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Drug-resistant Neisseria gonorrhoeae: latest developments

Abstract

Gonorrhea is the second most frequently reported notifiable disease in the United States and is becoming increasingly common in Europe. The purpose of this review was to assess the current state of drug-resistant Neisseria gonorrhoeae in order to evaluate future prospects for its treatment. An exhaustive literature search was conducted to include the latest research regarding drug resistance and treatment guidelines for gonorrhea. Gonococci have acquired all known resistance mechanisms to all antimicrobials used for treatment. Currently, the European Union, the United States, and the United Kingdom have established surveillance programs to assess, on a yearly basis, the development of gonococcal resistance. Current treatment guidelines are being threatened by the increasing number of ceftriaxone-, cefixime-, and azithromycin-resistant N. gonorrhoeae strains being detected worldwide. This has led the scientific community to develop new treatment options with new molecules in order to persevere in the battle against this “superbug”.

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References

  1. World Health Organization (WHO), Department of Reproductive Health and Research (2012) Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae. 36 pp

  2. Bolan GA, Sparling PF, Wasserheit JN (2012) The emerging threat of untreatable gonococcal infection. N Eng J Med 366:485–487. doi:10.1056/NEJMp1112456

    Article  Google Scholar 

  3. Centers for Disease Control and Prevention (CDC) (2012) Cephalosporin-resistant Neisseria gonorrhoeae public health response plan. 43 pp

  4. Bodoev IN, Il’ina EN (2015) Molecular mechanisms of drug resistance Neisseria gonorrhoeae: history and prospects. Mol Gen Mikrobiol Virusol 33(3):22–27

    CAS  PubMed  Google Scholar 

  5. Unemo M, del Rio C, Shafer WM (2016) Antimicrobial resistance expressed by Neisseria. gonorrhoeae: a major global public health problem in the 21st century. Microbiol Spectr 4(3). doi:10.1128/microbiolspec.EI10-0009-2015

  6. Fermer C, Kristiansen BE, Sköld O et al (1995) Sulfonamide resistance in Neisseria meningitidis as defined by site-directed mutagenesis could have its origin in other species. J Bacteriol 177(16):4669–4675

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Tribuddharat C, Pongpech P, Charoenwatanachokchai A et al (2016) Gonococcal antimicrobial susceptibility and prevalence of bla TEM-1, bla TEM-135 genes in Thailand. Jpn J Infect Dis

  8. Ropp PA, Hu M, Olesky M et al (2002) Mutations in ponA, the gene encoding penicillin-binding protein 1, and a novel locus, penC, are required for high-level chromosomally mediated penicillin resistance in Neisseria gonorrhoeae. Antimicrob Agents Chemother 46:769–777

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. de Curraize C, Kumanski S, Micaëlo M et al (2016) Ceftriaxone-resistant Neisseria gonorrhoeae isolates (2010 to 2014) in France characterized by using whole-genome sequencing. Antimicrob Agents Chemother 60(11):6962–6964. doi:10.1128/AAC.01568-16

    Article  PubMed  PubMed Central  Google Scholar 

  10. Serra-Pladevall J, Barberá MJ, Rodriguez S et al (2016) Neisseria gonorrhoeae antimicrobial susceptibility in Barcelona: penA, ponA, mtrR, and porB mutations and NG-MAST sequence types associated with decreased susceptibility to cephalosporins. Eur J Clin Microbiol Infect Dis 35(9):1549–1556. doi:10.1007/s10096-016-2696-7

    CAS  Article  PubMed  Google Scholar 

  11. Morse SA, Johnson SR, Biddle JW et al (1986) High-level tetracycline resistance in Neisseria gonorrhoeae is result of acquisition of streptococcal tetM determinant. Antimicrob Agents Chemother 30:664–670

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Phillips I (1976) Beta-lactamase-producing, penicillin-resistant gonococcus. Lancet 2:656–657

    CAS  Article  PubMed  Google Scholar 

  13. Davies C, Bussiere DE, Golden BL et al (1998) Ribosomal proteins S5 and L6: high-resolution crystal structures and roles in protein synthesis and antibiotic resistance. J Mol Biol 279:873–888

