1887
Research Open Access
Like 0

Abstract

Background

The first cases of extensively drug resistant gonorrhoea were recorded in the United Kingdom in 2018. There is a public health need for strategies on how to deploy existing and novel antibiotics to minimise the risk of resistance development. As rapid point-of-care tests (POCTs) to predict susceptibility are coming to clinical use, coupling the introduction of an antibiotic with diagnostics that can slow resistance emergence may offer a novel paradigm for maximising antibiotic benefits. Gepotidacin is a novel antibiotic with known resistance and resistance-predisposing mutations. In particular, a mutation that confers resistance to ciprofloxacin acts as the ‘stepping-stone’ mutation to gepotidacin resistance.

Aim

To investigate how POCTs detecting resistance mutations for ciprofloxacin and gepotidacin can be used to minimise the risk of resistance development to gepotidacin.

Methods

We use individual-based stochastic simulations to formally investigate the aim.

Results

The level of testing needed to reduce the risk of resistance development depends on the mutation rate under treatment and the prevalence of stepping-stone mutations. A POCT is most effective if the mutation rate under antibiotic treatment is no more than two orders of magnitude above the mutation rate without treatment and the prevalence of stepping-stone mutations is 1–13%.

Conclusion

Mutation frequencies and rates should be considered when estimating the POCT usage required to reduce the risk of resistance development in a given population. Molecular POCTs for resistance mutations and stepping-stone mutations to resistance are likely to become important tools in antibiotic stewardship.

Loading

Article metrics loading...

/content/10.2807/1560-7917.ES.2020.25.43.1900210
2020-10-29
2024-12-21
/content/10.2807/1560-7917.ES.2020.25.43.1900210
Loading
Loading full text...

Full text loading...

/deliver/fulltext/eurosurveillance/25/43/eurosurv-25-43-3.html?itemId=/content/10.2807/1560-7917.ES.2020.25.43.1900210&mimeType=html&fmt=ahah

