Investigational zoliflodacin was noninferior to standard therapy with ceftriaxone plus azithromycin in treating uncomplicated urogenital gonorrhea, an international phase III randomized trial showed.

Among over 900 patients, the microbiological cure rate was 90.9% among those who received a single dose of oral zoliflodacin compared with 96.2% for those who received intramuscular ceftriaxone plus oral azithromycin, reported Alison Luckey, BM, of the Global Antibiotic Research & Development Partnership in Geneva, Switzerland, and colleagues.

The estimated difference between the two groups in the microbiological intention-to-treat analysis was 5.3%, meeting the study’s noninferiority threshold of less than a 12% difference between the groups’ upper confidence intervals (10.2%), they noted in The Lancet.

Key secondary endpoints for pharyngeal and rectal infections showed similar microbiological cure rates between the treatment groups, though Luckey and team acknowledged that the study was not powered to show noninferiority for these endpoints.

“Considering the urgent global need for new gonorrhea treatments, the finding that a single-dose of oral zoliflodacin was efficacious at curing urogenital and rectal and pharyngeal gonorrhoea is encouraging in the context of population-level public health efforts to control disease,” they wrote.

Benefits with zoliflodacin could include better treatment access for patients who might otherwise go untreated, an effective therapeutic option in regions with ceftriaxone resistance, and preservation of other antibiotics classes’ effectiveness by slowing antimicrobial resistance, the study authors said.

The latest findings mirror phase II results with the drug, which showed a microbiological cure rate of 96% in patients with urogenital gonorrhea and all patients with rectal gonorrhea who received a single oral dose. Earlier this year, the FDA accepted zoliflodacin for priority review for the treatment of uncomplicated gonorrhea in patients ages 12 years and older, with a decision expected by Dec. 15.

Another new treatment option for gonorrhea is the antibiotic gepotidacin (Blujepa), which also proved noninferior to ceftriaxone and azithromycin for the treatment of uncomplicated urogenital gonorrhea in the phase III EAGLE-1 trial. Gepotidacin is approved to treat both uncomplicated urogenital gonorrhea in patients ages 12 and older, as well as uncomplicated urinary tract infection in women and girls ages 12 and up.

In an accompanying editorial, Kimberly Workowski, MD, of Emory University School of Medicine in Atlanta, noted that “the findings from this ambitious, multinational study represent an important advance in gonococcal treatment.”

Having only one preferred parenteral, ceftriaxone, to counter gonococcal infections is challenging, given its difficult administration and many outpatient clinics’ choice not to stock the drug, Workowski said.

With Neisseria gonorrhoeae’s “remarkable capacity” to evolve and develop antimicrobial resistance, she cautioned, new oral antimicrobials like zoliflodacin alone won’t be enough to roll back gonorrhea’s advance. “It’s essential to maintain enhanced global surveillance to monitor gonococcal resistance trends, recognize emerging resistance … and rapidly identify potential treatment failures,” Workowski added.

The study authors also conducted a subanalysis of what they called the more clinically relevant evaluable populations — those in the microbiological intention-to-treat population who didn’t vomit within 30 minutes of oral treatment. In that group, urogenital microbiological cure rates were 96.8% in the zoliflodacin group and 100% in the standard combination treatment group.

Among patients with uncomplicated pharyngeal or rectal gonorrhea, microbiological cure rates were 79.2% and 87.3%, respectively, with zoliflodacin versus 78.6% and 88.6%, respectively, with standard treatment. Cure rates were greater than 90% in both treatment groups in the evaluable populations.

The open-label trial included patients ages 12 years and older with symptoms of urethral or endocervical gonorrhea, a positive laboratory test for urogenital gonorrhea in the preceding 14 days, or a history of unprotected sexual contact in the preceding 14 days with someone with a confirmed N. gonorrhoeae infection. People with HIV were not excluded.

The trial was conducted between November 2019 and March 2023 at 17 outpatient clinics in Belgium, the Netherlands, South Africa, Thailand, and the U.S. The researchers randomized 930 patients in a 2:1 ratio to either zoliflodacin or combination ceftriaxone and azithromycin. The primary endpoint was the proportion of patients with microbiological cure (either negative or indeterminate N. gonorrhoeae culture) in the urogenital area at the day-6 test of cure visit in the microbiological intention-to-treat population.

Mean patient age was 29.7 years, 88% were assigned male at birth, 55% were Black or African American, 31% were Asian, and 12% were white. Nearly half of participants (46%) were from South Africa, 29% were from Thailand, 17% from the U.S., and 8% from Europe. Eighty percent of participants had urogenital gonorrhea, 12% had rectal gonorrhea, and 9% had pharyngeal gonorrhea.

Zoliflodacin resistance didn’t develop during the trial, with no noticeable changes to the drug’s N. gonorrhoeae minimum inhibitory concentrations in the three anatomical sites. Nearly half of patients in each treatment group — 46% in both — reported at least one treatment-emergent adverse event, though most were either mild or moderate.

Study limitations included its open-label design, which was made necessary due to the drugs’ oral and intramuscular delivery methods. In addition, the study included a low proportion of females and adolescents.

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