    CAS  Article  PubMed  Google Scholar 

  14. Ilina EN, Malakhova MV, Bodoev IN et al (2013) Mutation in ribosomal protein S5 leads to spectinomycin resistance in Neisseria gonorrhoeae. Front Microbiol 4:186. doi:10.3389/fmicb.2013.00186

    Article  PubMed  PubMed Central  Google Scholar 

  15. Belland RJ, Morrison SG, Ison C et al (1994) Neisseria gonorrhoeae acquires mutations in analogous regions of gyrA and parC in fluoroquinolone-resistant isolates. Mol Microbiol 14:371–380

    CAS  Article  PubMed  Google Scholar 

  16. Kunz AN, Begum AA, Wu H et al (2012) Impact of fluoroquinolone resistance mutations on gonococcal fitness and in vivo selection for compensatory mutations. J Infect Dis 205:1821–1829. doi:10.1093/infdis/jis277

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Roberts MC, Chung WO, Roe D et al (1999) Erythromycin-resistant Neisseria gonorrhoeae and oral commensal Neisseria spp. carry known rRNA methylase genes. Antimicrob Agents Chemother 43:1367–1372

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Folster JP, Johnson PJ, Jackson L et al (2009) MtrR modulates rpoH expression and levels of antimicrobial resistance in Neisseria gonorrhoeae. J Bacteriol 191:287–297. doi:10.1128/JB.01165-08

    CAS  Article  PubMed  Google Scholar 

  19. Morse SA, Johnson SR, Biddle JW et al (1986) High-level tetracycline resistance in Neisseria gonorrhoeae is result of acquisition of streptococcal tetM determinant. Antimicrob Agents Chemother 30:664–670

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Unemo M, Shafer WM (2014) Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev 27:587–613. doi:10.1128/CMR.00010-14

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Ohnishi M, Golparian D, Shimuta K et al (2011) Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob Agents Chemother 55:3538–3545. doi:10.1128/AAC.00325-11

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Unemo M, Golparian D, Nicholas R et al (2012) High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 56:1273–1280. doi:10.1128/AAC.05760-11

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Lahra MM, Ryder N, Whiley DM (2014) A new multidrug-resistant strain of Neisseria gonorrhoeae in Australia. N Eng J Med 371:1850–1851. doi:10.1056/NEJMc1408109

    Article  Google Scholar 

  24. Nakayama S, Shimuta K, Furubayashi K et al (2016) New ceftriaxone- and multidrug-resistant Neisseria gonorrhoeae strain with a novel mosaic penA gene isolated in Japan. Antimicrob Agents Chemother 60(7):4339–4341. doi:10.1128/AAC.00504-16

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Martin I, Sawatzky P, Liu G et al (2016) Decline in decreased cephalosporin susceptibility and increase in azithromycin resistance in Neisseria gonorrhoeae, Canada. Emerg Infect Dis 22(1):65–67. doi:10.3201/eid2201.151247

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Fifer H, Natarajan U, Jones L et al (2016) Failure of dual antimicrobial therapy in treatment of gonorrhea. N Engl J Med 734(35):2504–2506. doi:10.1056/NEJMc1512757

    Article  Google Scholar 

  27. World Health Organization (WHO) (2012) Strategies and laboratory methods for strengthening surveillance of sexually transmitted infections. Available online at: http://apps.who.int/iris/bitstream/10665/75729/1/9789241504478_eng.pdf

  28. Unemo M (2015) Current and future antimicrobial treatment of gonorrhoea—the rapidly evolving Neisseria gonorrhoeae continues to challenge. BMC Infect Dis 15:364. doi:10.1186/s12879-015-1029-2

    Article  PubMed  PubMed Central  Google Scholar 

  29. Japanese Society of Sexually Transmitted Infection (2011) Gonococcal infection. Sexually transmitted infections, diagnosis and treatment guidelines 2011. Jpn Sex Transm Dis 22(Suppl 1):52–59

    Google Scholar 

  30. Workowski KA, Bolan GA (2015) Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 64:1–137

    Article  PubMed  Google Scholar 

  31. Public Health Agency of Canada (2013) Canadian guidelines on sexually transmitted infections. Gonococcal infections chapter. Available online at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/assets/pdf/section-5-6-eng.pdf

