TOPLINE:

In a multinational phase 3 trial, a single dose of zoliflodacin, an oral, first-in-class spiropyrimidinetrione antibiotic, was non-inferior to that of ceftriaxone plus azithromycin in treating uncomplicated urogenital gonorrhoea and had a similar safety profile.

METHODOLOGY:

• Researchers conducted a phase 3 randomised trial to evaluate the efficacy and safety of zoliflodacin compared with those of ceftriaxone plus azithromycin in patients with uncomplicated urogenital gonorrhoea.
• A total of 930 patients (mean age, 29.7 years; 88% assigned male at birth) were randomly assigned to receive either a single oral dose of zoliflodacin 3 g (n = 621) or the comparator, a single dose of intramuscular ceftriaxone 500 mg plus oral azithromycin 1 g (n = 309).
• Clinical specimens, including urethral or endocervical, pharyngeal, and rectal swabs, were collected for Neisseria gonorrhoeae culture at baseline and at the test-of-cure visit; the follow-up continued through day 30.
• The primary endpoint was the microbiological cure rate at the urogenital site at the test-of-cure visit on day 6 (+2 days).
• Non-inferiority was concluded if the upper bound of the two-sided 95% CI for the primary endpoint was less than the prespecified 12% margin.

TAKEAWAY:

• In the microbiological intention-to-treat analysis, which included patients with culture-confirmed baseline urogenital N gonorrhoeae and no preexisting resistance to the comparator, zoliflodacin vs the comparator achieved a cure rate of 90.9% vs 96.2% (difference, 5.3%; 95% CI, 1.4%-8.6%), meeting the prespecified non-inferiority criterion.
• In the evaluable population, which excluded patients with non-assessable outcomes at the test-of-cure visit, urogenital microbiological cure rates were 96.8% with zoliflodacin and 100% with the comparator (difference, 3.2%; 95% CI, 1.1%-5.1%).
• Microbiological cure rates at the test-of-cure visit for pharyngeal and rectal infections were similar between treatment groups.
• Treatment-emergent adverse events were comparable between the two groups and were mostly mild or moderate; the most frequent adverse events were headache and neutropenia with zoliflodacin and injection-site pain and neutropenia with the comparator.

IN PRACTICE:

"[The study] data suggest a potential role for zoliflodacin as an effective oral treatment option for uncomplicated urogenital gonorrhoea," the authors wrote.

"Development of an effective oral regimen is an important advance that augments gonococcal treatment options. Enhanced surveillance and effective antimicrobial regimens are crucial for the development of evidence-based management guidance and health policy," an expert wrote in a commentary accompanying the journal article.

SOURCE:

This study was led by Alison Luckey, Global Antibiotic Research and Development Partnership, Geneva, Switzerland. It was published online on December 11, 2025, in The Lancet.

LIMITATIONS:

The open-label design may have influenced outcomes and could have contributed to an imbalance in missed test-of-cure visits between the two groups. Despite targeted outreach, women and adolescents were underrepresented, limiting the generalisability of the findings to these populations.

DISCLOSURES:

This study was sponsored by the Global Antibiotic Research and Development Partnership Foundation, with public funding received from multiple sources, including Germany's Federal Ministry of Research, Technology and Space; the UK Department of Health and Social Care; and Japan's Ministry of Health, Labour and Welfare. Three authors reported being employees of the sponsor. Several authors reported receiving institutional funding from the sponsor, research support, or consulting fees or having employment relationships with various pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.