Oral topoisomerase II inhibitors show no significant difference from ceftriaxone for uncomplicated gonorrhoeaOral Topoisomerase Inhibitors Show Promise for Treating Gonorrhoea

BACKGROUND: Increasing incidence and accelerating antimicrobial resistance have made gonorrhoea a major global health challenge. As ceftriaxone stands as the only reliably effective option, the development of new therapies is increasingly urgent. OBJECTIVE: This meta-analysis evaluates the efficacy and safety of oral antibiotics, gepotidacin and zoliflodacin, which target bacterial type II DNA topoisomerases and represent novel therapeutic options for uncomplicated gonorrhoea. METHODS: A search of CENTRAL, Embase, PubMed, and Web of Science to 10 July 2025 identified randomised controlled trials comparing zoliflodacin or gepotidacin with ceftriaxone-based therapy for uncomplicated gonorrhoea. The primary outcome was microbiological cure in the micro-ITT population across urogenital, rectal, and pharyngeal sites. Risk of bias was assessed using Cochrane RoB 2.0. Risk ratios were pooled using random-effects meta-analysis, with heterogeneity assessed by I and certainty of evidence evaluated using GRADE. RESULTS: Across three RCTs, urogenital microbiological cure rates were high in both groups (92% vs 94%). No significant differences were found between oral topoisomerase II inhibitors and ceftriaxone-based therapy for urogenital, rectal, or pharyngeal cure, although confidence intervals for extragenital outcomes remained wide. Adverse events were similar between groups. CONCLUSION: Preliminary evidence from a limited number of randomised controlled trials suggests that oral bacterial topoisomerase II inhibitors may represent promising treatment options for uncomplicated gonorrhoea. However, the current evidence remains limited, and further adequately powered clinical trials and post-approval surveillance are required to confirm their long-term efficacy, safety, and resistance implications.