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

Abstract

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.

World Health Organization Global Gonococcal Antimicrobial Surveillance Program (WHO GASP): review of new data and evidence to inform international collaborative actions and research efforts

“…Antimicrobials such as lefamulin, 112,113 SMT-571, 114 gepotidacin [115][116][117] and especially zoliflodacin 118-122 must be studied further. 123,124 In conclusion, gonococcal AMR remains a major global public health concern, which compromises treatment and control of gonorrhoea. WHO GASP, including its liaised GASPs, provides invaluable data regarding decreased susceptibility and resistance to therapeutically relevant antimicrobials.…”

The frontiers of addressing antibiotic resistance in Neisseria gonorrhoeae

“…70 71 Sitafloxacin may thus be a valuable tool in either dual or monotherapy as a more potent fluoroquinolone. 72 73 However, it faces major hurdles before it could be considered as a treatment for gonorrhea on a global scale. As of 2017, sitafloxacin was only approved in Japan, 74 with one major barrier to approval outside of Asia being the UVA phototoxicity in Caucasian but not Asian subjects.…”

“…Based on these results, solithromycin cannot be considered noninferior to dual therapy with ceftriaxone plus azithromycin, 80 and this, together with questions around liver hepatotoxicity, have stalled efforts to gain approval. 73 Gepotidacin is the founding member of a class of antibiotics known as the triazaacenaphthylenes and has broad in vitro activity against Gram-positive and Gram-negative organisms, 81 Although gepotidacin, like quinolones, targets type IIA topoisomerases, including DNA gyrase (gyrA) and topoisomerase IV (parC), it binds at a distinct target. 82 In clinical studies, gepotidacin was relatively safe and effective against gonococcus.…”

Gonorrhoea: tackling the global epidemic in the era of rising antimicrobial resistance

“…With very little second-line options available, Lewis reviews the search for new agents to manage NG and found that the pipeline is disappointingly sparse. 24 The authors discuss the latest evidence for ertapenem, modern fluoroquinolones (gemifloxacin, sitafloxacin, delafloxacin), solithromycin, gepotidacin and zoliflodacin, though none emerge as a clear winning candidate.…”