Cefepime-Enmetazobactam Shows Promise for ESBL-Producing Enterobacteriaceae

Investigational antibiotic combination cefepime-enmetazobactam was found to be superior to piperacillin-tazobactam in treating complicated urinary tract infections (cUTIs), according to findings from the phase 3 ALLIUM clinical trial.

The study was originally accepted for presentation at the 2020 European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), prior to its cancellation.

The global rise in antimicrobial-resistant gram-negative pathogens has driven development of new agents to treat infections caused by third-generation cephalosporin-resistant Enterobacterales, specifically those producing extended spectrum β-lactamases (ESBL).

“We anticipated excellent activity of this antibiotic,” investigator Keith Kaye, MD, of the University of Michigan Medical School, told Contagion^®. “The fact that it was superior to piperacillin-tazobactam and its notable efficacy in cUTIs due to ESBL-producers I found to be very exciting.”

The novel drug combines cefepime, a fourth-generation cephalosporin, with enmetazobactam, a novel extended-spectrum β-lactamase inhibitor.

The multicenter, randomized, controlled, double-blind trial involved patients at 112 sites in 19 countries. More than 1000 patients were enrolled in the trial, including 516 who received at least one dose of cefepime-enmetazobactam and 518 at least one dose of piperacillin-tazobactam. Only those with gram-negative infections that were non-resistant to the two drugs being compared were included, receiving two-hour continuous intravenous infusions of either 2 g cefepime/0.5 g enmetazobactam or 4 g piperacillin/0.5 g tazobactam every 8 hours for 7-14 days.

Success—defined as a combination of clinical cure and microbiological eradication—occurred in 273 of 345 (79.1%) patients treated with cefepime-enmetazobactam, compared with 196 of 333 (58.9%) treated with piperacillin-tazobactam. The clinical cure rate of cefepime-enmetazobactam was 92.5% compared with 88.9% for piperacillin-tazobactam.

Among patients infected with ESBL-producing pathogens, the success rate was 73.7% (56/76) for cefepime-enmetazobactam, and 51.6% (34/66) for piperacillin-tazobactam.

Adverse events, which were mostly mild to moderate, occurred in 50% (258/516) of patients treated with cefepime-enmetazobactam and 44% (228/518) of those who received piperacillin-tazobactam.

“Cefepime-enmetazobactam was very effective in treating cUTI, including against ESBL-producers. It also was safe and well-tolerated,” Kaye told Contagion^®. “Cefepime-enmetazobactam is a viable treatment option for cUTI due to gram-negative bacilli, and is intended to be a carbapenem-sparing option for those that are ESBL-producers.”

Kaye said next steps for the investigators include additional analysis of the study; presentation at IDWeek 2020; and manuscript preparation.

CUTIs affect more than 100 million people globally per year, requiring hospitalization in as many as 30% of cases. Antimicrobial resistance has made treating these cases more difficult and costly, with total annual health care costs in the United States estimated at $6 billion, according to a recent study.

Another abstract planned for ECCMID examined the use of ceftazidime-avibactam for patients with a variety of gram-negative bacterial infections, finding it to be safe and effective with similar results to comparators in treatment for cUTI, intra-abdominal infection (cIAI), hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).