The rise of drug-resistant Neisseria gonorrhoeae has prompted the urgent need for new antimicrobial treatments. Recent phase 3 clinical trial data for zoliflodacin and gepotidacin offer hope as potential new oral treatments for gonorrhea, including drug-resistant strains. Gonorrhea is the second most common sexually transmitted infection (STI), with over 82 million new infections globally each year, including 601,319 cases in the United States in 2023. The increasing resistance to ceftriaxone, the last recommended treatment, has led the CDC to declare drug-resistant N. gonorrhoeae an urgent threat, and the WHO to call it a high-priority pathogen.
Zoliflodacin
Zoliflodacin, the first in a new class of spiropyrimidinetrione antibiotics, inhibits bacterial type II topoisomerases (GyrB) and DNA biosynthesis, leading to double-strand cleavages. It binds to bacterial gyrase at sites distinct from fluoroquinolones and lacks cross-resistance to them.
In vitro analysis against 250 reference strains of clinical gonococcal isolates, including multi- and extensively drug-resistant strains, demonstrated lower minimum inhibitory concentrations (MICs) than most current or prior antimicrobials. The rate of spontaneous resistance mutations to zoliflodacin is low in vitro.
A phase 3 noninferiority randomized controlled trial compared oral zoliflodacin with ceftriaxone plus azithromycin for uncomplicated gonorrhea. The trial included 930 participants aged 12 years or older with uncomplicated gonorrhea from 15 sites in South Africa, Thailand, the United States, Belgium, and the Netherlands. Participants were randomly assigned in a 2:1 ratio to either a single 3 g dose of zoliflodacin (granules for oral suspension) or 500 mg ceftriaxone intramuscularly plus azithromycin in a single 1 g dose. The primary endpoint was microbiological cure at urogenital sites at the test-of-cure (TOC) visit (62 days), with a noninferiority margin of 12%.
The microbiological cure rate in the micro-ITT population was 90.9% for zoliflodacin compared with 96.2% for ceftriaxone/azithromycin (5.31% difference; 95% CI, 1.38%-8.65%). In the evaluable population, the rates were 96.8% and 100% (3.16% difference; 95% CI, 1.1%-5.14%), respectively. Regarding safety, the most common adverse effect for zoliflodacin was headache, with an overall similar rate of adverse effects compared with ceftriaxone/azithromycin, the majority being mild/moderate.
If approved, zoliflodacin would offer a new oral single-dose option for the treatment of gonorrhea.
Gepotidacin
Gepotidacin is a new triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interacting uniquely with the GyrA subunit of bacterial DNA gyrase and the parC subunit of bacterial topoisomerase IV, a novel binding site distinct from fluoroquinolones.
Gepotidacin's activity for N. gonorrhoeae was evaluated in vitro against 252 strains, including drug-resistant and extensively drug-resistant strains. It showed potent in vitro activity against all strains with no significant cross-resistance.
The EAGLE-1 trial, a phase 3, open-label, multicenter, comparator-controlled noninferiority study, included 602 participants aged 12 years or older with uncomplicated urogenital gonorrhea. Participants were randomly assigned to either two 3,000 mg doses of gepotidacin 10 to 12 hours apart or ceftriaxone 500 mg intramuscularly plus azithromycin. The primary endpoint was microbiological response at the day 4 to 8 TOC visit, with a noninferiority limit of -10%. Safety was evaluated at the day 14 to 21 visit.
The microbiological success rate was 92.6% for gepotidacin compared with 91.2% for ceftriaxone/azithromycin. In the microbiologically evaluable population, the cure rate was 100% in both groups. There was a higher rate of adverse effects in the gepotidacin group, driven by diarrhea and nausea. The study demonstrated noninferiority but did not meet superiority. There was a reasonable safety profile.
Pending full publications of these data, these two new oral agents may be future options in the armamentarium for treating gonorrhea infections, including drug-resistant strains.
