Cefepime/enmetazobactam effective for suspected gram-negative complicated UTI

Patients with complicated urinary tract infection (UTI) or acute pyelonephritis caused by gram-negative pathogens may fare better with cefepime/enmetazobactam than with piperacillin/tazobactam, as the former is associated with a greater likelihood of achieving treatment success, according to the results of a phase III trial.

In the primary analysis set, more patients who received cefepime/enmetazobactam achieved the primary endpoint of clinical cure with microbiological eradication (<103 CFU/mL in urine) at day 14 compared with those on piperacillin/tazobactam (79.1 percent vs 58.9 percent). [JAMA 2022;328:1304-1314]

The between-group difference in treatment success of 21.2 percent (95 percent confidence interval [CI], 14.3–27.9) indicated that cefepime/enmetazobactam was noninferior and met the criterion for superiority relative to piperacillin/tazobactam.

Treatment-emergent adverse events (TEAEs) occurred in 50.0 percent of patients treated with cefepime/enmetazobactam and 44.0 percent of those on with piperacillin/tazobactam. Frequently reported TEAEs were elevations in liver function parameters, namely alanine aminotransferase (11.4 percent vs 11.6 percent), aspartate aminotransferase (9.1 percent vs 8.9 percent), and blood bilirubin (5.8 percent vs 3.9 percent), with most being mild to moderate in severity.

TEAEs led to treatment discontinuation in 1.7 percent of patients in the cefepime/enmetazobactam group and 0.8 percent in the piperacillin/tazobactam group.

“These findings suggest that cefepime/enmetazobactam may be an appropriate empirical therapy for suspected gram-negative complicated UTI,” the investigators said.

Extended-spectrum β-lactamases

The trial randomized 1,041 patients (mean age 54.7 years, 55.0 percent female), among whom 1,034 (99.3 percent) received at least one dose of study drug and 995 (95.6 percent) completed the trial. The primary analysis set included 678 patients who received at least one dose of treatment and had a gram-negative bacterium that was susceptible to either treatment in urine at >10⁵ CFU/mL or the same gram-negative pathogen in both urine and blood. Treatment duration was a median of 8 days.

A total of 349 patients (51.5 percent) had acute pyelonephritis, 148 (21.8 percent) had a complicated UTI with a removable infection source, and 181 (26.7 percent) had a complicated UTI without a removable source of infection. The most common pathogen seen at baseline was Escherichia coli (76.4 percent), followed by Klebsiella pneumoniae (9.7 percent), Proteus mirabilis (5.6 percent), Pseudomonas aeruginosa (3.5 percent), and Enterobacter cloacae (1.5 percent).

“The combination of the β-lactam piperacillin with the β-lactamase inhibitor tazobactam is used commonly to treat complicated urinary tract infections (UTIs) and other serious infections. However, an increasing prevalence of extended-spectrum β-lactamases, which cause resistance to most β-lactams except carbapenems, limits the therapeutic benefit of β-lactams,” the investigators pointed out. [JAMA 2014;312:1438-1446; Open Forum Infect Dis 2019;6:S23-S33]

“Prescribing piperacillin/tazobactam for infections that may be caused by extended-spectrum β-lactamase–producing bacteria may not be appropriate,” they added.

Meanwhile, the fourth-generation cephalosporin cefepime exerts broad-spectrum activity against gram-negative pathogens and is used for treating UTIs, intra-abdominal infections, and pneumonia. Furthermore, the novel β-lactamase inhibitor enmetazobactam can restore the activity of cefepime against β-lactamase–producing gram-negative pathogens, with greater potency than piperacillin/tazobactam against extended-spectrum β-lactamase producers. [Expert Rev Anti Infect Ther 2008;6:805-824; J Glob Antimicrob Resist 2021;25:93-101]

“Cefepime/enmetazobactam has the potential to treat patients at risk for extended-spectrum β-lactamase–producing infections. In contrast, other approved β-lactam/β-lactamase inhibitor combinations indicated for the treatment of complicated UTI (eg, ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/cilastatin/relebactam) exhibit activity against carbapenem-resistant pathogens and should be reserved for carbapenem-resistant infections,” according to the investigators.