Zoliflodacin is a novel, first-in-class oral antibiotic developed for the treatment of uncomplicated gonorrhea. This drug belongs to a new class of antibiotics known as spiropyrimidinetriones. It offers a new treatment option for infections caused by Neisseria gonorrhoeae, the bacterium responsible for gonorrhea. Zoliflodacin is designed as a single-dose oral therapy, providing a convenient alternative to existing treatments.
The Growing Threat of Drug-Resistant Gonorrhea
Neisseria gonorrhoeae has developed resistance to nearly every class of antibiotics previously used to treat it. The bacterium quickly became resistant to drugs like sulfonamides in the 1930s, followed by penicillin, tetracycline, and fluoroquinolones. Currently, the Centers for Disease Control and Prevention (CDC) reports that only one class of antibiotics, cephalosporins, remains consistently effective for treating gonorrhea.
The increasing resistance poses a serious public health concern, with organizations like the CDC and the World Health Organization (WHO) warning about the potential for untreatable gonorrhea. If left unchecked, widespread resistance could lead to increased infection rates and more severe health consequences. Untreated gonorrhea can cause serious complications such as pelvic inflammatory disease, ectopic pregnancy, infertility in both men and women, and an increased risk of HIV transmission. The CDC designated drug-resistant N. gonorrhoeae as an “urgent threat” in its 2013 and 2019 antibiotic resistance reports, highlighting the need for new therapeutic options.
How Zoliflodacin Works
Zoliflodacin operates through a distinct mechanism of action. It inhibits a bacterial enzyme called DNA gyrase, a type II topoisomerase. This enzyme is essential for Neisseria gonorrhoeae to replicate its DNA, a process vital for bacterial multiplication and survival.
The drug’s mode of inhibition involves binding to bacterial gyrase at sites distinct from those targeted by fluoroquinolones, another class of DNA gyrase inhibitors. By disrupting DNA replication, zoliflodacin prevents the bacteria from dividing and growing. This mechanism allows zoliflodacin to be effective against strains of N. gonorrhoeae that have developed resistance to other antibiotics, including those resistant to ceftriaxone and azithromycin.
Clinical Trial Efficacy and Safety
Zoliflodacin has undergone extensive clinical evaluation, including a global Phase III study involving 930 participants with uncomplicated gonorrhea. This trial compared a single 3-gram oral dose of zoliflodacin to the current standard of care: an intramuscular injection of 500 mg ceftriaxone plus a 1-gram oral dose of azithromycin. The study demonstrated that zoliflodacin was statistically non-inferior to the standard dual therapy for achieving microbiological cure at urogenital sites.
The microbiological cure rate for zoliflodacin was 90.9%, compared to 96.2% for the ceftriaxone and azithromycin combination. Cure rates at extragenital sites, such as rectal infections, were comparable between treatment arms, though pharyngeal infections showed varied results. The safety profile of zoliflodacin was generally favorable, with the overall rate of adverse events comparable between the two treatment groups. Most side effects were mild to moderate in severity, and no serious adverse events or deaths were reported. Common side effects included gastrointestinal issues and headache.
Path to Public Use
Zoliflodacin’s regulatory journey has progressed with the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA). The FDA accepted this application on June 10, 2025, and granted zoliflodacin a Qualified Infectious Disease Product (QIDP) designation. This designation provides benefits such as Priority Review and Extended Market Exclusivity, intended to encourage the development of new drugs for serious infections caused by resistant pathogens.
The development of zoliflodacin has been a collaborative effort, involving Innoviva Specialty Therapeutics and the Global Antibiotic Research & Development Partnership (GARDP). GARDP, a non-profit organization, plays a role in ensuring global access to the drug, particularly in low- and middle-income countries. The Prescription Drug User Fee Act (PDUFA) target action date for the FDA’s decision on zoliflodacin is December 15, 2025. If approved, zoliflodacin would be the first new antibiotic for treating gonorrhea in decades, offering a new oral, single-dose option for patients.