The Increasing Burden of Multidrug-Resistant Neisseria Gonorrhoeae: Zoliflodacin to the Rescue?

In 2016, the World Health Organization declared Neisseria gonorrhoeae a priority sexually transmitted infection (STI), citing concerns regarding rising antibiotic resistance and limited therapeutic options.¹ Zoliflodacin, developed by Entasis Therapeutics and the Global Antibiotic Research and Development Partnership, received US Food and Drug Administration (FDA) approval as a single-dose oral treatment for uncomplicated urogenital gonorrhea as of December 12, 2025.^2,3 Bactericidal with a high susceptibility profile, it serves as a promising option for multidrug-resistant (MDR) gonorrhea, which is rising in incidence and prevalence alongside the general increase in gonorrhea cases in many countries with STI surveillance capabilities.⁴ Its single-dose administration also provides potential opportunities to enhance treatment access for an STI that has 82 million new cases each year, with over half a million new cases reported in the US.¹ Here, we review the clinical trial data that have brought zoliflodacin to market and explore its potentially important and unique role in future clinical practice.

Zoliflodacin’s uniqueness begins with its mechanism of action and molecular structure. It is the inaugural member of the spiropyrimidinetriones (SPT) drug class, which acts by inhibiting the relegation of bacterial DNA through stabilizing the cleavage complex formed with DNA gyrase, its primary target, and topoisomerase IV, its secondary target.⁵ While the focus on zoliflodacin’s activity has been mostly on the treatment of N gonorrhoeae, it is worth noting that it has some in vitro activity against Mycobacterium tuberculosis, gram-positive (including Streptococcus and Staphylococcus species), other fastidious gram-negative (including Haemophilus influenzae and Moraxella catarrhalis), atypical (Legionella pneumophila and Mycoplasma genitalium), and anaerobic (including Clostridioides difficile) bacterial species.^6-11 This spectrum of activity and, more importantly, the mechanistic similarity to fluoroquinolones (FQs) have raised questions about the risk of resistance. While DNA gyrase is a shared enzymatic target with the FQs, SPTs bind at a site separate from that of FQs.⁶ They are therefore a redesign of the wheel: Whereas FQs have been shown to interact with the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV, SPTs instead bind to residues on GyrB of DNA gyrase, without requiring the water-metal ion bridge of its quinolone neighbors.^11-13 Similar to FQs, zoliflodacin has been shown to favor interactions with gyrase over topoisomerase. Historically, this imbalanced targeting has facilitated the rise of FQ-resistant bacteria.⁹ However, microbiologic studies suggest that zoliflodacin retains activity even against FQ-resistance gyrase. Zoliflodacin has exhibited low cross-resistance with FQ-resistant and ceftriaxone- and azithromycin- resistant strains of N gonorrhoeae around the world.¹¹ Pathogenwatch identified 3 mutations associated with zoliflodacin resistance in N gonorrhoeae, but none were detected among nearly 13,000 genomes recorded in the database.¹² In what is the largest phase 3 trial to date, zoliflodacin proved itself to be noninferior to the standard treatment of uncomplicated urogenital gonorrhea, leading to its FDA approval on December 12, 2025.^3,4 This may be because it has high potency against DNA gyrase by generating more DNA cleavage and more stable bonds with enzymecleaved DNA compared with FQs.^{11, 13-15} While this suggests that SPTs may be less susceptible to rapid resistance development, comparisons will inevitably be made to gepotidacin.¹⁶ Gepotidacin is another novel topoisomerase recently receiving FDA approval for treatment of uncomplicated urogenital gonorrhea, which has balanced dual-targeting of topoisomerases II and IV and, in theory, may be less susceptible to rapid resistance development. As no headto- head trials examining gepotidacin vs zoliflodacin have been conducted, comparisons of efficacy and long-term durability against resistance have yet to be examined. However, currently available clinical data suggest similar efficacy (Table 1).