  32. Australasian Sexual Health Alliance (ASHA) (2016) Australian STI management guidelines for use in primary care. Available online at: http://www.sti.guidelines.org.au/sexually-transmissible-infections/gonorrhoea#management

  33. Bignell C, Unemo M (2013) 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS 24:85–92. doi:10.1177/0956462412472837

    CAS  Article  PubMed  Google Scholar 

  34. Kirkcaldy RD, Weinstock HS, Moore PC et al (2014) The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea. Clin Infect Dis 59:1083–1091. doi:10.1093/cid/ciu521

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Biedenbach DJ, Turner LL, Jones RN et al (2012) Activity of JNJ-Q2, a novel fluoroquinolone, tested against Neisseria gonorrhoeae, including ciprofloxacin-resistant strains. Diagn Microbiol Infect Dis 74:204–206. doi:10.1016/j.diagmicrobio.2012.06.006

    CAS  Article  PubMed  Google Scholar 

  36. Roberts MC, Remy JM, Longcor JD et al (2013) In vitro activity of delafloxacin against Neisseria gonorrhoeae clinical isolates. In: Proceedings of the STI & AIDS World Congress, Vienna, Austria, July 2013

  37. Hamasuna R, Yasuda M, Ishikawa K et al (2015) The second nationwide surveillance of the antimicrobial susceptibility of Neisseria gonorrhoeae from male urethritis in Japan, 2012–2013. J Infect Chemother 21:340–345. doi:10.1016/j.jiac.2015.01.010

    Article  PubMed  Google Scholar 

  38. Kazamori D, Aoi H, Sugimoto K et al (2014) In vitro activity of WQ-3810, a novel fluoroquinolone, against multidrug-resistant and fluoroquinolone-resistant pathogens. Int J Antimicrob Agents 44:443–449. doi:10.1016/j.ijantimicag.2014.07.017

    CAS  Article  PubMed  Google Scholar 

  39. Kerstein K, Fyfe C, Sutcliffe JA et al (2013) Eravacycline (TP-434) is active against susceptible and multidrug-resistant Neisseria gonorrhoeae. In: Proceedings of the 53rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Denver, Colorado, USA, 10–13 September 2013. Poster E-1181

  40. Zhang YY, Zhou L, Zhu DM et al (2004) In vitro activities of tigecycline against clinical isolates from Shanghai, China. Diagn Microbiol Infect Dis 50:267–281

    CAS  Article  PubMed  Google Scholar 

  41. Fujimoto K, Takemoto K, Hatano K et al (2013) Novel carbapenem antibiotics for parenteral and oral applications: in vitro and in vivo activities of 2-aryl carbapenems and their pharmacokinetics in laboratory animals. Antimicrob Agents Chemother 57:697–707. doi:10.1128/AAC.01051-12

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Jacobsson S, Golparian D, Phan LT et al (2015) In vitro activities of the novel bicyclolides modithromycin (EDP-420, EP-013420, S-013420) and EDP-322 against MDR clinical Neisseria gonorrhoeae isolates and international reference strains. J Antimicrob Chemother 70:173–177. doi:10.1093/jac/dku344

    CAS  Article  PubMed  Google Scholar 

  43. Golparian D, Fernandes P, Ohnishi M et al (2012) In vitro activity of the new fluoroketolide solithromycin (CEM-101) against a large collection of clinical Neisseria gonorrhoeae isolates and international reference strains, including those with high-level antimicrobial resistance: potential treatment option for gonorrhea? Antimicrob Agents Chemother 56:2739–2742. doi:10.1128/AAC.00036-12

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Koeth LM, Difranco-Fisher J (2013) In vitro activity of dalbavancin against Neisseria gonorrhoeae and development of a broth microdilution method. In: Proceedings of IDWeek 2013, San Francisco, California, USA, 2–6 October 2013. Poster 255

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Suay-García, B., Pérez-Gracia, M.T. Drug-resistant Neisseria gonorrhoeae: latest developments. Eur J Clin Microbiol Infect Dis 36, 1065–1071 (2017). https://doi.org/10.1007/s10096-017-2931-x

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  • DOI: https://doi.org/10.1007/s10096-017-2931-x

Keywords

  • Ceftriaxone
  • Azithromycin
  • Cefixime
  • Neisseria Gonorrhoeae
  • Gonorrhea