Neisseria gonorrhoeae Antimicrobial Resistance: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Angelo Roberto Raccagni.

The growing threat of antibiotic-resistant

Neisseria gonorrhoeae

, which causes gonorrhea, presents a current public health challenge. Over the years, the pathogen has developed resistance to different antibiotics, leaving few effective treatment options. High-level resistance to key drugs, including ceftriaxone, has become a concerning reality.

  • gonorrhoea
  • gonorrhea
  • drug resistance
  • antimicrobials

1. Introduction

Sexually transmitted infections (STIs) are a global public health challenge, severely affecting the quality of life and giving rise to substantial morbidity and mortality. STIs have a negative influence on the reproductive and child health, leading to complications such as infertility and pregnancy-related issues [1]. Most STIs facilitate the transmission of HIV, amplifying their impact on both national economies and the individual well-being [1]. Prioritizing STIs prevention and control is a paramount public health concern [2]. Curable STIs alone result in the loss of over eleven million disability-adjusted life years annually, and it is estimated that more than a million STIs are contracted daily worldwide, with infections including chlamydia, gonorrhea, syphilis, trichomoniasis, herpes simplex virus (HSV), human papillomavirus (HPV), and HIV falling under the broad category of these infections [2,3,4,5][2][3][4][5]. More than 1 million STIs every day are acquired. As reported by the WHO, in 2020, 374 million new infections with one of four STIs occurred. Chlamydia cases totaled 129 million, gonorrhea totaled 82 million, syphilis totaled 7.1 million and trichomoniasis totaled 156 million. Over 490 million people were believed to have genital herpes in 2016, and 300 million women were believed to have HPV infection.

2. Gonorrhea

Gonorrhea is the second most common bacterial STI inflicting considerable morbidity and substantial economic costs on a global scale [6]. Gonococci success as human pathogens is the result of several combined factors. The plethora of bacterial virulence factors allow efficient colonization of both male and female mucosae. The chameleon-like ability determined by the high-frequency antigenic and phase variation of core surface structures causes clonal variability. The ability to subvert and hide from the immune system by directly suppressing and interacting with immunological effectors and regulators allows re-infections. N. gonorrhoeae infections encompass a multi-step strategic process: pathogen highly efficient transmission; mucosal localized adherence; local proliferation and invasion; local inflammatory response; external or systemic dissemination. Presently, there is no effective vaccine directly targeting Neisseria gonorrhoeae available in clinical practice, although data support the possible use of multicomponent meningococcal serogroup B (4CMenB) vaccine to provide some cross-protection and also prevent Neisseria gonorrhoeae cases [2,3,4,5,6,7][2][3][4][5][6][7]. With the emergence of multidrug-resistant (MDR) strains and the lack of new antibiotics, the World Health Organization (WHO) has recognized the health sector’s response to the epidemic of STIs as a critical component in achieving universal health coverage [8]. This objective is delineated in the 2030 Agenda for Sustainable Development, encapsulating the Sustainable Development Goals (SDGs) [9,10][9][10]. However, the sustainable control of infections may not be reached with the current interventions, necessitating also innovative solutions.

3. Epidemiology

In 2016, eighty-seven million new cases of Neisseria gonorrhoeae were estimated worldwide, with varying prevalence and incidence across the world and higher risk among younger individuals [11]. The highest rates were observed in low and middle-income countries, as transmission is often linked to the socio-economic status. Notably, gonorrhea prevalence among women was high in the WHO African region, the Americas, and the Western Pacific, while lower prevalence was observed in Europe. However, an increase in cases in Western countries is currently observed, which can be attributed to improved diagnostics and evolving sexual networks [11,12][11][12]. Moreover, in the African region, Neisseria gonorrhoeae during pregnancy poses a substantial burden, reaching a prevalence comparable to that of malaria [13]. Focusing on Europe, an increasing trend in cases is observed among all key populations with the most significant rise observed among men who have sex with men (MSM) [14,15,16,17][14][15][16][17]. Moreover, international travels play a key role in the spread of multi-resistant STIs, and therefore, improved surveillance in international travelers is needed. However, reported data are likely underestimated due to underreporting and the presence of asymptomatic cases. The bacterium’s emergence as an MDR pathogen has led to its inclusion in the “WHO Priority Pathogens List for Research and Development of New Antibiotics” [10]. Remarkably, N. gonorrhoeae is the only STI in the list; the second level of priority [10]. Indeed, the “World Health Organization Global Gonococcal Antimicrobial Surveillance Program,” known as the WHO GASP, is designed to monitor the emergence of MDR and extensively drug-resistant (XDR) strains [18]. The WHO recommends discontinuing first-line treatments when failures or not susceptible isolates are above 5%. Data from 2015 to 2016 show that 100% of countries reported ciprofloxacin resistance, 80% reported resistance to azithromycin, 45% reported resistance to cefixime and 24% reported resistance to ceftriaxone [18]. Ceftriaxone resistance is rare in the Euro-GASP countries when compared to other regions, whilst azithromycin resistance is highly prevalent also in the European region, although travel-related spread of MDR lineages is observed [18]. Moreover, the WHO established the Global Antimicrobial Resistance Surveillance System (GLASS) in 2019 [19].

