can be limited by adverse reactions and increasing antimicrobial resistance (AMR) to first-line antibacterial drugs, including through production of extended-spectrum β-lactamases," the agency wrote.

The phase III trial from the previous NDA application (Trial 301, SURE-1) showed sulopenem etzadroxil/probenecid was superior to ciprofloxacin for the overall response rate 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.

Moreover, two previously conducted phase III trials -- one for complicated UTI (Trial 302, SURE-2) and another for complicated intra-abdominal infections (Trial 303, SURE-3) -- failed to meet their primary endpoints for noninferiority to a comparator and clinical response, respectively.

Findings from these trials "created uncertainty regarding the efficacy of sulopenem and the treatment of bacterial infections caused by pathogens relevant to uUTI," FDA staff wrote. As a result, the FDA advised Iterum to conduct another trial using another comparator.

According to details in an agency briefing document, the new trial data (Trial 310, REASSURE) demonstrated that sulopenem etzadroxil/probenecid was non-inferior to amoxicillin/clavulanate in overall clinical and microbiologic response and superior to its comparator in the micro-MITTS population.

However, the sample size of patients with amoxicillin/clavulanate-resistant organisms (n=67) in the trial was too small to allow for conclusions regarding efficacy of sulopenem etzadroxil/probenecid in that population, FDA staff pointed out.

Also, Trials 301 and 310 were not designed to evaluate the efficacy of sulopenem etzadroxil/probenecid in the treatment of antimicrobial resistant uUTI or in women who had failed first-line treatment, the agency said.

Regulators warned that "inappropriate use of the drug may contribute to AMR or increase cross-resistance to other carbapenems," such as during empiric use in the outpatient setting. They also voiced concerns that oral sulopenem etzadroxil/probenecid may be used off-label for the treatment of complicated UTI or other infections, as step-down treatment after IV therapy.

"Careful antimicrobial stewardship and consideration by guideline committees are needed to ensure appropriate positioning of sulopenem etzadroxil/probenecid in the hierarchy of treatment options for uUTI," the FDA said.

Nearly 5,000 patients have been exposed to sulopenem IV and/or sulopenem etzadroxil/probenecid across its development, the FDA wrote. No serious or unexpected safety signals have emerged, but some hypersensitivity reactions and mild elevations of liver enzymes have occurred. Gastrointestinal disturbance and vulvovaginal yeast infections are the most common adverse events associated with sulopenem.

Currently, carbapenem drugs are the mainstay for treatment of infections caused by ESBL-producers, but they all require IV administration and are not recommended for empirical treatment.

On Monday, the FDA advisory committee will discuss sulopenem etzadroxil/probenecid's risks and benefits and what medical providers should know to ensure appropriate use.

The agency does not plan to vote on the drug's approval until October 25. If approved, sulopenem would be the first oral penem antibiotic marketed in the U.S.

Katherine Kahn is a staff writer at MedPage Today, covering the infectious diseases beat. She has been a medical writer for over 15 years.

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Largest Ever Phage Therapy Trial Shows Promise For UTI Treatment

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UTI Treatment Tied To Delayed Diagnosis Of Advanced Bladder Cancer

Treatment for urinary tract infections (UTI) is associated with delayed diagnosis of advanced bladder cancer, a nationwide population-based study finds.

Investigators matched 29,921 patients with bladder cancer from the 2008-2019 Swedish National Urinary Bladder Cancer Register to 149,467 individuals free from any urinary tract cancer in the general population. UTI treatment rates were higher among patients with bladder cancer, especially those with muscle-invasive (MIBC) or metastatic disease.

The odds of being diagnosed with MIBC or metastatic bladder cancer rather than nonmuscle-invasive disease (NMIBC) were significantly increased 28% for men and 42% for women who received at least 1 antibiotic prescription commonly used for UTI compared with no antibiotic prescription within the past 3 years, Christel Häggström, MSc, of Umeå University in Sweden, and colleagues reported in European Urology Oncology.

As the number of antibiotic prescriptions increased, so did the risk for advanced bladder cancer. Among patients with 2-4, 5-9, and more than 9 prescriptions, the odds of an advanced bladder diagnosis rather than NMIBC significantly increased 1.3-, 1.6-, and 3.0-fold for men, respectively, and 1.4-, 1.6-, and 2.5-fold for women, respectively.

Using NMIBC or MIBC diagnosis as a reference, the odds of a metastatic bladder cancer diagnosis were significantly increased 2.6- and 2.1-fold for men and women, respectively, with more than 9 prescriptions.

"Our findings raise the question of whether the association between repeated UTI treatments and more advanced [bladder cancer] stage at diagnosis is an indicator of delayed diagnostic workup," Häggström's team wrote. "In addition, they may indicate that UTI is associated with more aggressive tumors with a higher prevalence of necrosis and urinary tract obstruction that predispose affected individuals to recurrent bacteriuria, apart from causing symptoms similar to a UTI."

The investigators did not have the clinical data to determine whether bladder cancer symptoms were possibly misdiagnosed as UTI or whether bladder cancer triggered an infection. They also could not account for other prescriptions possibly related to diagnostic delays, such as treatments for benign prostatic hyperplasia or irritative bladder symptoms. The team encouraged granular research.

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