Resistant gonorrhoea: east meets west
Authors: Peter A Rice, Xiao-Hong Su
Journal: The Lancet Infectious Diseases (2018)

In 2016 and 2018, two treatment failures of ceftriaxone and azithromycin, used in combination, were reported in the UK in men who contracted gonococcal infections in Asia,1Fifer H Natarajan U Jones L et al.Failure of dual antimicrobial therapy in treatment of gonorrhea.N Engl J Med. 2016; 374: 2504-2506Crossref PubMed Scopus (217) Google Scholar, 2Public Health EnglandUK case of Neisseria gonorrhoeae with high-level resistance to azithromycin and resistance to ceftriaxone acquired abroad.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/694655/hpr1118_MDRGC.pdfDate: March 29, 2018Date accessed: April 25, 2018Google Scholar once again suggesting that antimicrobial resistance of Neisseria gonorrhoeae is spreading. These treatment failures indicate the potentially waning efficacy and usefulness of this combination, which is currently recommended as the first-line therapy. Surveillance of antimicrobial resistance is paramount if resistance patterns of these and other antimicrobials are to be recognised in a timely manner that enables meaningful intervention and prevention of the spread of resistant organisms. Antimicrobial susceptibility testing (phenotyping) for antimicrobial resistance is considered the gold-standard test. There are some key limitations to the more commonly used methods of genotyping, such as N gonorrhoeae multi-antigen sequence typing (NG-MAST) and multilocus sequence typing (MLST), which indicate associated antimicrobial resistance determinants but do not directly identify antimicrobial resistance. The genotypes of N gonorrhoeae strains that are identified by use of these methods, which include antimicrobial resistance determinants, often do not correlate directly with the mean inhibitory concentrations of antimicrobials against these strains. In their Article in The Lancet Infectious Diseases, Simon Harris and colleagues3Harris SR Cole MJ Spiteri G et al.Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe: a genomic survey.Lancet Infect Dis. 2018; (published online May 15.)http://dx.doi.org/10.1016/S1473-3099(18)30225-1Summary Full Text Full Text PDF PubMed Scopus (116) Google Scholar used whole genome sequencing (WGS) for comprehensive genetic analyses of more than 1000 Neisseria gonorrhoeae strains that were isolated in 2013 in 20 European countries that participated in the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP). As expected, NG-MAST genogroups (designated from the closely related NG-MAST sequence types) fit the WGS phylogeny relatively well; however, separation into clades (the branches of the WGS phylogeny trees) avoided separation of clinically important, phylogenetically related isolates while also excluding phylogenetically unrelated (less relevant) isolates. WGS therefore maintains the breadth of analysis that is necessary to identify known antimicrobial resistance determinants and can also identify new antimicrobial resistance determinants. MLST and NG-MAST, although sensitive in their association with known antimicrobial resistance determinants, can be non-specific. An advantage of WGS or MLST and NG-MAST over phenotyping is that these genotyping methods enable detection of modest changes to the genetic organisation of strains before changes to antimicrobial resistance (phenotypic) patterns occur; monitoring genes, therefore, makes for a timely sentinel-based, surveillance system. However, superior resolution of WGS versus NG-MAST and MLST, when WGS is linked to epidemiological data, could enable even earlier identification of antimicrobial resistance outbreaks and novel high-risk clones. Harris and colleagues evaluated pairwise geographical and cophenetic distances (phylogenetic distances between pairs of isolates) at the level of single nucleotide polymorphisms, which provided the resolution for comparison at the whole genome level by WGS that is not possible with MLST or NG-MAST. With WGS, these baseline comparisons showed patterns in the same locations, the same country, and bordering countries. WGS used in this manner enables recognition of genetic mixing as would occur in transmission from one of these locations to another, allowing identification of local hot spots or outbreaks.4Lahra MM Martin I Demczuk W et al.Cooperative recognition of internationally disseminated cetriaxone-resistant Neisseria gonorrhoeae strain.Emerg Infect Dis. 2018; 24: 735-743Crossref Scopus (129) Google Scholar, 5Fifer H Cole M Hughes G et al.Sustained transmission of high-level azithromycin-resistant Neisseria gonorrhoeae in England: an observational study.Lancet Infect Dis. 2018; 18: 573-581Summary Full Text Full Text PDF PubMed Scopus (73) Google Scholar This method adds a dynamic feature to WGS, making it potentially capable of recognising small genomic changes that might be clinically or epidemiologically important as quickly as the sequences are generated and examined, almost in real time. Harris and colleagues also used bioinformatics6Ansari MA Didelot X Bayesian inference of the evolution of a phenotype distribution on a phylogenetic tree.Genetics. 