Cefepime–taniborbactam bests meropenem for complicated UTI

Patients with complicated urinary tract infection (UTI) may fare better with cefepime–taniborbactam than with meropenem, with the combination having been associated with much higher treatment success rates in the phase III CERTAIN-1 trial.

In the microbiologic intention-to-treat (microITT) population, the primary outcome of the composite of microbiologic and clinical success at test of cure on trial days 19 to 23 occurred with significantly greater frequency in the cefepime–taniborbactam arm than in the meropenem arm (70.6 percent vs 58.0 percent). This established the superiority of the combination treatment (treatment difference, 12.6 percentage points, 95 percent confidence interval, 3.1–22.2; p=0.009). [N Engl J Med 2024;390:611-622]

“[M]icrobiologic success was defined as a reduction of all gram-negative bacterial pathogens found at baseline to less than 10³ CFU per millilitre. Clinical success was defined as symptomatic resolution or return to preinfection baseline of all core signs and symptoms, with no use of additional antibacterial agents for complicated UTI,” the investigators said.

“Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime–taniborbactam had higher composite success and clinical success,” they added.

Cefepime–taniborbactam consistently showed superiority over meropenem across subgroups defined by age, infection type, disease severity (bacteraemia and systemic inflammatory response syndrome [SIRS]), renal impairment, and baseline pathogen and phenotypic resistance category.

Safety

“Cefepime–taniborbactam, which contains the highest recommended dose of cefepime (2 g every 8 hours), had a similar risk of adverse events and serious adverse events (AEs) as meropenem,” the investigators noted.

AEs occurred in 35.5 percent of patients in the cefepime–taniborbactam arm and in 29.0 percent of those in the meropenem arm. Both treatment arms had mostly mild to moderate AEs that did not result in treatment discontinuation. Headache, diarrhoea, constipation, hypertension, and nausea were the most common AEs.

The rates of serious AEs were 2.0 percent in the cefepime–taniborbactam arm and 1.8 percent in the meropenem arm, with COVID-19 and pyelonephritis being the most frequently reported in the respective treatment arms. One case of angioedema and one of gastrointestinal candidiasis occurred in the combination arm and were considered to be related to treatment. One patient in the combination arm died, with the death unrelated to the trial drug.

Taken together, the efficacy and safety data support cefepime–taniborbactam as a promising treatment option for patients with complicated UTI and acute pyelonephritis caused by Enterobacterales species and Pseudomonas aeruginosa, including antimicrobial-resistant strains, according to the investigators.

CERTAIN-1

The microITT population included 436 hospitalized adults, among whom 57.8 percent had complicated UTI, 42.2 percent had acute pyelonephritis, and 13.1 percent had bacteraemia. There were 24.3 percent of patients who met the criteria for SIRS.

The patients were randomly assigned to receive treatment with intravenous cefepime–taniborbactam 2.5 g (n=293, mean age 56.5 years, 54.9 percent female, 87.7 percent White) or meropenem 1 g (n=143, mean age 55.8 years, 48.3 percent female, 91.6 percent White) every 8 hours for 7 days. Treatment duration could be extended up to 14 days in case of bacteraemia.

The majority (95.9 percent) of baseline pathogens identified in the microITT population belonged to the Enterobacterales family. Of the pathogens, 22.0 percent were resistant to cefepime, 26.6 percent produced extended-spectrum β-lactamases, and 35.6 percent were multidrug-resistant. The median treatment duration among patients with bacteraemia was 12 days in the cefepime–taniborbactam group and 14 days in the meropenem group.

“The treatment duration was fixed at 7 days in patients without bacteraemia, a period that was consistent with current recommendations for shorter therapy. However, the lack of oral stepdown antibiotics, the fixed duration of intravenous therapy, and the requirement for inpatient participation may not reflect clinical practice in all regions of the world,” the investigators noted.

“Most trial patients (81.9 percent of the microITT population) were located in eastern Europe. However, even though regional differences may exist in susceptibility patterns, geographic location did not alter either the pathophysiological features of complicated UTI or the expected response to antibiotics, because inclusion in the primary analysis population required that both trial drugs were active against the baseline pathogens,” they added.