title: Emergence and evolution of internationally disseminated cephalosporin-resistant Neisseria gonorrhoeae clones from 1995 to 2005 in Japan.
abstract: BACKGROUND
  Neisseria gonorrhoeae strains with resistance to extended-spectrum cephalosporins (ESCs), last options for first-line monotherapy of gonorrhoea, likely emerged and initially disseminated in Japan, followed by international transmission. In recent years, multi-locus sequence typing (MLST) ST1901 and N. gonorrhoeae multiantigen sequence typing (NG-MAST) ST1407 isolates with the mosaic penicillin-binding protein (PBP) 2 XXXIV have accounted for most ESC resistance globally. Our aim was to elucidate the initial emergence and transmission of ESC-resistant strains by detailed examination of N. gonorrhoeae isolates from 1995 to 2005 in Kanagawa, Japan.
  
  
  METHODS
  N. gonorrhoeae isolates were examined phenotypically (n = 690) and genetically (n = 372) by agar dilution method (cefixime, ceftriaxone and ciprofloxacin), penA gene sequencing, MLST and NG-MAST.
  
  
  RESULTS
  Already in 1995, one cefixime-resistant (CFM-R) isolate was found, which is the first CFM-R isolate described globally. After 1996, the prevalence of CFM-R and CFM-decreased susceptibility (CFM-DS) isolates significantly increased, with the peak resistance level in 2002 (57.1% CFM-R). In 1997-2002, the CFM-R MLST ST7363 strain type with the mosaic PBP 2 X was predominant among CFM-R/DS isolates. The first CFM-R/DS MLST ST1901 clone(s), which became the predominant CFM-R/DS strain type(s) already in 2003-2005, possessed the mosaic PBP 2 X, which was possibly originally transferred from the MLST ST7363 strains, and subsequently acquired the mosaic PBP 2 XXXIV. The first MLST ST1901 and NG-MAST ST1407 isolate was identified in Kanagawa already in 2003.
  
  
  CONCLUSIONS
  The two main internationally spread cefixime-resistant gonococcal clones, MLST ST7363 and ST1901 (NG-MAST ST1407 most frequent internationally) that also have shown their capacity to develop high-level ceftriaxone resistance (superbugs H041 and F89), likely emerged, evolved and started to disseminate in the metropolitan area, including Kanagawa, in Japan, which was followed by global transmission.
authors.affiliation: National Institute of Infectious Diseases, Tokyo, Japan. shimuta@nih.go.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Shimuta
authors.affiliation: Kanagawa Prefectural Institute of Public Health, Kanagawa, Japan. watanabe.nfa0@pref.kanagawa.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: National Institute of Infectious Diseases, Tokyo, Japan. shuichin@niid.go.jp.
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Nakayama
authors.affiliation: National Institute of Infectious Diseases, Tokyo, Japan. ishihara@niid.go.jp.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Morita-Ishihara
authors.affiliation: Kanagawa Prefectural Institute of Public Health, Kanagawa, Japan. kuroki.gcg3@pref.kanagawa.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kuroki
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. magnus.unemo@regionorebrolan.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Unemo
authors.affiliation: National Institute of Infectious Diseases, Tokyo, Japan. ohnishi7@nih.go.jp.|Department of Bacteriology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan. ohnishi7@nih.go.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohnishi
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics; D002511:Cephalosporins / Q000494:pharmacology* / Q000627:therapeutic use; D004269:DNA, Bacterial / Q000032:analysis; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D006069:Gonorrhea / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007564:Japan; D008826:Microbial Sensitivity Tests; D058885:Multilocus Sequence Typing; D009344:Neisseria gonorrhoeae / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D015995:Prevalence; D017422:Sequence Analysis, DNA
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; D004269:DNA, Bacterial