2016; 204: 89-98Crossref PubMed Scopus (22) Google Scholar to model evolving phenotypes. In this case, the authors analysed distribution of degree of sensitivity (susceptible, intermediate, and resistant) of gonococcal strains to three antimicrobials and, independently, sexual orientation of the patients, which is a novel use of WGS that provides information in a separate dimension. But how do sensitive and specific genomic techniques inform and address the problem represented by the two cases with failed combined therapy? The NG-MAST genogroup G1407 was the predominant serogroup in Euro-GASP in 2013, and accounted for the greatest extent of cephalosporin resistance. However, G1407 decreased from 23% prevalence7Chisholm SA Unemo M Quaye N et al.Molecular epidemiological typing within the European Gonococcal Antimicrobial Resistance Surveillance Programme reveals predominance of a multidrug-resistant clone.Euro Surveill. 2013; 18Crossref PubMed Google Scholar in 2009–10 to 17% in 2013 in Harris and colleagues' subsequent study. Since 2009–10, antimicrobial resistance patterns of N gonorrhoeae have changed in the EU/EEA. In 2012, combination therapy (ceftriaxone plus azithromycin), which was already being used in several countries, was officially recommended for all European countries.8Bignell C Unemo M 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults.Int J STD AIDS. 2013; 24: 85-92Crossref PubMed Scopus (314) Google Scholar Cefixime resistance declined to 4·8%; however, azithromycin resistance rose to 6·7% overall,9Cole MJ Spiteri G Jacobsson S et al.Overall low extended-spectrum cephalosporin resistance but high azithromycin resistance in Neisseria gonorrhoeae in 24 European countries, 2015.BMC Infect Dis. 2017; 17: 617Crossref PubMed Scopus (76) Google Scholar, 10European Centre for Disease Prevention and ControlSurveillance report. Gonococcal antimicrobial susceptibility surveillance in Europe 2012.https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/gonococcal-antimicrobial-susceptibility-surveillance-Europe-2012.pdfDate: July, 2014Date accessed: April 25, 2018Google Scholar with strains from Cyprus and Greece together showing 28·6% resistance to azithromycin. Much of the antimicrobial resistance originates in Asia and is transmitted to Europe (such as in the two patients with treatment failure). Between 2013 and 2016, China reported a significant increase (from 1·9% to 3·3%) in gonococcal strains that showed both resistance to azithromycin and decreased susceptibility to ceftriaxone.11Yin YP Han Y Dai XQ et al.Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: a retrospective study of national surveillance data from 2013 to 2016.PLoS Med. 2018; 15: e1002499Crossref PubMed Scopus (64) Google Scholar The proportion of isolates with decreased susceptibility to ceftriaxone fluctuated between 9·7% and 12·2%, and the prevalence of azithromycin-resistant isolates was 18·6% during this period. 11Yin YP Han Y Dai XQ et al.Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: a retrospective study of national surveillance data from 2013 to 2016.PLoS Med. 2018; 15: e1002499Crossref PubMed Scopus (64) Google Scholar Further, in eastern Chinese cities, resistance to azithromycin rose more than four-fold (from 7% to 32%) from 2008 to 2014.12Wan C Li Y Le WJ et al.Increasing resistance to azithromycin of Neisseria gonorrhoeae in eastern Chinese cities: mechanisms and genetic diversity of resistant Nanjing isolates.Antimicrob Agents Chemother. 2018; (published online March 12.)DOI:10.1128/AAC.02499-17Crossref Scopus (23) Google Scholar A key step in management of antimicrobial resistance of gonococci in Europe will be global collaboration in identifying gonococcal WGSs from Asian strains, some of which are likely to spread to Europe. The 2017 International Forum on Gonococcal Infections and Resistance, held in Shenzen in Guangdong, China, and led by Xiang-Sheng Chen was a crucial step forward in establishing these ties.13Chen XS Proceedings of the 2017 International Forum on Gonococcal Infections and Resistance (2017 IFGIR) in Shenzhen, China.Sex Transm Dis. 2018; (published online Apr 17.)DOI;10.1097/OLQ.0000000000000859Crossref Scopus (4) Google Scholar We declare no competing interests. Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe: a genomic surveyTo our knowledge, we provide the first use of joint analysis of WGS and epidemiological data in an international programme for regional surveillance of sexually transmitted infections. WGS provided enhanced understanding of the distribution of antimicrobial resistance clones, including replacement with clones that were more susceptible to antimicrobials, in several risk groups nationally and regionally. We provide a framework for genomic surveillance of gonococci through standardised sampling, use of WGS, and a shared information architecture for interpretation and dissemination by use of open access software. Full-Text PDF Open Access