Cefepime/Enmetazobactam Demonstrates Superiority in Test of Noninferiority to Piperacillin/Tazobactam for Complicated UTI

A novel β-lactamase inhibitor, enmetazobactam, in combination with cefepime demonstrated superiority in a test for noninferiority to piperacillin/tazobactam for complicated urinary tract infection (UTI) or acute pyelonephritis, in a randomized clinical trial conducted at 90 sites on 4 continents.

Keith Kaye, MD, Robert Wood Johnson Medical School, New Brunswick, New Jersey, and colleagues sought to determine whether the β-lactamase inhibitor could restore the effectiveness of the 4th generation cephalosporin against the increasing prevalence of β-lactam-resistant pathogens.

"Prescribing piperacillin/tazobactam for infections that may be caused by extended-spectrum β-lactamase (ESBL) -producing bacteria may not be appropriate," Kaye and colleagues observed. "New therapeutic options are needed."

The potential for enmetazobactam to serve that need is partly a function of its structure, which is similar to that of tazobactam but differs in a manner which enhances bacterial cell penetration, explained Sonali Advani, MBBS, MPH, Division of Infectious Diseases, Duke University School of Medicine Durham, North Carolina, and Kimberly Claeys, PharmD, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, in accompanying commentary.

There is also in-vitro evidence, Kaye and colleagues point to, of enmetazobactam restoring the activity of cefepine against class A serine β-lactamase-producing Enterobacterales; and showing that enmetazobactam/cefepime is more potent than piperacillin/tazobactam against ESBL producers. In addition, they note that prior studies have demonstrated that enmetazobactam and cefepime have similar pharmacokinetic profiles—with similar rates of urinary excretion and half-lives—which facilitates the fixed combination dosing.

The randomized, double-blind multicenter study was designed to ascertain noninferiority of the study drug combination, defined as clinical cure and microbiologic eradication in at least 90 percent of the proportion attaining that in the standard care comparator group.

"The noninferiority comparison to a reproducibly effective and reliable drug is required by both the US Food and Drug Administration and the European Medicines Agency to register new antibiotics for complicated UTI," explain Kaye and colleagues.

Patients with a clinical diagnosis of complicated UTI or acute pyelonepritis caused by gram-negative urinary pathogens were randomized to receive either a 2-hour infusion of cefepime 2gm/enmetazobactam 0.5gm (n=1034) or of piperacillin 4gm/tazobactam 0.5gm (n=995) every 8 hours for 7 days; and up to 14 days in patients with a positive blood culture at baseline.

Kaye and colleagues report that the study drug combination surpassed the criteria of noninferiority, to demonstrate superiority in the primary measure: 79.1% of those receiving cefepime/enmetazobactam, compared to 58.9% of those receiving piperacillin/tazobactam (between group difference, 21.2% [95% CI 14.3-37.9%]).

"These findings support future clinical studies to compare the efficacy of efepime/enmetazobactam vs a carbapenem in patients with infections caused by extended-spectrum β-lactamases," Kaye and colleagues concluded.

Advani and Claeys agree that the study drug combination showed promise, but also that additional data are needed, "on how best to position this agent in clinical settings beyond those of randomized trials, including specific populations that would most benefit ..."

They also expressed concern with several aspects of the trial methodology, including the non-traditional dosing regimen of the piperacillin/tazobactam (typically administered at 6 hour intervals), which might have confounded it exerting full inhibitory effects. Further, they point out, "the use of piperacillin-tazobactam for complicated UTI cause by ESBL-producing pathogens, especially with secondary bacteremia, has been controversial."

Additionally, Advani and Claeys question the inclusion of microbiologic eradication in the primary efficacy end point. They point out that many patients can have chronic or recurrent asymptomatic bacteriuria, which may persist after clinical symptoms have resolved. They note also that most UTI recurrences are not due to treatment failure, but from reinfection or lack of source control.

"Hence, it may be time to revisit the inclusion of microbiologic eradication in the primary end point for UTI therapeutics," they opine.