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Cefepime-taniborbactam, an investigational beta-lactam and beta-lactamase inhibitor combination, was superior to meropenem for the treatment of hospitalized patients with complicated urinary tract infection (UTI), including acute pyelonephritis, a phase III randomized study showed.

In the microbiologic intention-to-treat (ITT) population, the composite microbiologic and clinical success rate with the combination at test-of-cure (trial days 19 to 23) was 70.6% versus 58% with meropenem (P=0.009), reported Paul C. McGovern, MD, senior vice president of Venatorx Pharmaceuticals in Malvern, Pennsylvania, and colleagues.

That difference in success rate was sustained at days 28 to 35 (63.8% vs 51.7%, respectively), they noted in the .

The results were consistent across subgroups of patients, including those with potentially more severe disease (bacteremia or systemic inflammatory response syndrome) and across baseline pathogens and antimicrobial-resistance categories.

"Thus, cefepime-taniborbactam was shown to be a potential treatment option for patients with complicated UTI and acute pyelonephritis caused by Enterobacterales species and Pseudomonas aeruginosa, including antimicrobial-resistant strains," McGovern and team wrote.

Based on results from this trial, known as , Venatorx Pharmaceuticals submitted a new drug application for cefepime-taniborbactam for complicated UTIs, including pyelonephritis, which the company said was accepted by the FDA with a PDUFA target action date of February 22.

With increasing antibiotic resistance, clinicians are left with less effective treatment options for complicated UTIs, Rotimi Sewedo Nettey, MD, of Baylor College of Medicine in Houston, told 番茄社区app.

"In terms of this study, the value add I see is that [the combination] specifically has a role in treating patients that have Enterobacter-driven infections, and potentially any kind of ESBL [extended-spectrum beta-lactamase]-producing organism," said Nettey, who was not involved with CERTAIN-1. "There is a clear advantage for those patients."

CERTAIN-1 included 661 patients, with 436 in the microbiologic ITT population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). Mean age was 56-57, 48-55% were women, and 88-92% were white.

Baseline pathogens in the microbiologic ITT population included Enterobacterales species (95.9%), primarily Escherichia coli (69%), Klebsiella pneumoniae (13.8%), Proteus mirabilis (4.6%), and Enterobacter cloacae complex (3.9%). P. aeruginosa was identified among 4.1% of participants.

The majority of patients (57.8%) had a complicated UTI, and 42.2% had acute pyelonephritis. Bacteremia was present in 13.1% of the patients at baseline, while about a quarter met the criteria for systemic inflammatory response syndrome.

Patients were randomly assigned in a 2:1 ratio to receive cefepime-taniborbactam 2.5 g intravenously over a 2-hour period every 8 hours plus meropenem placebo, or meropenem 1 g intravenously over a 30-minute period every 8 hours plus cefepime-taniborbactam placebo for 7 days (which could be extended up to 14 days in cases of bacteremia).

Microbiologic success was defined as the reduction of all gram-negative bacterial pathogens found at baseline from 105 colony-forming units/mL or more to less than 103 colony-forming units/mL in urine culture obtained at the post-treatment visit, while clinical success was defined as symptomatic resolution or a return to pre-infection baseline of all core signs and symptoms.

Adverse events (AEs) occurred in 35.5% of patients in the cefepime-taniborbactam group and 29% in the meropenem group, most of which were mild or moderate in severity. Premature discontinuation of a trial drug occurred in 3% and 0.9%, respectively.

The most frequently reported AEs in the cefepime-taniborbactam group were headache, gastrointestinal events (including diarrhea, constipation, and nausea), and hypertension. Clostridium difficile infection was reported in three patients in the cefepime-taniborbactam group and in no patients in the meropenem group.

Serious AEs occurred in 2% of the cefepime-taniborbactam group and 1.8% of the meropenem group. The most frequently reported serious AEs were COVID-19, which was reported in two patients in the cefepime-taniborbactam group, and pyelonephritis, which was reported in two patients in the meropenem group.

In the cefepime-taniborbactam group, two serious AEs (angioedema and gastrointestinal candidiasis) were considered by the investigators to be related to the trial drug.

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