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  • Opinion
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Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance

Abstract

The best available data indicate that the world is heading towards a pandemic of extensively drug-resistant Neisseria gonorrhoeae. At the same time, clinical microbiology laboratories have moved away from using culture-based methods to diagnose gonorrhoea, thus undermining our ability to detect antimicrobial resistance (AMR) using current technologies. In this Opinion article, we discuss the problem of N. gonorrhoeae AMR, particularly emerging resistance to the cephalosporin ceftriaxone, outline current concerns about the surveillance of N. gonorrhoeae AMR and propose the use of molecular methods on a large scale to systematically enhance surveillance.

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Figure 1: The history of Neisseria gonorrhoeae antimicrobial resistance.
Figure 2: Neisseria gonorrhoeae-targeting antibiotics and the corresponding resistance genes.

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References

  1. Holmes, K. K. et al. in Sexually Transmitted Diseases 4th edn 627–645 (McGraw Hill, 2008).

    Google Scholar 

  2. Workowski, K. A., Berman, S. M. & Douglas, J. M. Emerging antimicrobial resistance in Neisseria gonorrhoeae: urgent need to strengthen prevention strategies. Ann. Intern. Med. 148, 606–613 (2008).

    Article  Google Scholar 

  3. Barry, P. M. & Klausner, J. D. The use of cephalosporins for gonorrhea: the impending problem of resistance. Expert. Opin. Pharmacother. 10, 555–577 (2009).

    Article  CAS  Google Scholar 

  4. Livermore, D. M. Has the era of untreatable infections arrived? J. Antimicrob. Chemother. 64, i29–i36 (2009).

    Article  CAS  Google Scholar 

  5. Lewis, D. A. The Gonococcus fights back: is this time a knock out? Sex. Transm. Infect. 86, 415–421 (2010).

    Article  Google Scholar 

  6. Kirkcaldy, R., Ballard, R. & Dowell, D. Gonococcal resistance: are cephalosporins next? Curr. Infect. Dis. Rep. 13, 196–204 (2011).

    Article  Google Scholar 

  7. Tapsall, J. W. et al. Meeting the public health challenge of multidrug- and extensively drug-resistant Neisseria gonorrhoeae. Expert Rev. Anti Infect. Ther. 7, 821–834 (2009).

    Article  Google Scholar 

  8. Ohnishi, M. et al. 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 (2011).

    Article  CAS  Google Scholar 

  9. Ohnishi, M. et al. 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 (2012).

    Article  Google Scholar 

  10. Ohnishi, M., Ono, E., Shimuta, K., Watanabe, H. & Okamura, N. Identification of TEM-135 β-lactamase in penicillinase-producing Neisseria gonorrhoeae strains in Japan. Antimicrob. Agents Chemother. 54, 3021–3023 (2010).

    Article  CAS  Google Scholar 

  11. Nakayama, S.-I. et al. Molecular analyses of TEM genes and their corresponding penicillinase-producing Neisseria gonorrhoeae isolates in Bangkok, Thailand. Antimicrob. Agents Chemother. 56, 916–920 (2012).

    Article  CAS  Google Scholar 

  12. Golparian, D. et al. 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 (2012).

    Article  CAS  Google Scholar 

  13. Livermore, D. M. et al. Activity of ertapenem against Neisseria gonorrhoeae. J. Antimicrob. Chemother. 54, 280–281 (2004).

    Article  CAS  Google Scholar 

  14. Ross, J. D. C. & Lewis, D. A. Cephalosporin resistant Neisseria gonorrhoeae: time to consider gentamicin? Sex. Transm. Infec. 88, 6–8 (2012).

    Article  CAS  Google Scholar 

  15. Easmon, C. S. et al. Spectinomycin as initial treatment for gonorrhoea. BMJ 289, 1032–1034 (1984).

    Article  CAS  Google Scholar 

  16. Kirkcaldy, B. Treatment of gonorrhea in an era of emerging cephalosporin resistance and results of a randomized trial of new potential treatment options. Sex. Trans. Infect. 89, A14 (2013).

