Investigational oral antibiotic noninferior to dual therapy for uncomplicated gonorrhoea

In the treatment of uncomplicated urogenital gonorrhoea, a single dose of the novel oral antibiotic zoliflodacin shows similar efficacy and safety profile as the ceftriaxone plus azithromycin combination, as shown in a multinational phase III study.

The primary endpoint of microbiological cure occurred in 90.9 percent of patients who received zoliflodacin vs 96.2 percent of those treated with ceftriaxone plus azithromycin. The between-group difference of 5.3 percent (95 percent confidence interval [CI], 1.4–8.6) was within the prespecified noninferiority margin. [Lancet 2026;407:147-160]

Similar rates of microbiological cure between the zoliflodacin and dual therapy arms were seen for both the pharyngeal (79.2 percent vs 78.6 percent, respectively) and rectal (87.3 percent vs 88.6 percent, respectively) sites of infection. However, the investigators acknowledged that the study was not powered to show noninferiority for these endpoints, and the number of participants with extragenital infections was small despite a large study population.

In terms of safety, zoliflodacin was generally well tolerated. Treatment-emergent adverse events (TEAEs) occurred in 46 percent of patients each in the zoliflodacin and dual therapy arms. The most common TEAEs were headache (10 percent), neutropenia (7 percent), and leukopenia (4 percent) in the zoliflodacin group and injection site pain (12 percent), neutropenia (8 percent), and diarrhoea (7 percent) in the dual therapy group. Most of these events were mild or moderate in severity, and no serious TEAEs were documented.

“Considering the urgent global need for new gonorrhoea 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,” the investigators said.

Zoliflodacin is a first-in-class spiropyrimidinetrione with a novel bacterial target and a distinct mechanism of action, having shown potent in-vitro activity against N gonorrhoeae, including multidrug-resistant strains. This drug, according to the investigators, may “reduce antibiotic selection pressure” and “help preserve the effectiveness of other antibiotic classes, notably, ceftriaxone.”

Furthermore, zoliflodacin could improve access to treatment for patients with beta-lactam hypersensitivity or needle aversion, as well as in regions where ceftriaxone resistance is prevalent, they added.

Currently, only one other oral antibiotic, namely gepotidacin, out of the several tested for uncomplicated urogenital gonorrhoea has shown noninferiority to standard-of-care ceftriaxone. This drug is approved for the treatment of uncomplicated urogenital gonorrhoea in patients aged 12 years and older, as well as uncomplicated urinary tract infection in women and girls at least 12 years of age. [Lancet 2025;405:1608-1620]

No evidence of resistance

In a linked commentary, Dr Kimberly Workowski from the Emory University School of Medicine in Atlanta, Georgia, US, described the findings from the multinational phase III study as “an important advance in gonococcal treatment.” [Lancet 2026;407:106-107]

A notable finding was that there was no evidence zoliflodacin resistance emerging in either treatment group during the trial, Workowski said, while also acknowledging that N gonorrhoeae “has a remarkable capacity to adapt, developing resistance to antimicrobials over time.”

She underscored the importance of maintaining enhanced global surveillance to monitor gonococcal resistance trends in order to rapidly identify emerging resistance (eg, the effect of doxycycline postexposure prophylaxis) and potential treatment failures.

“Introduction of prompt and accurate diagnostics to identify infection and potential resistance determinants at the point of care, with provision of directed treatment, would enhance antimicrobial stewardship,” Workowski said.

Zoliflodacin trial

The phase III trial included 930 participants aged 12 years and up (mean age 29.7 years, 88 percent male, 31 percent Asian) with clinical suspicion of uncomplicated urogenital gonorrhoea, enrolled at outpatient clinics across Belgium, the Netherlands, South Africa, Thailand, and US.

The participants were randomly assigned to receive treatment with a single oral 3-g dose of zoliflodacin (n=621) or a single intramuscular 500-mg dose of ceftriaxone plus a single oral 1-g dose of azithromycin (n=309).

Microbiological cure was defined as the eradication of Neisseria gonorrhoeae, determined through urethral or endocervical culture at test of cure (day 6).