References

  1. Unemo M. Current and future antimicrobial treatment of gonorrhoea - the rapidly evolving Neisseria gonorrhoeae continues to challenge. BMC Infect Dis. 2015;15(1):364.  https://doi.org/10.1186/s12879-015-1029-2  PMID: 26293005 
  2. Wi T, Lahra MM, Ndowa F, Bala M, Dillon JR, Ramon-Pardo P, et al. Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action. PLoS Med. 2017;14(7):e1002344.  https://doi.org/10.1371/journal.pmed.1002344  PMID: 28686231 
  3. World Health Organization (WHO). WHO Guidelines for the Treatment of Neisseria gonorrhoeae. Geneva: WHO. 2016. Available from: https://www.who.int/reproductivehealth/publications/rtis/gonorrhoea-treatment-guidelines/en/
  4. Day MJ, Spiteri G, Jacobsson S, Woodford N, Amato-Gauci AJ, Cole MJ, et al. Stably high azithromycin resistance and decreasing ceftriaxone susceptibility in Neisseria gonorrhoeae in 25 European countries, 2016. BMC Infect Dis. 2018;18(1):609.  https://doi.org/10.1186/s12879-018-3528-4  PMID: 30509194 
  5. Fifer H, Natarajan U, Jones L, Alexander S, Hughes G, Golparian D, et al. Failure of Dual Antimicrobial Therapy in Treatment of Gonorrhea. N Engl J Med. 2016;374(25):2504-6.  https://doi.org/10.1056/NEJMc1512757  PMID: 27332921 
  6. World Health Organization (WHO). Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Geneva: WHO. 27 Feb 2017. Available from: https://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/
  7. Allan-Blitz LT, Humphries RM, Hemarajata P, Bhatti A, Pandori MW, Siedner MJ, et al. Implementation of a Rapid Genotypic Assay to Promote Targeted Ciprofloxacin Therapy of Neisseria gonorrhoeae in a Large Health System. Clin Infect Dis. 2017;64(9):1268-70. PMID: 28034887 
  8. Farrell DJ, Sader HS, Rhomberg PR, Scangarella-Oman NE, Flamm RK. In Vitro Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2017;61(3):e02047-16.  https://doi.org/10.1128/AAC.02047-16  PMID: 28069643 
  9. Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, et al. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature. 2010;466(7309):935-40.  https://doi.org/10.1038/nature09197  PMID: 20686482 
  10. Scangarella-Oman NE, Hossain M, Dixon PB, Ingraham K, Min S, Tiffany CA, et al. Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2018;62(12):e01221-18.  https://doi.org/10.1128/AAC.01221-18  PMID: 30249694 
  11. Scangarella-Oman N, Hossain M, Dixon P, Ingraham K, Min S, Tiffany C, et al. P2.38 Microbiological analysis from a phase ii study in adults evaluating single doses of gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea caused by Neisseria gonorrhoeae. Sex Transm Infect. 2017;93(Suppl 2):A84.
  12. Garnett GP, Mertz KJ, Finelli L, Levine WC, St Louis ME. The transmission dynamics of gonorrhoea: modelling the reported behaviour of infected patients from Newark, New Jersey. Philos Trans R Soc Lond B Biol Sci. 1999;354(1384):787-97.  https://doi.org/10.1098/rstb.1999.0431  PMID: 10365404 
  13. Hethcote H, Yorke J. Gonorrhea transmission dynamics and control. Berlin: Springer. 1984.
  14. Whittles LK, White PJ, Didelot X. Estimating the fitness cost and benefit of cefixime resistance in Neisseria gonorrhoeae to inform prescription policy: A modelling study. PLoS Med. 2017;14(10):e1002416.  https://doi.org/10.1371/journal.pmed.1002416  PMID: 29088226 
  15. Taylor SN, Morris DH, Avery AK, Workowski KA, Batteiger BE, Tiffany CA, 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(4):504-12.  https://doi.org/10.1093/cid/ciy145  PMID: 29617982 
  16. Office for National Statistics (ONS). United Kingdom population mid-year estimate 2016. London: ONS. [Accessed: 25 Nov 2017]. Available from: www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationestimates/timeseries/ukpop/pop
  17. Didelot X, Dordel J, Whittles LK, Collins C, Bilek N, Bishop CJ, et al. Genomic Analysis and Comparison of Two Gonorrhea Outbreaks. MBio. 2016;7(3):e00525-16.  https://doi.org/10.1128/mBio.00525-16  PMID: 27353752 
  18. Brittain C, Childs M, Duley L, Harding J, Hepburn T, Meakin G, et al. Gentamicin versus ceftriaxone for the treatment of gonorrhoea (G-TOG trial): study protocol for a randomised trial. Trials. 2016;17(1):558.  https://doi.org/10.1186/s13063-016-1683-8  PMID: 27881151 
  19. Bjedov I, Tenaillon O, Gérard B, Souza V, Denamur E, Radman M, et al. Stress-induced mutagenesis in bacteria. Science. 2003;300(5624):1404-9.  https://doi.org/10.1126/science.1082240  PMID: 12775833 
  20. Yang J, Annamalai T, Cheng B, Banda S, Tyagi R, Tse-Dinh YC. Antimicrobial Susceptibility and SOS-Dependent Increase in Mutation Frequency Are Impacted by Escherichia coli Topoisomerase I C-Terminal Point Mutation. Antimicrob Agents Chemother. 2015;59(10):6195-202.  https://doi.org/10.1128/AAC.00855-15  PMID: 26248366 
