title: Prevalence, risk factors, outcomes, and molecular epidemiology of mcr-1-positive Enterobacteriaceae in patients and healthy adults from China: an epidemiological and clinical study.
abstract: The mcr-1 gene confers transferable colistin resistance. mcr-1-positive Enterobacteriaceae (MCRPE) have attracted substantial medical, media, and political attention; however, so far studies have not addressed their clinical impact. Herein, we report the prevalence of MCRPE in human infections and carriage, clinical associations of mcr-1-positive Escherichia coli (MCRPEC) infection, and risk factors for MCRPEC carriage.
  
  
  
  We undertook this study at two hospitals in Zhejiang and Guangdong, China. We did a retrospective cross-sectional assessment of prevalence of MCRPE infection from isolates of Gram-negative bacteria collected at the hospitals from 2007 to 2015 (prevalence study). We did a retrospective case-control study of risk factors for infection and mortality after infection, using all MCRPEC from infection isolates and a random sample of mcr-1-negative E coli infections from the retrospective collection between 2012 and 2015 (infection study). We also did a prospective case-control study to assess risk factors for carriage of MCRPEC in rectal swabs from inpatients with MCRPEC and mcr-1 negative at the hospitals and collected between May and December, 2015, compared with mcr-1-negative isolates from rectal swabs of inpatients (colonisation study). Strains were analysed for antibiotic resistance, plasmid typing, and transfer analysis, and strain relatedness.
  
  
  
  We identified 21 621 non-duplicate isolates of Enterobacteriaceae, Acinetobacter spp, and Pseudomonas aeruginosa from 18 698 inpatients and 2923 healthy volunteers. Of 17 498 isolates associated with infection, mcr-1 was detected in 76 (1%) of 5332 E coli isolates, 13 (<1%) of 348 Klebsiella pneumoniae, one (<1%) of 890 Enterobacter cloacae, and one (1%) of 162 Enterobacter aerogenes. For the infection study, we included 76 mcr-1-positive clinical E coli isolates and 508 mcr-1-negative isolates. Overall, MCRPEC infection was associated with male sex (209 [41%] vs 47 [63%], adjusted p=0·011), immunosuppression (30 [6%] vs 11 [15%], adjusted p=0·011), and antibiotic use, particularly carbapenems (45 [9%] vs 18 [24%], adjusted p=0·002) and fluoroquinolones (95 [19%] vs 23 [30%], adjusted p=0·017), before hospital admission. For the colonisation study, we screened 2923 rectal swabs from healthy volunteers, of which 19 were MCRPEC, and 1200 rectal swabs from patients, of which 35 were MCRPEC. Antibiotic use before hospital admission (p<0·0001) was associated with MCRPEC carriage in 35 patients compared with 378 patients with mcr-1-negative E coli colonisation, whereas living next to a farm was associated with mcr-1-negative E coli colonisation (p=0·03, univariate test). mcr-1 could be transferred between bacteria at high frequencies (10-1to 10-3), and plasmid types and MCRPEC multi-locus sequence types (MLSTs) were more variable in Guangdong than in Zhejiang and included the human pathogen ST131. MCRPEC also included 17 unreported ST clades.
  
  
  
  In 2017, colistin will be formally banned from animal feeds in China and switched to human therapy. Infection with MRCPEC is associated with sex, immunosuppression, and previous antibiotic exposure, while colonisation is also associated with antibiotic exposure. MLST and plasmid analysis shows that MCRPEC are diversely spread throughout China and pervasive in Chinese communities.
  
  
  
  National Key Basic Research Program of China, National Natural Science Foundation of China/Zhejiang, National Key Research and Development Program, and MRC, UK.
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Tropical Diseases Control (Ministry of Education), Program of Immunology, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Guo-Bao
authors.initials: GB
authors.lastname: Tian
authors.affiliation: The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Medical Microbiology and Infectious Disease, Institute of Infection & Immunity, UHW Main Building, Heath Park Hospital, Cardiff, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Tyrrell
authors.affiliation: Program of Immunology, Institute of Human Virology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhu, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.affiliation: The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Li
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh Medical Center, PA, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Doi
authors.affiliation: The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ren
authors.affiliation: Key Laboratory of Tropical Diseases Control (Ministry of Education), Program of Immunology, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lan-Lan
authors.initials: LL
authors.lastname: Zhong
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Zhangqi
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Key Laboratory of Tropical Diseases Control (Ministry of Education), Program of Immunology, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Kun-Jiao
authors.initials: KJ
authors.lastname: Zeng
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Shaolin
authors.initials: S
authors.lastname: Wang
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistant of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Liu
authors.affiliation: Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Congming
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Medical Microbiology and Infectious Disease, Institute of Infection & Immunity, UHW Main Building, Heath Park Hospital, Cardiff, UK. Electronic address: WalshTR@cardiff.ac.uk.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Walsh
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China. Electronic address: sjz@cau.edu.cn.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D015780:Carbapenems / Q000627:therapeutic use; D016022:Case-Control Studies; D002681:China; D003091:Colistin / Q000008:administration & dosage; D003430:Cross-Sectional Studies; D024881:Drug Resistance, Bacterial / Q000276:immunology*; D004755:Enterobacteriaceae / Q000187:drug effects / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000453:epidemiology* / Q000276:immunology; D064368:Healthy Volunteers; D006801:Humans; D017720:Molecular Epidemiology; D010957:Plasmids / Q000276:immunology; D015995:Prevalence; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D015780:Carbapenems; D003091:Colistin