ALLIUM Trial: Cefepime-Enmetazobactam Superior to Piperacillin-Tazobactam for ESBL-Producing Enterobacterales

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Antimicrobial-resistant infections, in particular those caused by gram-negative pathogens that also produce extended spectrum β-lactamases (ESBL), represent a growing threat across the globe as investigators race to develop novel therapeutics. Complicated urinary tract infections (cUTI), in particular, constitute a massive health burden on patients, affecting more than 100 million people per year globally.

Contagion® previously reported on results from the phase 3 ALLIUM clinical trial of Allecra Therapeutics’ investigational antibiotic combination of cefepime-enmetazobactam (FPE), and now the research team presents additional findings during the virtual ID Week 2020.

FPE fuses enmetazobactam, a novel ESBL inhibitor, with cefepime, a fourth-generation cephalosporin, to target infections, specifically cUTI and acute pyelonephritis (AP), caused by ESBL-producing Enterobacterales.

In the ALLIUM trial, FPE demonstrated superiority to piperacillin-tazobactam (PTZ) in a subgroup of patients with ESBL-producing baseline uropathogens (ESBL-BU).

“We anticipated excellent activity of this antibiotic,” investigator Keith Kaye, MD, of the University of Michigan Medical School, told Contagion® earlier this year. “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.”

For this double-blind, multicenter trial, a total of 1034 participants with either cUTI or AP were randomized 1:1 to receive either 2 g cefepime/0.5 g enmetazobactam or 4 g piperacillin/0.5 g tazobactam. Each treatment arm received the study drug combination every 8 hours via a 2-hour infusion for 7 to 14 days. For the primary analysis, success was defined as a combination of clinical cure and microbiological eradication in the microbiological modified intent-to-treat population (mMITT) at test-of-cure (TOC).

Investigators also performed subgroup analyses on patients with ESBL-BU non-resistant to FPE (MIC≤8 µg/ml) and PTZ (MIC≤64 µg/ml), as well as on patients with ESBL-BU resistant to either agent (FPE MIC ≥16 µg/ml or PTZ MIC≥128 µg/ml).

FPE demonstrated superiority to PTZ, with success observed in 273 of 345 (79.1%) patients, compared with 196 of 333 (58.9%) at TOC (difference, 21.2%; 95% CI: 14.3, 27.9).

According to the results, the prevalence rate of ESBL-BU in the first subgroup was 20.9% (142/678), with 99.3% (141/142) expressing a CTX-M-type (-1, -3, -9, -14, -15, -27, -55, -91, -169) and 3.5% (5/142) co-expressing AmpC (CMY-2/-59). In this group, FPE (56/76, 73.7%) was superior to PTZ (34/66, 51.5%) at TOC (difference 30.2%; 95% CI: 13.4, 45.1).

In the other subgroup, the “ESBL-BU prevalence rate was 22.3% (172/771), with 6.4% (11/172) co-expressing AmpC (CMY-2/-4/-59/-99), 4.7% (8/172) co-expressing a metallo-β-lactamase (VIM-1, NDM-1), and 2.3% (4/172) co-expressing OXA-48,” the study reads. In those patients, FPE superiority (67/91, 73.6%) was also observed when compared with PTZ (41/81, 50.6%) at TOC (difference 30.0%; 95% CI: 14.9, 43.3).

“Cefepime-enmetazobactam was very effective in treating cUTI, including against ESBL-producers. It also was safe and well-tolerated,” Kaye said. “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.”

The study, “Cefepime-Enmetazobactam Demonstrates Superiority to Piperacillin-Tazobactam in a Subgroup of Patients with Complicated Urinary Tract Infections/Acute Pyelonephritis Caused by Extended Spectrum β-Lactamase-Producing Enterobacterales,” was presented virtually at ID Week 2020.