    Google Scholar 

  17. Centers for Disease, Control and Prevention. Ceftriaxone-resistant Neisseria gonorrhoeae public health response plan [online], (2012).

  18. Department of Reproductive Health and Research, World Health Organization. Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae [online], (2012).

  19. Centers for Disease Control and Prevention. Update to CDC's sexually transmitted diseases treatment guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR 61, 590–594 (2012).

  20. Bignell, C. & Fitzgerald, M. UK national guideline for the management of gonorrhoea in adults, 2011. Int. J. STD AIDS. 22, 541–547 (2011).

    Article  CAS  Google Scholar 

  21. Bignell, C. et al. 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. Int. J. STD AIDS 24, 85–92 (2013).

    Article  CAS  Google Scholar 

  22. Tapsall, J. W. Antibiotic Resistance in Neisseria gonorrhoeae (WHO, 2001).

    Google Scholar 

  23. Zhao, S. et al. Genetics of chromosomally mediated intermediate resistance to ceftriaxone and cefixime in Neisseria gonorrhoeae. Antimicrob. Agents Chemother. 53, 3744–3751 (2009).

    Article  CAS  Google Scholar 

  24. Ameyama, S. et al. Mosaic-like structure of penicillin-binding protein 2 gene (penA) in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime. Antimicrob. Agents Chemother. 46, 3744–3749 (2002).

    Article  CAS  Google Scholar 

  25. Tomberg, J., Unemo, M., Davies, C. & Nicholas, R. A. Molecular and structural analysis of mosaic variants of penicillin-binding protein 2 conferring decreased susceptibility to expanded-spectrum cephalosporins in Neisseria gonorrhoeae: role of epistatic mutations. Biochemistry 49, 8062–8070 (2010).

    Article  CAS  Google Scholar 

  26. Tomberg, J. et al. Identification of amino acids conferring high-level resistance to expanded-spectrum cephalosporins in the penA gene from Neisseria gonorrhoeae strain H041. Antimicrob. Agents Chemother. 57, 3029–3036 (2013).

    Article  CAS  Google Scholar 

  27. Unemo, M. & Nicholas, R. A. Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea. Future Microbiol. 7, 1401–1422 (2012).

    Article  CAS  Google Scholar 

  28. Akasaka, S. et al. Emergence of cephem- and aztreonam-high-resistant Neisseria gonorrhoeae that does not produce β-lactamase. J. Infect. Chemother. 7, 49–50 (2001).

    Article  CAS  Google Scholar 

  29. Tanaka, M. et al. Analysis of mutations within multiple genes associated with resistance in a clinical isolate of Neisseria gonorrhoeae with reduced ceftriaxone susceptibility that shows a multidrug-resistant phenotype. Int. J. Antimicrob. Agents 27, 20–26 (2006).

    Article  CAS  Google Scholar 

  30. de Vries, H. J., van der Helm, J. J., Schim van der Loeff, M. F. & van Dam, A. P. Multidrug-resistant Neisseria gonorrhoeae with reduced cefotaxime susceptibility is increasingly common in men who have sex with men, Amsterdam, the Netherlands. Euro. Surveill. 17, 19330 (2009).

    Google Scholar 

  31. Australian Gonococcal Surveillance Programme. Annual report of Australian Gonococcal Surveillance Programme 2008. Commun. Dis. Intell. 34, 89–95 (2009).

  32. Cole, M. J. et al. European surveillance of antimicrobial resistance in Neisseria gonorrhoeae. Sex. Transm. Infect. 86, 427–432 (2010).

    Article  Google Scholar 

  33. Golparian, D., Hellmark, B., Fredlund, H. & Unemo, M. Emergence, spread and characteristics of Neisseria gonorrhoeae isolates with in vitro decreased susceptibility and resistance to extended-spectrum cephalosporins in Sweden. Sex. Transm. Infect. 86, 454–460 (2010).