4. Clinical Presentation

Gonorrhea infections involve the genital, rectal, and pharyngeal regions and may be either asymptomatic or symptomatic. Most acute lower tract infections in females, around 80–90% of cases, are asymptomatic, while lower tract infections in men are symptomatic in approximately 45% of cases. Extra-genital gonococcal infections are often asymptomatic among both men and women [3,11][3][11]. Complications can arise from both symptomatic and asymptomatic infections. The most common adverse outcomes are related to sexual and reproductive health and include upper genital tract dissemination, leading to pelvic inflammatory disease (PID), Fitz Hugh Curtis syndrome, tubal-ovarian abscess, epididymo-orchitis, bartholinitis, penile lymphangitis, and edema [11,20][11][20]. Genital tract scarring and adverse pregnancy outcomes also contribute to gonorrhea morbidity [11,20,21,22,23][11][20][21][22][23]. Rarely, gonorrhea may also present as disseminated gonococcal infection (DGI), which include gonococcemia, gonococcal arthritis, tenosynovitis, osteomyelitis, endocarditis, and meningitis [24,25][24][25]. Lastly, gonorrhea increases the risk of HIV acquisition, transmission, with often presence of co-infection with other STIs [26,27][26][27].

5. Novel Antibiotics Showing Inferiority to First-Line Treatment Options

The demand for effective new treatment options for gonorrhea has been a persistent challenge marked by several attempts to address the evolving landscape of antimicrobial resistance. Despite efforts of researchers and pharmaceutical companies, some promising clinical trials failed to demonstrate the non-inferiority of investigational products when compared to the existing first-line treatment options for gonorrhea.

5.1. Solithromycin

Solithromycin is a broad-spectrum fluoro-ketolide which was evaluated in clinical trials for the treatment of gonorrhea. It exhibited high activity against most gonococcal strains, including drug-resistant ones. However, its progress for gonococcal treatment was interrupted due to its failure to demonstrate non-inferiority compared to the ceftriaxone [42,43,44][28][29][30]. Overall, 261 volunteers were treated with either solithromycin or ceftriaxone and azithromycin. Of these, 80% in the solithromycin group and 84% in the combination group achieved gonorrhoeae eradication. The difference was not significant enough to conclude that solithromycin was non-inferior to standard of care. The solithromycin group also experienced more frequently adverse events, as diarrhea and nausea. Therefore, solithromycin as a single 1000 mg dose is not recommended as a first-line treatment for gonorrhea [44][30].

5.2. Delafloxacin

Delafloxacin is a novel broad-spectrum fluoroquinolone with increased potency and target affinity compared to older fluoroquinolones. Studies showed activity against MDR N. gonorrhoeae. However, delafloxacin was found in a clinical trial to not be a reliable treatment for urogenital gonorrhea given the high rate of observed treatment failures. Overall, 460 participants were randomly assigned to receive either 900 mg of oral delafloxacin or ceftriaxone. Delafloxacin had a urogenital cure rate of 85% compared to 91% of ceftriaxone, not meeting the non-inferiority margin [45][31].

6. New Antibiotics Candidates

Promising antimicrobial agents in advanced clinical development for gonorrhea treatment include zoliflodacin and gepotidacin. Following discussion on the rationale for use of these novel treatments, wresearchers here present insight on the ongoing clinical trials and their design. In order to investigate this aspect, weresearchers conducted systematic research on Clinical Trials.org regarding ongoing interventional clinical trials using key terms “Gonorrhea; Gonorrhoea; Gonococcal; Neisseria gonorrhoeae; Gonococcal infection; Neisseria gonorrheae infection; Gonococcal infections”.

