Emergence of an extensively drug-resistant Neisseria gonorrhoeae clone
Authors: Sebastiaan J van Hal, Norelle Sherry, Geoff Coombs, Shakeel Mowlaboccus, David M Whiley, Monica M Lahra
Journal: The Lancet Infectious Diseases (2024)

The increasing detection of Neisseria gonorrhoeae isolates with an extensively drug-resistant phenotype (ie, ceftriaxone minimum inhibitory concentration [MIC] ≥0·125 mg/L, plus high-level resistance to azithromycin [MIC ≥256 mg/L])1European Centre for Disease Prevention and ControlExtensively drug-resistant (XDR) Neisseria gonorrhoeae in the United Kingdom and Australia. Stockholm.https://www.ecdc.europa.eu/sites/default/files/documents/RRA-Gonorrhoea,%20Antimicrobial%20resistance-United%20Kingdom,%20Australia.pdfDate: May 7, 2018Date accessed: July 14, 2024Google Scholar is of grave concern.2Ouk V Pham CD Wi T van Hal SJ Lahra MM The Enhanced Gonococcal Surveillance Programme, Cambodia.Lancet Infect Dis. 2023; 23: e332-e333Summary Full Text Full Text PDF PubMed Google Scholar, 3Ouk V Say HL Virak M et al.World Health Organization Enhanced Gonococcal Antimicrobial Surveillance Programme, Cambodia, 2023.Emerg Infect Dis. 2024; 30: 1493-1495Crossref PubMed Scopus (0) Google Scholar At the genome level, the penA 60.001 allele explains ceftriaxone resistance, while azithromycin high-level resistance is due to the 23S RNA mutation, A2059G. Before 2022, only three extremely drug-resistant cases (with two sequences from one patient before and after therapy from the UK), all belonging to single multi-locus sequence type (MLST; hereafter referred to as ST), ST12309, were reported. Since 2022, 16 cases have been documented, all ST-16406. Herein, we report six additional ST16406 cases from the Australian Gonococcal Surveillance Programme (AGSP; appendix p 2). We first placed these extremely drug-resistant strains within a global context by constructing a phylogenetic tree inclusive of 83 ceftriaxone-resistant, penA 60.001 sequences downloaded from the National Center for Biotechnology Information.4van der Veen S Global transmission of the penA allele 60.001–containing high-level ceftriaxone-resistant gonococcal FC428 clone and antimicrobial therapy of associated cases: a review.Infect Microbes Dis. 2023; 5: 13-20Crossref Scopus (11) Google Scholar All known extremely drug-resistant sequences (n=26) were clustered together and originated from a single ancestor that is consistent with a distinct emergence event and ongoing clonal expansion (figure A). To investigate this event further, a time-tree approach was implemented using BactDating (version 1.1.1) specifying the collection year as the tip date.5Didelot X Croucher NJ Bentley SD Harris SR Wilson DJ Bayesian inference of ancestral dates on bacterial phylogenetic trees.Nucleic Acids Res. 2018; 46: e134Crossref PubMed Scopus (129) Google Scholar For optimal resolution, closely related isolates, irrespective of antimicrobial susceptibility, were included following a core genome MLST single linkage analysis specifying a mismatch threshold of 100 alleles through PubMLST and PathogenWatch6Jolley KA Bray JE Maiden MCJ Open-access bacterial population genomics: BIGSdb software, the PubMLST.org website and their applications.Wellcome Open Res. 2018; 3: 124Crossref PubMed Scopus (1604) Google Scholar, 7Sánchez-Busó L Yeats CA Taylor B et al.A community-driven resource for genomic epidemiology and antimicrobial resistance prediction of Neisseria gonorrhoeae at Pathogenwatch.Genome Med. 2021; 13: 61Crossref PubMed Scopus (62) Google Scholar because no isolates could be confidently selected on the basis of ST (appendix p 2). An additional 61 isolates were identified, including nine additional ST12309 sequences, all ceftriaxone-susceptible, from Australia, China, Cyprus, Japan, Sweden, and the UK. This genomic analysis showed that ST16406 emerged from an ST12309 ancestor, following three separate and discrete genomic events over a 5-year timeframe (figure B). The initial key event was the fixation of the 23S RNA A2059G mutation in the population leading to azithromycin high-level resistance in 2012 (95% CI 2011–2013), due to antimicrobial selection pressure. This event was followed by a lateral gene transfer event (rather than sequential mutations) of the penA 60.001 allele replacing the penA 2.002 allele in 2014 (95% CI 2013–2014) leading to ceftriaxone resistance. The final change was estimated to occur in 2016 (95% CI 2014–2017) when a single mutation (G→C) occurred at position 138 of the housekeeping fumC gene leading to the emergence of ST16406, a single locus variant of ST12039 (figure B; appendix p 3). Our analysis provides evidence for the rapid emergence and expansion of the ST16406 N gonorrhoeae extremely drug-resistant clone in southeast Asia, highlighting the need for improved surveillance models, especially because most reported cases occurred in populations who are not typically targeted for surveillance. These improvements should include broadening surveillance populations and directed testing for ceftriaxone resistance for the presence of the penA 60.001 allele. The demonstrated genomic link between emergence of extremely drug-resistant clones and azithromycin use strengthens calls to re-evaluate the use of azithromycin in empiric therapy. Although some settings have already removed azithromycin as empiric therapy in guidelines for sexually transmitted infections,8Workowski KA Bachmann LH Chan PA et al.Sexually transmitted infections treatment guidelines, 2021.MMWR Recomm Rep. 2021; 70: 1-187Crossref PubMed Scopus (1037) Google Scholar, 9Fifer H Saunders J Soni S Sadiq ST FitzGerald M 2018 UK national guideline for the management of infection with Neisseria gonorrhoeae.Int J STD AIDS. 2020; 31: 4-15Crossref PubMed Scopus (155) Google Scholar no clear consensus exists. Regardless, the extremely drug-resistant clone is likely to have a substantial effect on gonococcal disease control in the short term, as demonstrated by the multiple sentinel cases (ie, beyond southeast Asia). The extremely drug-resistant isolates were reported in countries where established or enhanced gonococcal antimicrobial resistance surveillance is conducted, and, therefore, largely represent sentinel events indicative of regional reservoirs that will become apparent in the countries themselves over time. Two additional extremely drug-resistant cases were detected by the AGSP during the preparation of this Correspondence. These findings add further weight to high-level concerns regarding the uncertainty of future gonococcal disease treatment and control and further demonstrate the urgent need for an effective vaccine and the development of new therapeutic options. DMW reports research funding from the Australian Research Council for unrelated research paid to institution of work. All other authors declare no competing interests. All data relevant to this Correspondence are available in the appendix. The AGSP is funded by the Australian Government Department of Health and Aged Care. We thank Kerrie Stevens and Sandra Johnston for their input on this manuscript, and thank the National Neisseria Network, Australia. Download .pdf (.79 MB) Help with pdf files Supplementary appendix