    Article  Google Scholar 

  34. Martin, I. et al. Trends in antimicrobial resistance in Neisseria gonorrhoeae isolated in Canada: 2000–2009. Sex. Transm. Dis. 38, 892–898 (2011).

    Article  CAS  Google Scholar 

  35. Carannante, A. et al. Cefixime and ceftriaxone susceptibility of Neisseria gonorrhoeae in Italy from 2006 to 2010. Clin. Microbiol. Infect. 18, 558–564 (2012).

    Article  CAS  Google Scholar 

  36. US Centers for Disease Control and Prevention. Cephalosporin susceptibility among Neisseria gonorrhoeae isolates — United States, 2000–2010. MMWR 60, 873–877 (2011).

  37. Chisholm, S. A. et al. Emergence of a Neisseria gonorrhoeae clone showing decreased susceptibility to cefixime in England and Wales. J. Antimicrob. Chemother. 66, 2509–2512 (2011).

    Article  CAS  Google Scholar 

  38. Whiley, D. M. et al. Reduced susceptibility to ceftriaxone in Neisseria gonorrhoeae is spread internationally by genetically distinct gonococcal populations. J. Antimicrob. Chemother. 66, 1186–1187 (2011).

    Article  CAS  Google Scholar 

  39. Cámara, J. et al. Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain. J. Antimicrob. Chemother. 67, 1858–1860 (2012).

    Article  Google Scholar 

  40. Bissessor, M. et al. Differing Neisseria gonorrhoeae bacterial loads in the pharynx and rectum in men who have sex with men: implications for gonococcal detection, transmission, and control. J. Clin. Microbiol. 49, 4304–4306 (2011).

    Article  CAS  Google Scholar 

  41. Department of Reproductive Health and Research, World Health Organization. Strategies and laboratory methods for strengthening surveillance of sexually transmitted infection 2012. (WHO, 2012).

  42. Martin, I. M. C. et al. Rapid sequence-based identification of gonococcal transmission clusters in a large metropolitan area. J. Infect. Dis. 189, 1497–1505 (2004).

    Article  CAS  Google Scholar 

  43. Unemo, M. & Dillon, J. A. Review and international recommendation of methods for typing Neisseria gonorrhoeae isolates and their implications for improved knowledge of gonococcal epidemiology, treatment, and biology. Clin. Microbiol. Rev. 24, 447–458 (2011).

    Article  Google Scholar 

  44. Palmer, H. M., Young, H., Graham, C. & Dave, J. Prediction of antibiotic resistance using Neisseria gonorrhoeae multi-antigen sequence typing. Sex. Transm. Infect. 84, 280–284 (2008).

    Article  CAS  Google Scholar 

  45. Buono, S. et al. Using the Neisseria gonorrhoeae multi-antigen sequence-typing method to assess strain diversity and antibiotic resistance in San Francisco, California. Microb. Drug Resist. 18, 510–517 (2012).

    Article  CAS  Google Scholar 

  46. Chisholm, S. A. et al. Molecular epidemiological typing within the European Gonococcal Antimicrobial Resistance Surveillance Programme reveals predominance of a multidrug-resistant clone. Euro Surveill. 18, 20358 (2013).

    PubMed  Google Scholar 

  47. Whiley, D. M. et al. Neisseria gonorrhoeae multi-antigen sequence typing using non-cultured clinical specimens. Sex. Transm. Infect. 1, 51–55 (2010).

    Article  Google Scholar 

  48. Siedner, M. J. et al. Real-time PCR assay for detection of quinolone-resistant Neisseria gonorrhoeae in urine samples. J. Clin. Microbiol. 45, 1250–1254 (2007).

    Article  CAS  Google Scholar 

  49. Su, X. & Lind, I. Molecular basis of high-level ciprofloxacin resistance in Neisseria gonorrhoeae strains isolated in Denmark from 1995 to 1998. Antimicrob. Agents Chemother. 45, 117–123 (2001).

