A novel β-lactamase inhibitor, enmetazobactam, in combination with cefepime, demonstrated superiority in a non-inferiority test to piperacillin/tazobactam in complicated or acute urinary tract infections (UTIs) in a randomized clinical trial conducted at 90 sites on 4 continents pyelonephritis.
Keith Kaye, MD, Robert Wood Johnson Medical School, New Brunswick, NJ, 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 can be caused by extended-spectrum β-lactamase (ESBL)-producing bacteria may not be appropriate,” Kaye and colleagues observed. “New therapeutic options are required.”
Enmetazobactam’s potential to fill this need is partly a function of its structure, which is similar to tazobactam but differs in a way that improves bacterial cell penetration, explained Sonali Advani, MBBS, MPH, Department 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 comments.
There is also in vitro evidence that Kaye and colleagues point out that enmetazobactam restores the activity of cefepin against serine-β-lactamase-producing class A enterobacteria; and show that enmetazobactam/cefepime is more potent than piperacillin/tazobactam against ESBL producers. Additionally, they note that previous studies have shown that enmetazobactam and cefepime have similar pharmacokinetic profiles — with similar urinary clearance rates and half-lives — facilitating fixed combination dosing.
The randomized, double-blind, multi-center study was designed to determine non-inferiority of the study drug combination, defined as clinical cure and microbiological eradication, in at least 90 percent of the proportion achieving that in the standard of care comparator group.
“The non-inferiority comparison with 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 UTIs,” explain Kaye and colleagues.
Patients with a clinical diagnosis of complicated UTI or acute pyelonepritis caused by urinary Gram-negative pathogens were randomized to receive either a 2-hour infusion of cefepime 2 g/enmetazobactam 0.5 g (n=1034) or piperacillin 4 g /tazobactam 0.5g (n=1034). =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’s drug combination exceeded the non-inferiority criteria to demonstrate superiority on the primary measure: 79.1% of those receiving cefepime/enmetazobactam compared to 58.9% of those receiving piperacillin/tazobactam received (difference between groups 21.2% [95% CI 14.3-37.9%]).
“These results support future clinical studies comparing the efficacy of efepime/enmetazobactam with a carbapenem in patients with infections caused by broad-spectrum β-lactamases,” concluded Kaye and colleagues.
Advani and Claeys agree that the study drug combination was promising, but also that additional data is needed “on how best to position this agent in clinical settings beyond randomized trials, including specific populations that may benefit most.” would …”
They also expressed concern about several aspects of the study methodology, including the non-traditional dosing regimen of piperacillin/tazobactam (typically given at 6-hour intervals), which may have confounded exerting full inhibitory effects. Furthermore, they point out that “the use of piperacillin-tazobactam in complicated UTI causes by ESBL-producing pathogens, particularly secondary bacteremia, has been controversial.”
In addition, Advani and Claeys question the inclusion of microbiological eradication in the primary efficacy endpoint. They point out that many patients may have chronic or recurrent asymptomatic bacteriuria, which may persist after clinical symptoms have resolved. They also point out that most UTI recurrences are not due to treatment failure but to reinfection or a lack of source control.
“Therefore, it may be time to reconsider including microbiological eradication in the primary endpoint for UTI therapeutics,” they suggest.
