The results of a phase 3 clinical trial indicate that a novel combination antibiotic may soon be available for treatment of complicated urinary tract infections (cUTIs) caused by multidrug-resistant gram-negative bacteria.
The trial results, published this week in JAMA, show that cefepime/enmetazobactam, which combines a fourth-generation cephalosporin with a novel beta-lactamase inhibitor, was noninferior to piperacillin/tazobactam in patients with cUTIs or acute pyelonephritis, and met superiority criteria with respect to clinical cure and microbiologic eradication.
The trial investigators say that with the increasing prevalence of bacteria carrying extended-spectrum beta-lactamases (ESBLs), which are enzymes that cause resistance to most beta-lactam antibiotics, more therapeutic options are needed for difficult-to-treat infections. Piperacillin/tazobactam has been a widely used therapy for cUTIs and other infections caused by ESBL-producing bacteria because it's an effective an alternative to carbapenems. But resistance to the treatment has been rising, and the authors say it may no longer be appropriate.
"These findings suggest that cefepime/enmetazobactam may be an appropriate empirical therapy for suspected gram-negative complicated UTI," they wrote.
Based on these results, French biopharmaceutical company Allecra Therapeutics said in a press release that it is planning to complete a submission for marketing authorization for cefepime/enmetazobactam to the European Medicines Agency by the end of the year. The company is also preparing to submit a New Drug Application to the US Food and Drug Administration.
Better overall treatment success
For the randomized, controlled, double-blind trial, investigators with Allecra and the Robert Wood Johnson Medical Center enrolled adults with complicated UTIs or acute pyelonephritis at 90 hospitals in Europe, North America, Central and South America, and South Africa. Participants were randomized 1:1 to receive an infusion of cefipime/enmetazobactam or piperacillin/tazobactam every 8 hours for 7 days.
The primary analysis looked at all patients who received at least one dose of the study drug and had a gram-negative pathogen present in urine culture at 105 culture-forming units per milliliter (or the same pathogen in both urine and blood cultures) that was not resistant to either treatment. The primary outcome was the proportion of patients in the primary analysis who achieved overall treatment success—defined as clinical cure combined with microbiologic eradication. The prespecified noninferiority margin was 10%.
Of the 1,041 randomized patients (mean age, 57.4 years; 55% women), 1,034 received at least one dose of a study drug, with 516 patients receiving cefipime/enmetazobactam and 518 in the piperacillin/tazobactam arm. Average treatment duration was 8 days.
Among the primary analysis cohort (678 patients), overall treatment success was achieved in 79.1% of patients in the cefipime/enmetazobactam arm and 58.9% of those treated with piperacillin/tazobactam. The between-group difference of 21.2 percentage points (95% confidence interval [CI], 14.3 to 27.9) indicated noninferiority. Cefipime/enmetazobactam also met the criterion for superiority compared with piperacillin/tazobactam.
In the 20.9% of patients with an ESBL-producing baseline pathogen, 73.7% in the cefepime/enmetazobactam group achieved the composite outcome of clinical cure and microbiologic eradication, compared with 51.5% in the piperacillin/tazobactam arm (between-group difference, 30.2 percentage points; 95% CI, 13.4 to 45.1).
Treatment-emergent adverse events occurred in 50.0% of patients treated with cefepime/enmetazobactam and 44.0% of those treated with piperacillin/tazobactam. Most of these events were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% of participants who received cefepime/enmetazobactam and 0.8% of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events.
Questions about use in clinical settings
In an editorial that accompanies the study, infectious disease experts from Duke University School of Medicine and the University of Maryland School of Pharmacy say that while the results are exciting, they also raise some issues about how cefipime/enmetazobactam should be used.
They point out that the relevance of superiority, which in this case was driven mainly by a difference in the microbiologic eradication in the two groups, is questionable. And they questions whether microbiologic eradication is a useful endpoint, since UTI patients often have chronic or recurrent asymptomatic bacteriuria that persists after clinical cure.
In addition, they note that trial participants were mostly White (94%), ages 18 to 64 years (61.5%), and were all recruited outside the United States, which means the results may not be generalizable. Furthermore, nearly 80% of participants didn't have an ESBL-producing pathogen.
"While this agent shows promise for treating acute pyelonephritis or complicated UTI secondary to ESBL-producing gram-negative pathogens, more 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 from this therapy, and reviewing financial implications for both patients and health systems," Sonali Advani, MBBS, MPH, and Kimberly Claeys, PharmD, wrote.
