Zoliflodacin for uncomplicated gonorrhea: clinical evidence and implications beyond ceftriaxone plus azithromycin

Globally, gonorrhea remains a common sexually transmitted infection that can lead to serious sexual and reproductive health complications if left untreated. Management has become more challenging due to the rapid progression of antimicrobial resistance in Neisseria gonorrhoeae. Currently, ceftriaxone-based regimens continue to be the standard treatment; however, the sudden demand for new treatment options is highlighted by concerns regarding resistance, the requirement for intramuscular administration, and the declining effectiveness of azithromycin.

This review aims to evaluate the emerging role of zoliflodacin in the treatment of gonorrhea, with an emphasis on its potential to serve as a resistance-focused alternative, its oral administration, and its novel antimicrobial target.

A narrative literature search was conducted using PubMed, Google Scholar, and Scopus to identify relevant studies published between 2016 and 2026. Randomized clinical trials, systematic reviews, narrative reviews, and international guidelines from the WHO, ECDC, and CDC were included. Literature selection was guided by SANRA.

A single 3-g oral dose of zoliflodacin appears to exhibit high microbiological cure rates for uncomplicated urogenital and rectal gonorrhea, and it is not less effective than ceftriaxone plus azithromycin for urogenital infections, according to Phase 2 and recent global Phase 3 clinical trials, which reported mild gastrointestinal side effects. Its mechanism of action provides limited evidence of resistance and is effective against multidrug-resistant Neisseria gonorrhoeae.

Zoliflodacin represents a potentially effective oral alternative to the current ceftriaxone-based regimen for gonorrhea. With routine observation and careful stewardship, these findings may contribute significantly to the expansion of future treatment strategies.