6.1. Zoliflodacin

Zoliflodacin, a novel topoisomerase inhibitor, effectively inhibits bacterial DNA biosynthesis, making it useful for treating uncomplicated gonorrhea. Its distinct mode of action suggests potential efficacy also against fluoroquinolone-resistant strains [43,46,47,48,49,50][29][32][33][34][35][36]. Phase II trials demonstrated its safety and tolerability among subjects with gonorrhea. Participants were randomly assigned to receive a single oral dose of either 2 g or 3 g of zoliflodacin or ceftriaxone. The primary outcome measure was the proportion of urogenital microbiologic cure. Microbiologic cure at urogenital sites was documented in 96% of participants who received 2 g of zoliflodacin, 96% who received 3 g, and 100% who received ceftriaxone. Reported adverse events were mostly gastrointestinal. Zoliflodacin showed promise in treating urogenital and rectal gonococcal infections but was less effective for pharyngeal infections. This limitation is consistent with previous recommendations for other drugs, such as spectinomycin and other fluoroquinolones [46][32].

6.2. Gepotidacin

Gepotidacin, a triazaacenaphthylene antibiotic, shows bactericidal effects by inhibiting the DNA topoisomerase II activity. It demonstrated low MIC values against various gonococcal strains, including ciprofloxacin-resistant ones. Combination studies with other antibiotics showed also a synergistic effect. A phase II trial indicated a 95% success rate in treating uncomplicated genitourinary gonorrhea [42,51,52,53][28][37][38][39]. Overall, 69 participants received either a 1500 mg or 3000 mg single oral dose of gepotidacin. Microbiological eradication of the infection was achieved by 97% and 95% of participants in the 1500 mg and 3000 mg groups, respectively, without treatment-limiting adverse events. A single, oral dose of gepotidacin was indeed highly effective for the treatment of uncomplicated urogenital infections [53][39].