  21. Schook PO, Stohl EA, Criss AK, Seifert HS. The DNA-binding activity of the Neisseria gonorrhoeae LexA orthologue NG1427 is modulated by oxidation. Mol Microbiol. 2011;79(4):846-60.  https://doi.org/10.1111/j.1365-2958.2010.07491.x  PMID: 21299643 
  22. Nagel M, Reuter T, Jansen A, Szekat C, Bierbaum G. Influence of ciprofloxacin and vancomycin on mutation rate and transposition of IS256 in Staphylococcus aureus. Int J Med Microbiol. 2011;301(3):229-36.  https://doi.org/10.1016/j.ijmm.2010.08.021  PMID: 21115395 
  23. Vestergaard M, Paulander W, Marvig RL, Clasen J, Jochumsen N, Molin S, et al. Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa. Int J Antimicrob Agents. 2016;47(1):48-55.  https://doi.org/10.1016/j.ijantimicag.2015.09.014  PMID: 26597931 
  24. Spratt BG, Bowler LD, Zhang QY, Zhou J, Smith JM. Role of interspecies transfer of chromosomal genes in the evolution of penicillin resistance in pathogenic and commensal Neisseria species. J Mol Evol. 1992;34(2):115-25.  https://doi.org/10.1007/BF00182388  PMID: 1556747 
  25. De Silva D, Peters J, Cole K, Cole MJ, Cresswell F, Dean G, et al. Whole-genome sequencing to determine transmission of Neisseria gonorrhoeae: an observational study. Lancet Infect Dis. 2016;16(11):1295-303.  https://doi.org/10.1016/S1473-3099(16)30157-8  PMID: 27427203 
  26. Grad YH, Kirkcaldy RD, Trees D, Dordel J, Harris SR, Goldstein E, et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet Infect Dis. 2014;14(3):220-6.  https://doi.org/10.1016/S1473-3099(13)70693-5  PMID: 24462211 
  27. Ezewudo MN, Joseph SJ, Castillo-Ramirez S, Dean D, Del Rio C, Didelot X, et al. Population structure of Neisseria gonorrhoeae based on whole genome data and its relationship with antibiotic resistance. PeerJ. 2015;3:e806.  https://doi.org/10.7717/peerj.806  PMID: 25780762 
  28. World Health Organization (WHO). Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae. Geneva: WHO; 2012. Available from: https://apps.who.int/iris/handle/10665/44863
  29. Babraham Institute. Babraham Bioinformatics. FastQC. Cambridge: Babraham Institute. 2012. Available from: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/
  30. Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. ArXiv13033997 Q-Bio. 2013. Available from: https://arxiv.org/abs/1303.3997
  31. Walker BJ, Abeel T, Shea T, Priest M, Abouelliel A, Sakthikumar S, et al. Pilon: an integrated tool for comprehensive microbial variant detection and genome assembly improvement. PLoS One. 2014;9(11):e112963.  https://doi.org/10.1371/journal.pone.0112963  PMID: 25409509 
  32. Harris SR, Cole MJ, Spiteri G, Sánchez-Busó L, Golparian D, Jacobsson S, et al. Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe: a genomic survey. Lancet Infect Dis. 2018;18(7):758-68.  https://doi.org/10.1016/S1473-3099(18)30225-1  PMID: 29776807 
  33. Grad YH, Harris SR, Kirkcaldy RD, Green AG, Marks DS, Bentley SD, et al. Genomic Epidemiology of Gonococcal Resistance to Extended-Spectrum Cephalosporins, Macrolides, and Fluoroquinolones in the United States, 2000-2013. J Infect Dis. 2016;214(10):1579-87.  https://doi.org/10.1093/infdis/jiw420  PMID: 27638945 
  34. Levin BR, Bonten MJ. Cycling antibiotics may not be good for your health. Proc Natl Acad Sci USA. 2004;101(36):13101-2.  https://doi.org/10.1073/pnas.0404970101  PMID: 15340145 
  35. Tuite AR, Gift TL, Chesson HW, Hsu K, Salomon JA, Grad YH. Impact of Rapid Susceptibility Testing and Antibiotic Selection Strategy on the Emergence and Spread of Antibiotic Resistance in Gonorrhea. J Infect Dis. 2017;216(9):1141-9.  https://doi.org/10.1093/infdis/jix450  PMID: 28968710 
  36. Fingerhuth SM, Low N, Bonhoeffer S, Althaus CL. Detection of antibiotic resistance is essential for gonorrhoea point-of-care testing: a mathematical modelling study. BMC Med. 2017;15(1):142.  https://doi.org/10.1186/s12916-017-0881-x  PMID: 28747205 
  37. Frénoy A, Bonhoeffer S. Death and population dynamics affect mutation rate estimates and evolvability under stress in bacteria. bioRxiv. 2017.  https://doi.org/10.1101/224675 
  38. Obolski U, Hadany L. Implications of stress-induced genetic variation for minimizing multidrug resistance in bacteria. BMC Med. 2012;10(1):89.  https://doi.org/10.1186/1741-7015-10-89  PMID: 22889082 
/content/10.2807/1560-7917.ES.2020.25.43.1900210
Loading

Data & Media loading...

Supplementary data

Submit comment
Close
Comment moderation successfully completed
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error