Gepotidacin Shows Potential in Treating Resistant Neisseria Gonorrhoeae
Results indicated that further evaluation of gepotidacin in the treatment of gonorrhea is warranted.
Gepotidacin, a novel triazaacenaphthelene bacterial type II topoisomerase inhibitor, shows promise and potential in treating resistant Neisseria gonorrhoeae through a unique interaction, according to study results published in Antimicrobial Agents and Chemotherapy.
The prevalence of gonorrhea infections has risen steadily in recent years, while effective treatment options have decreased as a result of increasing antimicrobial resistance in Neisseria gonorrhoeae. As a result, novel antibacterial agents and treatment strategies are needed to address the threat of potentially untreatable gonorrhea. Gepotidacin is a first-in-class triazaacenaphthelene bacterial type II topoisomerase inhibitor being developed for the treatment of gonorrhea by interacting in a unique way against most target pathogens resistant to established antibacterial agents, including drug-resistant N gonorrhoeae strains.
A previous phase 2 study demonstrated that gepotidacin was 96% effective in eradicating N gonorrhoeae from participants but warrants further clinical evaluation. Therefore, this study (ClinicalTrials.gov identifier: NCT02294682) evaluated microbiologic correlates of successful treatment of N gonorrhoeae isolates in the aforementioned phase 2 study of gepotidacin for therapy of uncomplicated urogenital gonorrhea.
Data was used from the phase 2, randomized, multicenter, open-label, dose-ranging, single oral dose study of gepotidacin (1500 mg or 3000 mg in a 1:1 ratio stratified by gender) for the treatment of urogenital gonorrhea. In this study, a single oral dose of gepotidacin was administered at baseline followed by test-of-cure 3 to 7 days after dosing. Pretreatment and test-of-cure urogenital swab and rectal and pharyngeal specimens were obtained. The evaluable population consisted of 69 randomly assigned participants (67 male and 2 female) with culture-confirmed urogenital gonorrhea at baseline who received gepotidacin and returned for test-of-cure. Of the 69 participants, 2 also had culture-confirmed pharyngeal gonorrhea and 3 had culture-confirmed rectal gonorrhea.
Using data from the oral gepotidacin phase 2 urogenital gonorrhea study, antibacterial susceptibility, quinolone resistance-determining region genotyping of GyrA and ParC subunits, sequence typing, frequency of resistance, and efficacy assessments based on pharmacokinetic/pharmacodynamics magnitudes were studied. Microbiologic success was defined as culture-confirmed eradication of N gonorrhoeae at test-of-cure; microbiologic failure was defined as culture-confirmed bacterial persistence of N gonorrhoeae at time of test-of-cure or the inability to determine the response of the baseline pathogen at test-of-cure.
Gepotidacin was active against the 69-baseline urogenital N gonorrhoeae isolates; gepotidacin minimum inhibitory concentrations (MICs) ranged from £0.06 to 1 µg/mL (MIC90= 0.5 µg/mL). The ratio of the area under the free-drug concentration-time curve to MIC (fAUC/MIC) for gepotidacin was associated with therapeutic success of 100% for fAUC/MICs ³48 and decreased to 63% for fAUC/MICs £25. Isolates that were failures carried mutations implicated in gepotidacin binding sites.
Overall, the study investigators concluded that, “These results indicate that further evaluation of gepotidacin in the treatment of gonorrhea is warranted, including demonstration that higher exposures increase efficacy and suppress resistance in key isolate subsets."
Scangarella-Oman NE, Hossain M, Dixon PB, et al. Microbiological analysis from a phase 2 randomized study in adults evaluating single oral doses of gepotidacin in the treatment of uncomplicated urogenital gonorrhea caused by Neisseria gonorrhoeae [published online September 24, 2018]. Antimicrob Agents Chemother. doi:10.1128/AAC.01221-18