Gepotidacin (Blujepa), first new oral antibiotic class in decades

Antibiotic resistance had been eroding the reliability of standard regimens for uncomplicated urinary tract infection and gonorrhea for years before gepotidacin reached approval. Fluoroquinolone resistance in E. coli, the dominant UTI pathogen, had risen high enough that many guidelines had already downgraded the class from first-line use in uncomplicated cystitis. Neisseria gonorrhoeae presented an even more urgent problem: after fluoroquinolone resistance rendered that class obsolete for gonorrhea around 2007, ceftriaxone became the last reliable option, and strains with reduced ceftriaxone susceptibility had been documented across multiple continents. The pipeline of new gonorrhea therapeutics had been nearly empty for three decades.

Gepotidacin belongs to a new chemical class, the triazaacenaphthylenes, and works by inhibiting bacterial type IIA topoisomerases through a binding site distinct from the one targeted by fluoroquinolones. Because the mechanism operates at a different location on the enzyme, existing fluoroquinolone resistance mutations, including the common gyrA and parC substitutions, do not confer resistance to gepotidacin. That dual topoisomerase inhibition, hitting both DNA gyrase and topoisomerase IV simultaneously at a new site, raises the barrier to de novo resistance development. GSK developed the drug through a public-private partnership with the U.S. Biomedical Advanced Research and Development Authority and the Defense Threat Reduction Agency, dating to 2013.

The EAGLE-2 and EAGLE-3 phase 3 trials for uncomplicated UTI compared gepotidacin against nitrofurantoin and demonstrated non-inferiority; the FDA approved gepotidacin under the brand name Blujepa in March 2025 for uncomplicated UTIs caused by susceptible organisms. A separate phase 3 trial for uncomplicated gonorrhea found a 93% cure rate with gepotidacin, compared with 91% for standard ceftriaxone-based treatment, and the FDA approved the gonorrhea indication in December 2025.

The gonorrhea indication, cleared one day before the FDA approved zoliflodacin (Nuzolvence), a second new antibiotic for the same infection, made gepotidacin one of the first new oral antibiotic classes for gonorrhea in over three decades. Infectious disease specialists had been monitoring the situation closely: as of the early 2020s, dual therapy with ceftriaxone plus azithromycin had already been modified to ceftriaxone alone after azithromycin resistance rose, and the field was functioning with a single-drug option backed by a narrowing spectrum. Gepotidacin's activity against fluoroquinolone-resistant N. gonorrhoeae was the specific property that made it clinically relevant to that gap.

Gepotidacin's spectrum does not cover the full range of organisms encountered in complicated UTI or upper tract infections, so its role in clinical practice is relatively specific: uncomplicated cystitis in settings where resistance limits the standard options, and gonorrhea where fluoroquinolone resistance is documented or suspected. For infectious disease physicians managing urogenital pathogens with resistance, the approval added a mechanistically distinct option that had not existed in oral form for a generation.