References

  1. Rowley, J.; Vander Hoorn, S.; Korenromp, E.; Low, N.; Unemo, M.; Abu-Raddad, L.J.; Chico, R.M.; Smolak, A.; Newman, L.; Gottlieb, S.; et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: Global prevalence and incidence estimates, 2016. Bull. World Health Organ. 2019, 97, 548P–562P.
  2. Global Health Sector Strategy on Sexually Transmitted Infections, 2016–2021; World Health Organization: Geneva, Switzerland, 2016; Available online: https://www.who.int/publications/i/item/WHO-RHR-16.09 (accessed on 20 October 2023).
  3. Philibert, P.; Khiri, H.; Pénaranda, G.; Camus, C.; Drogoul, M.-P.; Halfon, P. High Prevalence of Asymptomatic Sexually Transmitted Infections among Men Who Have Sex with Men. J. Clin. Med. 2014, 3, 1386–1391.
  4. Marchese, V.; Tiecco, G.; Storti, S.; Degli Antoni, M.; Calza, S.; Gulletta, M.; Viola, F.; Focà, E.; Matteelli, A.; Castelli, F.; et al. Syphilis Infections, Reinfections and Serological Response in a Large Italian Sexually Transmitted Disease Centre: A Monocentric Retrospective Study. J. Clin. Med. 2022, 11, 7499.
  5. Evans, A.M.; Salnikov, M.; Gameiro, S.F.; Maleki Vareki, S.; Mymryk, J.S. HPV-Positive and -Negative Cervical Cancers Are Immunologically Distinct. J. Clin. Med. 2022, 11, 4825.
  6. Kirkcaldy, R.D.; Weston, E.; Segurado, A.C.; Hughes, G. Epidemiology of gonorrhoea: A global perspective. Sex. Health 2019, 16, 401–411.
  7. Raccagni, A.R.; Alberton, F.; Castagna, A.; Nozza, S. Vaccines against Emerging Sexually Transmitted Infections: Current Preventive Tools and Future Perspectives. New Microbiol. 2022, 45, 9–27.
  8. Unemo, M.; Bradshaw, C.S.; Hocking, J.S.; de Vries, H.J.C.; Francis, S.C.; Mabey, D.; Marrazzo, J.M.; Sonder, G.J.B.; Schwebke, J.R.; Hoornenborg, E.; et al. Sexually transmitted infections: Challenges ahead. Lancet Infect. Dis. 2017, 17, e235–e279.
  9. Sustainable Development Goals. United Nations. Available online: https://sdgs.un.org/goals (accessed on 20 October 2023).
  10. Global Priority List of Antibiotic-Resistant Bacteria; World Health Organization: Geneva, Switzerland, 2017; Available online: https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed (accessed on 20 October 2023).
  11. WHO Guidelines for the Treatment of Neisseria Gonorrhoeae; World Health Organization: Geneva, Switzerland, 2016; Available online: https://www.who.int/publications-detail-redirect/9789241549691 (accessed on 20 October 2023).
  12. Sexually Transmitted Disease Surveillance 2018; US Department of Health and Human Services, CDC: Atlanta, GA, USA, 2019. Available online: https://www.cdc.gov/std/stats18/STDSurveillance2018-full-report.pdf (accessed on 20 October 2023).
  13. Chico, R.M.; Mayaud, P.; Ariti, C.; Mabey, D.; Ronsmans, C.; Chandramohan, D. Prevalence of malaria and sexually transmitted and reproductive tract infections in pregnancy in sub-Saharan Africa: A systematic review. JAMA 2012, 307, 2079–2086.
  14. Gonorrhoea Annual Epidemiological Report for 2018. Stockholm, European Centre for Diseases Prevention and Control. 2020. Available online: https://www.ecdc.europa.eu/sites/default/files/documents/gonorrhoea-annual-epidemiological-report-2018.pdf (accessed on 20 October 2023).
  15. Sonnenberg, P.; Clifton, S.; Beddows, S.; Field, N.; Soldan, K.; Tanton, C.; Mercer, C.H.; da Silva, F.C.; Alexander, S.; Copas, A.J.; et al. Prevalence, risk factors, and uptake of interventions for sexually transmitted infections in Britain: Findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet 2013, 382, 1795–1806.
  16. Unigwe, I.; Yang, S.; Song, H.J.; Lo-Ciganic, W.-H.; Hincapie-Castillo, J.; Cook, R.L.; Park, H. Trends in Sexually Transmitted Infections in United States Ambulatory Care Clinics from 2005–2016. J. Clin. Med. 2022, 11, 71.
  17. Orzechowska, M.; Cybulski, M.; Krajewska-Kulak, E.; Sobolewski, M.; Gniadek, A.; Niczyporuk, W. Comparative Analysis of the Incidence of Selected Sexually Transmitted Viral Infections in Poland in 2010–2015: A Retrospective Cohort Study. J. Clin. Med. 2022, 11, 3448.
  18. Unemo, M.; Lahra, M.M.; Cole, M.; Galarza, P.; Ndowa, F.; Martin, I.; Dillon, J.R.; Ramon-Pardo, P.; Bolan, G.; Wi, T. World Health Organization Global Gonococcal Antimicrobial Surveillance Program (WHO GASP): Review of new data and evidence to inform international collaborative actions and research efforts. Sex. Health 2019, 16, 412–425.
  19. Global Antimicrobial Resistance and Use Surveillance System (GLASS); World Health Organization: Geneva, Switzerland, 2019; Available online: https://www.who.int/initiatives/glass (accessed on 20 October 2023).
  20. Brunham, R.C.; Gottlieb, S.L.; Paavonen, J. Pelvic inflammatory disease. N. Engl. J. Med. 2015, 372, 2039–2048.