    Article  CAS  Google Scholar 

  50. Magooa, M. P., Müller, E. E., Gumede, L. & Lewis, D. A. Determination of Neisseria gonorrhoeae susceptibility to ciprofloxacin in clinical specimens from men using a real-time PCR assay. Int. J. Antimicrob. Agents 42, 63–67 (2013).

    Article  CAS  Google Scholar 

  51. Fluit, A. C., Visser, M. R. & Schmitz, F.-J. Molecular detection of antimicrobial resistance. Clin. Microbiol. Rev. 14, 836–871 (2001).

    Article  CAS  Google Scholar 

  52. Goire, N. et al. Enhancing gonococcal antimicrobial resistance surveillance: a real-time PCR assay for detection of penicillinase-producing Neisseria gonorrhoeae by use of noncultured clinical samples. J. Clin. Microbiol. 2, 513–518 (2011).

    Article  Google Scholar 

  53. Speers, D. J,, Fisk, R. E, Goire, N, & Mak, D. B. Non-culture Neisseria gonorrhoeae molecular penicillinase production surveillance demonstrates the long-term success of empirical dual therapy and informs gonorrhoea management guidelines in a highly endemic setting. J. Antimicrob. Chemother. http://dx.doi.org/10.1093/jac/dkt501; (2013).

  54. Goire, N. et al. Enhanced gonococcal antimicrobial surveillance in the era of ceftriaxone resistance: a real-time PCR assay for direct detection of the Neisseria gonorrhoeae H041 strain. J. Antimicrob. Chemother. 67, 902–905 (2012).

    Article  CAS  Google Scholar 

  55. Goire, N. et al. Polymerase chain reaction-based screening for the ceftriaxone-resistant Neisseria gonorrhoeae F89 strain. Euro Surveill. 18, 20444 (2013).

    Article  CAS  Google Scholar 

  56. Gose, S. et al. Neisseria gonorrhoeae and extended-spectrum cephalosporins in California: surveillance and molecular detection of mosaic penA. BMC Infect. Dis. 13, 570 (2013).

    Article  Google Scholar 

  57. Katz, A. R. et al. Neisseria gonorrhoeae with high-level resistance to azithromycin: case report of the first isolate identified in the United States. Clin. Infect. Dis. 54, 841–843 (2012).

    Article  CAS  Google Scholar 

  58. Balashov, S., Mordechai, E., Adelson, M. E. & Gygax, S. E. Multiplex bead suspension array for screening Neisseria gonorrhoeae antibiotic resistance genetic determinants in noncultured clinical samples. J. Mol. Diagn. 15, 116–129 (2012).

    Article  Google Scholar 

  59. Grad, Y. H. et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet Infect. Dis. http:dx.doi.org/10.1016/S1473-3099(13)70693-5 (2014).

  60. Tabrizi, S. N. et al. Analytical evaluation of GeneXpert CT/NG, the first genetic point-of-care assay for simultaneous detection of Neisseria gonorrhoeae and Chlamydia trachomatis. J. Clin. Microbiol. 51, 1945–1947 (2013).

    Article  Google Scholar 

  61. Spizz, G. et al. Rheonix CARD® technology: an innovative and fully automated molecular diagnostic device. Point Care 11, 42–51 (2012).

    PubMed  PubMed Central  Google Scholar 

  62. Doseeva, V. et al. Multiplex isothermal helicase-dependent amplification assay for detection of Chlamydia trachomatis and Neisseria gonorrhoeae. Diagn. Microbiol. Infect. Dis. 71, 354–365 (2011).

    Article  CAS  Google Scholar 

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Acknowledgements

This article results from the Gonorrhoea Resistance Assessment by Nucleic acid Detection (GRAND) study supported by an Australian National Health and Medical Research Council (NHMRC) Project Grant (APP1025517).

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Correspondence to David M. Whiley.

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Goire, N., Lahra, M., Chen, M. et al. Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance. Nat Rev Microbiol 12, 223–229 (2014). https://doi.org/10.1038/nrmicro3217

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