Zoliflodacin’s approval for uncomplicated urogenital gonorrhea arises from studies that suggest its comparable efficacy to existing therapies and, in turn, the hope that it may serve as an addition to the limited antimicrobial armamentarium for MDR gonorrhea. The phase 2 trial (NCT02257918) was a multicenter, randomized, open-label study that compared a single oral dose of 2 g or 3 g of zoliflodacin against a 500-mg intramuscular dose of ceftriaxone in adults with uncomplicated urogenital gonorrhea, with 3 g previously determined to be the dose with the most favorable pharmacokinetic and safety profiles.^17,18 The study demonstrated a 96% cure rate of urogenital gonorrhea for both doses of zoliflodacin (compared with 100% with ceftriaxone), as well as a 100% cure rate in all subjects with rectal gonorrhea with zoliflodacin. However, zoliflodacin was less efficacious for pharyngeal gonorrhea (50% with 2 g; 82% with 3 g).¹⁸ The phase 3 trial (NCT03959527) was an international, randomized, open-label, noninferiority study that enrolled 930 subjects in 17 clinics across 5 countries, comparing a single oral dose of 3 g of zoliflodacin with a combination treatment of 500-mg intramuscular injection of ceftriaxone and 1 g of oral azithromycin with a primary end point being the proportion of patients demonstrating microbiologic cure at test-of-cure visit. Ultimately, 930 patients were enrolled, with 621 patients receiving zoliflodacin and 309 receiving ceftriaxone and azithromycin, and 21% of patients had concomitant infection with HIV. Zoliflodacin was found to be noninferior for the treatment of uncomplicated urogenital gonorrhea (90.9% cure rate with zoliflodacin; 96.2% for the comparator). The safety profile was similar across treatment groups, with gastrointestinal adverse events (AEs) being the most common AEs. Zoliflodacin also exhibited similar cure rates for pharyngeal gonorrhea (79.2% zoliflodacin vs 78.6% ceftriaxone/azithromycin) and rectal gonorrhea (87.3% zoliflodacin vs 88.6% ceftriaxone/azithromycin). However, this study was not powered enough to evaluate noninferiority for the secondary end points (Table 2).¹⁹ Perhaps most notably, there was no evidence of emerging zoliflodacin resistance by the end of the trial.

These results provide important implications for the future of urogenital gonorrhea treatment, particularly as previous potential oral antibiotics have failed to demonstrate noninferiority against ceftriaxone, save for gepotidacin.¹⁹

Several key questions remain. First, the role of zoliflodacin in the treatment of extragenital gonorrhea has not been clearly defined. While clinical trials have shown promise in curing pharyngeal and rectal gonorrhea, a dedicated, sufficiently powered study is still needed to confirm its efficacy at these sites.^18,19 Second, the efficacy of zoliflodacin in addressing gonorrhea in pregnant patients, patients with disseminated gonorrhea, and patients with pelvic inflammatory disease remains uninvestigated, as these populations were excluded from clinical trials. Third, cost and accessibility are always of concern with new therapeutics such as zoliflodacin: If the drug is financially inaccessible, the ease of administration and efficacy as an oral antibiotic may not be enough to keep it on the market without public-private partnerships. Lastly, there is the question of what to do when resistance inevitably emerges: What is the role of dual antibiotic therapy utilizing zoliflodacin? In vitro studies have demonstrated that dual therapy combinations, such as those with zoliflodacin and ceftriaxone, cefixime, gentamicin, and tetracycline, rapidly killed N gonorrhoeae with low resistance–emergence potential.²⁰ However, clinical trials evaluating combination therapy with zoliflodacin have not yet been conducted. Overall, zoliflodacin has shown great efficacy in curing uncomplicated urogenital gonorrhea, demonstrating it is a promising oral treatment option against N gonorrhoeae, with a particular opportunity to address MDR gonococcal infections. However, its longevity as an MDR gonococcal agent is not just about the speed of resistance development but also about how stakeholders choose to use and access the agent for this and other infections to come.

References

1.Multi-drug resistant gonorrhoea. World Health Organization. October 22, 2025. Accessed March 12, 2026. https://www.who.int/news-room/fact-sheets/detail/multi-drug-resistant-gonorrhoea

2.FDA approves two oral therapies to treat gonorrhea. News release. US Food and Drug Administration. December 12, 2025. Accessed March 9, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-two-oral-therapies-treat-gonorrhea

3. Innoviva Specialty Therapeutics receives FDA new drug application acceptance for zoliflodacin, a first-in-class oral antibiotic for uncomplicated gonorrhea in adults. June 10, 2025. Accessed February 14, 2026. https://innovivaspecialtytherapeutics.com/innoviva-specialty-therapeutics-receives-fda-new-drug-application-acceptance-for-zoliflodacin-a-first-in-class-oral-antibiotic-for-uncomplicated-gonorrhea-in-adults/

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