New treatment options for Neisseria gonorrhoeae in the era of emerging antimicrobial resistance

Neisseria gonorrhoeae, the causative agent of gonorrhoea, has rapidly evolved from an exquisitely susceptible pathogen into a 'superbug' with the capacity to exhibit an extensively drug resistant (XDR) phenotype. The threat of untreatable gonorrhoea now looms on the horizon while the arsenal of effective antimicrobial agents diminishes with time. Ceftriaxone remains the mainstay of first-line therapy as a single agent or as the backbone of a dual therapy regimen. The implementation of new assays to facilitate 'precision' treatment, based on the prediction of N. gonorrhoeae susceptibility to old anti-gonococcal drugs, may enable sparing use of ceftriaxone in those countries that can afford this technology. A few existing drugs, such as ertapenem, can be repositioned to help manage multi-drug resistant and XDR gonorrhoea. Recent clinical trials involving solithromycin and delafloxacin have generated disappointing results in that both agents failed to show non-inferiority to conventional ceftriaxone-based regimens. At present, zoliflodacin and gepotidacin appear to be the most promising antimicrobial agents in clinical development. Both drugs performed well in eradicating urogenital gonorrhoea in recent Phase 2 trials; however, treatment failures were reported at the oropharyngeal site, which is an important site of infection in men who have sex with men and sex workers. Given this observation, it is unlikely that either of these new agents could be promoted for monotherapy of gonorrhoea. The pre-clinical pipeline remains relatively empty of agents likely to progress to clinical development for gonorrhoea treatment and increased investment into gonorrhoea-specific drug discovery is recommended.