Abstract
The first extensively drug resistant (XDR) Neisseria gonorrhoeae strain with high resistance to the extended-spectrum cephalosporin ceftriaxone was identified in 2009 in Japan, but no other strain with this antimicrobial-resistance profile has been reported since. However, surveillance to date has been based on phenotypic methods and sequence typing, not genome sequencing. Therefore, little is known about the local population structure at the genomic level, and how resistance determinants and lineages are distributed and evolve. We analysed the whole-genome sequence data and the antimicrobial-susceptibility testing results of 204 strains sampled in a region where the first XDR ceftriaxone-resistant N. gonorrhoeae was isolated, complemented with 67 additional genomes from other time frames and locations within Japan. Strains resistant to ceftriaxone were not found, but we discovered a sequence type (ST)7363 sub-lineage susceptible to ceftriaxone and cefixime in which the mosaic penA allele responsible for reduced susceptibility had reverted to a susceptible allele by recombination. Approximately 85 % of isolates showed resistance to fluoroquinolones (ciprofloxacin) explained by linked amino acid substitutions at positions 91 and 95 of GyrA with 99 % sensitivity and 100 % specificity. Approximately 10 % showed resistance to macrolides (azithromycin), for which genetic determinants are less clear. Furthermore, we revealed different evolutionary paths of the two major lineages: single acquisition of penA X in the ST7363-associated lineage, followed by multiple independent acquisitions of the penA X and XXXIV in the ST1901-associated lineage. Our study provides a detailed picture of the distribution of resistance determinants and disentangles the evolution of the two major lineages spreading worldwide.
Highlights
Antimicrobial resistance (AMR) is one of the greatest threats to human health and needs to be monitored and addressed at a global level [1, 2]
For the 204 strains sampled in the Japanese prefectures of Kyoto and Osaka in 2015 (Table S1) and reference strain H041 (WHO X), a clonal phylogeny with branch lengths corrected to account for homologous recombination was inferred using ClonalFrameML (Fig. 1)
The penA alleles have been designated according to amino acid sequences encoded by the whole gene, and alleles such as X and XXXIV were termed ‘mosaic’ because the second half of their DNA sequences appear to have been imported from other Neisseria spp. that are naturally resistant to extended-spectrum cephalosporin (ESC) through homologous recombination events [51]
Summary
Antimicrobial resistance (AMR) is one of the greatest threats to human health and needs to be monitored and addressed at a global level [1, 2]. The number of infections caused by multidrug-resistant bacteria is increasing globally. Received 16 May 2018; Accepted 9 July 2018 Author affiliations: 1Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Tokyo, Japan; 2Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan; 3Virology Section, Division of Microbiology, Osaka Institute of Public Health, Osaka, Japan; 4Department of Microbiology, Kanagawa Prefectural Institute of Public Health, Kanagawa, Japan; 5Department of Urology, Graduate School of Medicine, Gifu University, Gifu, Japan; 6Department of Infectious Disease Epidemiology, Imperial College, London, UK. Data statement: All supporting data, code and protocols have been provided within the article or through supplementary data files. Two supplementary tables and seven supplementary figures are available with the online version of this article
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