title: Shifts in the Antibiotic Susceptibility, Serogroups, and Clonal Complexes of Neisseria meningitidis in Shanghai, China: A Time Trend Analysis of the Pre-Quinolone and Quinolone Eras.
abstract: BACKGROUND
  Fluoroquinolones have been used broadly since the end of the 1980s and have been recommended for Neisseria meningitidis prophylaxis since 2005 in China. The aim of this study was to determine whether and how N. meningitidis antimicrobial susceptibility, serogroup prevalence, and clonal complex (CC) prevalence shifted in association with the introduction and expanding use of quinolones in Shanghai, a region with a traditionally high incidence of invasive disease due to N. meningitidis.
  
  
  RESULTS
  A total of 374 N. meningitidis isolates collected by the Shanghai Municipal Center for Disease Control and Prevention between 1965 and 2013 were studied. Shifts in the serogroups and CCs were observed, from predominantly serogroup A CC5 (84%) in 1965-1973 to serogroup A CC1 (58%) in 1974-1985, then to serogroup C or B CC4821 (62%) in 2005-2013. The rates of ciprofloxacin nonsusceptibility in N. meningitidis disease isolates increased from 0% in 1965-1985 to 84% (31/37) in 2005-2013 (p < 0.001). Among the ciprofloxacin-nonsusceptible isolates, 87% (27/31) were assigned to either CC4821 (n = 20) or CC5 (n = 7). The two predominant ciprofloxacin-resistant clones were designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A. The ChinaCC4821-R1-C/B clone acquired ciprofloxacin resistance by a point mutation, and was present in 52% (16/31) of the ciprofloxacin-nonsusceptible disease isolates. The ChinaCC5-R14-A clone acquired ciprofloxacin resistance by horizontal gene transfer, and was found in 23% (7/31) of the ciprofloxacin-nonsusceptible disease isolates. The ciprofloxacin nonsusceptibility rate was 47% (7/15) among isolates from asymptomatic carriers, and nonsusceptibility was associated with diverse multi-locus sequence typing profiles and pulsed-field gel electrophoresis patterns. As detected after 2005, ciprofloxacin-nonsusceptible strains were shared between some of the patients and their close contacts. A limitation of this study is that isolates from 1986-2004 were not available and that only a small sample of convenience isolates from 1965-1985 were available.
  
  
  CONCLUSIONS
  The increasing prevalence of ciprofloxacin resistance since 2005 in Shanghai was associated with the spread of hypervirulent lineages CC4821 and CC5. Two resistant meningococcal clones ChinaCC4821-R1-C/B and ChinaCC5-R14-A have emerged in Shanghai during the quinolone era. Ciprofloxacin should be utilized with caution for the chemoprophylaxis of N. meningitidis in China.
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institute of Medical Microbiology and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Chen
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qinglan
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Intensive Care Unit, Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
authors.forename: Gangyi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Fupin
authors.initials: F
authors.lastname: Hu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institute of Medical Microbiology and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Di
authors.initials: D
authors.lastname: Qu
authors.affiliation: Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Minggui
authors.initials: M
authors.lastname: Wang
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002681:China / Q000453:epidemiology; D006801:Humans; D008585:Meningitis, Meningococcal / Q000188:drug therapy* / Q000453:epidemiology; D008826:Microbial Sensitivity Tests; D058885:Multilocus Sequence Typing; D009345:Neisseria meningitidis / Q000187:drug effects*; D015995:Prevalence; D015363:Quinolones / Q000627:therapeutic use*; D065288:Serogroup; D014504:Urban Health
chemical_list: D000900:Anti-Bacterial Agents; D015363:Quinolones