A New, More Effective UTI Drug

Researchers uncover a treatment combination that is particularly effective against drug-resistant cases of urinary tract infections.

A new drug combination has been shown to be more effective, especially against stubborn, drug-resistant infections, according to an international study led by a Rutgers University researcher comparing new and older treatments for complex urinary tract infections.

Researchers from the ALLIUM Phase 3 clinical trial reported their findings in the Journal of the American Medical Association (JAMA), demonstrating that cefepime and enmetazobactam were more successful than the conventional treatment of piperacillin and tazobactam in treating complicated urinary tract infections and acute pyelonephritis (AP), a bacterial infection that causes kidney inflammation. Urinary tract infections are considered complicated when they are coupled with risk factors such as fevers, sepsis, urinary obstruction, or catheters, all of which increase the likelihood of antibiotic failure.

“This new antibiotic was superior to the standard-of-care therapy,” said Keith Kaye, chief of the Division of Allergy, Immunology, and Infectious Diseases and a professor of medicine at Rutgers Robert Wood Johnson Medical School.

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“It represents an exciting option for treatment,” said Kaye, the principal investigator of the study and lead author of the publication.

This drug combination, according to Kaye, also combats an often-dangerous type of bacterial illness caused by pathogens known as extended-spectrum beta-lactamase (ESBL) infections, named after an enzyme produced by the bacteria. Many antibiotics used to treat infections, such as penicillins and cephalosporins, are ineffective against ESBL-producing bacteria.

“We are looking for antibiotics that are active against resistant bacteria, such as ESBLs, and we found this new combination to be highly effective,” Kaye said.

The trial was conducted at 90 sites in Europe, North and Central America, South America, and South Africa from September 2018 to November 2019. More than 1,000 patients participated in the study. Some 79 percent of the patients receiving the new combination of cefepime and enmetazobactam were successfully treated for their illness, as opposed to 58.9 percent of those receiving the conventional treatment of piperacillin and tazobactam.

Of the 20 percent of patients from the overall group belonging to the subset of those with ESBL infections, 73 percent of the patients receiving cefepime and enmetazobactam achieved a clinical cure, as opposed to 51 percent of the patients on the standard therapy.

The antibiotic cefepime is a fourth-generation cephalosporin that was approved for use in the 1990s and is available generically. Enmetazobactam, an experimental drug made by the French biopharmaceutical company Allecra Therapeutics, is a beta-lactamase inhibitor, meaning it attacks the beta-lactamases, including the types of enzymes produced by ESBL-producing bacteria. The drug combination has been granted Qualified Infectious Disease Product and Fast Track designation by the U.S. Food and Drug Administration (FDA).

Kaye said he expected the company to apply for FDA approval early next year.

More than 2.8 million antimicrobial-resistant infections occur in the U.S. each year, and more than 35,000 people die from them, according to a report from the U.S. Centers for Disease Control and Prevention (CDC). In a 2019 study on antibiotic resistance, the CDC characterized ESBLs as a serious threat to human health.

A JAMA editorial by Sonali Advani and Kimberly Claeys, both of Duke University School of Medicine, praised the Rutgers-led study: “The clinical trial by Kaye et al presents a promising novel antibiotic therapy that expands the limited armamentarium for resistant organisms and an exciting new therapeutic option for the management of acute pyelonephritis or complicated [urinary tract infection].”

References: “Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis A Randomized Clinical Trial” by Keith S. Kaye, MD, Adam Belley, Ph.D., Philip Barth, Ph.D., Omar Lahlou, PharmD, Philipp Knechtle, Ph.D., Paola Motta, Ph.D. and Patrick Velicitat, MD, 4 October 2022, JAMA.
DOI: 10.1001/jama.2022.17034

“Cefepime/Enmetazobactam for Complicated Urinary Tract Infections” by Sonali D. Advani, MBBS, MPH and Kimberly Claeys, PharmD, 4 October 2022, JAMA.
DOI: 10.1001/jama.2022.15228

The study was funded by Allecra Therapeutics.