Cefepime-enmetazobactam, a novel β-lactam/β-lactamase inhibitor combination, is noninferior to piperacillin-tazobactam in treating complicated urinary tract infection (UTI) and acute pyelonephritis, investigators report.
In the double-blind phase 3 ALLIUM trial (ClinicalTrials.gov Identifier: NCT03687255), investigators randomly assigned 520 patients with complicated UTI or acute pyelonephritis from gram-negative pathogens to receive cefepime-enmetazobactam and 521 patients to receive piperacillin-tazobactam. Patients received either cefepime, 2 g/enmetazobactam, 0.5 g or piperacillin, 4 g/tazobactam, 0.5 g during a 2-hour infusion every 8 hours for at least 7 days. The primary outcome was a composite of clinical resolution of signs and symptoms (clinical cure) combined with microbiological eradication of infection at day 14.
The primary outcome occurred in 79.1% the cefepime-enmetazobactam group compared with 58.9% of the piperacillin-tazobactam group – a between-group difference of 21.2% that met the prespecified noninferiority criterion of at least 10%, Keith S. Kaye, MD, MPH, of Robert Wood Johnson Medical School, New Brunswick, New Jersey, and colleagues reported in JAMA. Clinical cure rates did not differ significantly between groups. Results were driven by significantly higher microbiological eradication in the cefepime-enmetazobactam group (82.9% vs 64.9%).
Of the cohort, 142 patients (20.9%) had extended-spectrum β-lactamases (ESBL)-producing pathogens at baseline. A greater proportion of these patients receiving cefepime-enmetazobactam than piperacillin-tazobactam (73.7% vs 51.5%) achieved the primary outcome.
Treatment-emergent adverse events occurred in 50.0% and 44.0% of the cefepime-enmetazobactam and piperacillin-tazobactam group, respectively. The vast majority were mild to moderate in severity (89.9% vs 88.6%). The most common events were elevations of liver function parameters: alanine aminotransferase (11.4% vs 11.6%), aspartate aminotransferase (9.1% vs 8.9%), and blood bilirubin (5.8% vs 3.9%), the investigators reported. Adverse events prompted 1.7% of the cefepime-enmetazobactam group and 0.8% of the piperacillin-tazobactam group to discontinue therapy.
In an accompanying editorial, Sonali D. Advani, MBBS, MPH, of Duke University School of Medicine, Durham, North Carolina, and Kimberly Claeys, PharmD, of the University of Maryland School of Pharmacy, Baltimore, praised the new research.
“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 UTI,” Dr Advani and Claeys wrote.
The authors stressed, however, that more research is needed on best use of the novel combination therapy in clinical settings and for specific populations. For example, the study excluded patients with cytopenias, immunocompromising conditions or therapies, severe kidney impairment, liver disease, and pregnancy, precluding efficacy assessment in these groups. In addition, the vast majority of the cohort were White (93.9%) with other ethnic groups underrepresented.
“The clinical outcomes data suggest that cefepime/enmetazobactam may be an option for treating complicated UTIs or acute pyelonephritis in adults when the pathogen is likely to be resistant to first-line empirical therapies or demonstrates an ESBL genotype, but is susceptible to cefepime/enmetazobactam,” the editorialists wrote.
Disclosure: This research was supported by Allecra Therapeutics. Please see the original reference for a full list of disclosures.
Kaye KS, Belley A, Barth P, et al. 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. JAMA. 328(13):1304-1314. Published online October 4, 2022. doi:10.1001/jama.2022.17034
Advani SD, Claeys K. Cefepime/enmetazobactam for complicated urinary tract infections. JAMA. 328(13):1299-1301. Published online October 4, 2022. doi:10.1001/jama.2022.15228