  21. Grant, J.S.; Chico, R.M.; Lee, A.C.; Low, N.; Medina-Marino, A.; Molina, R.L.; Morroni, C.; Ramogola-Masire, D.; Stafylis, C.; Tang, W.; et al. Sexually Transmitted Infections in Pregnancy: A Narrative Review of the Global Research Gaps, Challenges, and Opportunities. Sex. Transm. Dis. 2020, 47, 779–789.
  22. Heumann, C.L.; Quilter, L.A.; Eastment, M.C.; Heffron, R.; Hawes, S.E. Adverse Birth Outcomes and Maternal Neisseria gonorrhoeae Infection: A Population-Based Cohort Study in Washington State. Sex. Transm. Dis. 2017, 44, 266–271.
  23. Kondracki, A.J.; Li, W.; Bursac, Z.; Mokhtari, M.; Reddick, B.; Barkin, J.L. Interaction Effects of Maternal Sexually Transmitted Infections with Prenatal Care Utilization Status on Preterm Birth and Low Birthweight: U.S. National Data. J. Clin. Med. 2022, 11, 5184.
  24. Crew, P.E.; Abara, W.E.; McCulley, L.; Waldron, P.E.; Kirkcaldy, R.D.; Weston, E.J.; Bernstein, K.T.; Jones, S.C.; Bersoff-Matcha, S.J. Disseminated Gonococcal Infections in Patients Receiving Eculizumab: A Case Series. Clin. Infect. Dis. 2019, 69, 596–600.
  25. Laga, M.; Meheus, A.; Piot, P. Epidemiology and control of gonococcal ophthalmia neonatorum. Bull. World Health Organ. 1989, 67, 471–477.
  26. Guvenc, F.; Kaul, R.; Gray-Owen, S.D. Intimate Relations: Molecular and Immunologic Interactions between Neisseria gonorrhoeaeand HIV-1. Front. Microbiol. 2020, 11, 1299.
  27. Bernstein, K.T.; Marcus, J.L.; Nieri, G.; Philip, S.S.; Klausner, J.D. Rectal gonorrhea and chlamydia reinfection is associated with increased risk of HIV seroconversion. J. Acquir. Immune Defic. Syndr. 2010, 53, 537–543.
  28. Lewis, D.A. New treatment options for Neisseria gonorrhoeae in the era of emerging antimicrobial resistance. Sex. Health 2019, 16, 449–456.
  29. Mancuso, A.M.; Gandhi, M.A.; Slish, J. Solithromycin (CEM-101): A New Fluoroketolide Antibiotic and Its Role in the Treatment of Gonorrhea. J. Pharm. Pract. 2018, 31, 195–201.
  30. Chen, M.Y.; McNulty, A.; Avery, A.; Whiley, D.; Tabrizi, S.N.; Hardy, D.; Das, A.F.; Nenninger, A.; Fairley, C.K.; Hocking, J.S.; et al. Solithromycin versus ceftriaxone plus azithromycin for the treatment of uncomplicated genital gonorrhoea (SOLITAIRE-U): A randomised phase 3 non-inferiority trial. Lancet Infect. Dis. 2019, 19, 833–842.
  31. Hook, E.W., 3rd; Golden, M.R.; Taylor, S.N.; Henry, E.; Tseng, C.; Workowski, K.A.; Swerdlow, J.; Nenninger, A.; Cammarata, S. Efficacy and Safety of Single-Dose Oral Delafloxacin Compared with Intramuscular Ceftriaxone for Uncomplicated Gonorrhea Treatment: An Open-Label, Noninferiority, Phase 3, Multicenter, Randomized Study. Sex. Transm. Dis. 2019, 46, 279–286.
  32. Taylor, S.N.; Marrazzo, J.; Batteiger, B.E.; Hook, E.W., 3rd; Seña, A.C.; Long, J.; Wierzbicki, M.R.; Kwak, H.; Johnson, S.M.; Lawrence, K.; et al. Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea. N. Engl. J. Med. 2018, 379, 1835–1845.
  33. Bradford, P.A.; Miller, A.A.; O’Donnell, J.; Mueller, J.P. Zoliflodacin: An Oral Spiropyrimidinetrione Antibiotic for the Treatment of Neisseria gonorrheae, Including Multi-Drug-Resistant Isolates. ACS Infect. Dis. 2020, 6, 1332–1345.
  34. Luckey, A.; Alirol, E.; Delhomme, S.; O’Donnell, J.; Bettiol, E.; Mueller, J.; O’Brien, S.; Gillon, J.Y. Effect of food on the pharmacokinetics of zoliflodacin granules for oral suspension: Phase I open-label randomized cross-over study in healthy subjects. Clin. Transl. Sci. 2023, 16, 770–780.
  35. Newman, L.M.; Kankam, M.; Nakamura, A.; Conrad, T.; Mueller, J.; O’Donnell, J.; Osborn, B.L.; Gu, K.; Saviolakis, G.A. Thorough QT Study to Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for Gonorrhea, on Cardiac Repolarization in Healthy Adults. Antimicrob. Agents Chemother. 2021, 65, e0129221.
  36. O’Donnell, J.; Lawrence, K.; Vishwanathan, K.; Hosagrahara, V.; Mueller, J.P. Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers. Antimicrob. Agents Chemother. 2018, 63, e01808-18.
  37. Watkins, R.R.; Thapaliya, D.; Lemonovich, T.L.; Bonomo, R.A. Gepotidacin: A novel, oral, ‘first-in-class’ triazaacenaphthylene antibiotic for the treatment of uncomplicated urinary tract infections and urogenital gonorrhoea. J. Antimicrob. Chemother. 2023, 78, 1137–1142.
  38. Scangarella-Oman, N.E.; Hossain, M.; Perry, C.R.; Tiffany, C.; Powell, M.; Swift, B.; Dumont, E.F. Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea. Sex. Transm. Infect. 2023, 99, 64–69.
  39. Taylor, S.N.; Morris, D.H.; Avery, A.K.; Workowski, K.A.; Batteiger, B.E.; Tiffany, C.A.; Perry, C.R.; Raychaudhuri, A.; Scangarella-Oman, N.E.; Hossain, M.; et al. Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation. Clin. Infect. Dis. 2018, 67, 504–512.
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