Drug resistance has made the sexually transmitted infection hard to treat, with more than 13,000 cases reported in Australia so far this year.
A new oral antibiotic is emerging as a potential breakthrough in treating drug-resistant gonorrhoea, researchers say.
Treating the sexually transmitted infection has become a challenge due to antimicrobial resistance, which in turn has made it harder to control outbreaks.
Gepotidacin, a first-in-class antibacterial agent, has shown strong potential to treat uncomplicated urogenital gonorrhoea, including strains that are resistant to traditional antibiotics, according to a new paper published this month in The Lancet Infectious Diseases.
The researchers reported latest results from the EAGLE-1 phase 3 clinical trial, that showed gepotidacin was non-inferior to current first-line therapy – a combination of injectable ceftriaxone and oral azithromycin – in effectively eradicating Neisseria gonorrhoeae, the bacterium responsible for gonorrhoea.
The trial enrolled 622 participants from various countries and evaluated the effectiveness of two oral doses of gepotidacin (3000mg each) against the current standard treatment (an injection of 500mg ceftriaxone combined with 1g of oral azithromycin).
“Gepotidacin is an investigational oral antibiotic with activity and efficacy against N. gonorrhoeae, including drug-resistant strains, with an acceptable safety and tolerability profile,” the authors wrote.
“The potential introduction of a novel oral antibacterial with proven in-vitro activity and in-vivo efficacy would represent a significant advancement in patient care for uncomplicated gonorrhoea.”
In Australia so far this year there have been 13,192 cases of gonococcal infection, according to the Department of Health and Aged Care’s National Notifiable Surveillance System.
This compares to 12,043 cases in the first quarter of 2024. There were 44,549 cases reported in 2025.
The bulk of the cases so far this year have been in NSW (4348), followed by Victoria (3576), Queensland (2392), Western Australia (1557), South Australia (698), Northern Territory (404), ACT (154) and Tasmania (63).
N. gonorrhoeae globally has become largely resistant to many of the oral antibiotics that were once effective in treating it – usually penicillins, tetracyclines, macrolides such as azithromycin, and fluoroquinolones.
The shift to a combination of oral azithromycin and injected ceftriaxone has reduced treatment flexibility and presented challenges in resource-limited settings, where administering injections can be more difficult than prescribing oral medication.
An associated editorial and additional article on the WHO’s Bacterial Priority Pathogens List 2024 were published in same edition of The Lancet Infectious Diseases.
The BPPL provides a guide for global action against AMR, helping countries, researchers, and policymakers decide where to focus resources and efforts in fighting bacteria that are becoming harder to treat due to resistance.
It identifies gram-negative bacteria and rifampicin-resistant tuberculosis as the top threats. It also lists four bacteria as having a critical need for new antibiotics to replace those that are losing effectiveness: salmonella, shigella, N. gonorrhoeae and Staphylococcus aureus.
“The findings reinforce the urgent need for sustained research and development investments, international collaboration, and multifaceted interventions, including new antibiotics, vaccines, enhanced surveillance, infection prevention, and expanded water, sanitation, and hygiene initiatives, particularly in resource-limited settings,” the authors wrote.
“The 2024 BPPL highlights the need for innovation – not only in drug development but also in diagnostics, treatment strategies, and scalable public health solutions – to combat AMR effectively. This updated list provides a robust, evidence-based framework to guide and prioritise global efforts against AMR.”
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N. gonorrhoeae appears twice in the WHO list, first for resistance to fluoroquinolones and then for resistance to third-generation cephalosporins.
“Gonococci can easily pick up genetic material from other bacteria, including antibiotic resistance genes; this ability has fostered over the years resistance to tetracyclines, macrolides (including azithromycin), sulphonamides and trimethoprim combinations, and, more recently, quinolones,” the authors wrote.
But some good news is on the horizon. A recent phase 3 trial of the first-in-class antibiotic zoliflodacin (single oral suspension dose of 3g) demonstrated non-inferiority of microbiological cure at the urogenital site to 500mg of intramuscular ceftriaxone plus 1g of oral azithromycin.
The EAGLE-1 phase 3 clinical trial found that gepotidacin also showed promise.
“The potential availability of two different new antibiotics which mechanisms of action are not affected by existing resistance genes could offer hope for managing gonorrhoea cases caused by pan-resistant bacteria,” they wrote.
“Moreover, on April 2, researchers from the universities of Konstanz, Germany, and Vienna, Austria, discovered a new class of antibiotic (called 2-nonyl-4-quinolone N-oxide) that selectively kills N. gonorrhoeae, through activation of endogenous toxins.
“While very early, these results show that there is potential for further new drugs to be tested and possibly reach clinical development.”
Another research area in which the use of antibiotics to reduce of gonorrhoea was being explored is post-exposure prophylaxis (PEP) with doxycycline.
While recent trials such as DOXYVAC and DoxyPEP have shown that the use of doxycycline after condomless sex may reduce the incidence of a first episode of chlamydia or syphilis, its impact on gonorrhoea has been less clear.
“What we are seeing with N gonorrhoeae is a challenge that could extend easily to other bacteria with worsening of the antimicrobial resistance landscape,” the authors said in their editorial.
“Investment in research for new antimicrobials and efficacious prevention methods are key to prevent gonorrhoea from getting out of control in the coming years.”
The Lancet Infectious Diseases 2025, online 14 April; editorial; BPPL
