title: Import and spread of extended-spectrum β-lactamase-producing Enterobacteriaceae by international travellers (COMBAT study): a prospective, multicentre cohort study.
abstract: International travel contributes to the dissemination of antimicrobial resistance. We investigated the acquisition of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) during international travel, with a focus on predictive factors for acquisition, duration of colonisation, and probability of onward transmission.
  
  
  
  Within the prospective, multicentre COMBAT study, 2001 Dutch travellers and 215 non-travelling household members were enrolled. Faecal samples and questionnaires on demographics, illnesses, and behaviour were collected before travel and immediately and 1, 3, 6, and 12 months after return. Samples were screened for the presence of ESBL-E. In post-travel samples, ESBL genes were sequenced and PCR with specific primers for plasmid-encoded β-lactamase enzymes TEM, SHV, and CTX-M group 1, 2, 8, 9, and 25 was used to confirm the presence of ESBL genes in follow-up samples. Multivariable regression analyses and mathematical modelling were used to identify predictors for acquisition and sustained carriage, and to determine household transmission rates. This study is registered with ClinicalTrials.gov, number NCT01676974.
  
  
  
  633 (34·3%) of 1847 travellers who were ESBL negative before travel and had available samples after return had acquired ESBL-E during international travel (95% CI 32·1-36·5), with the highest number of acquisitions being among those who travelled to southern Asia in 136 of 181 (75·1%, 95% CI 68·4-80·9). Important predictors for acquisition of ESBL-E were antibiotic use during travel (adjusted odds ratio 2·69, 95% CI 1·79-4·05), traveller's diarrhoea that persisted after return (2·31, 1·42-3·76), and pre-existing chronic bowel disease (2·10, 1·13-3·90). The median duration of colonisation after travel was 30 days (95% CI 29-33). 65 (11·3%) of 577 remained colonised at 12 months. CTX-M enzyme group 9 ESBLs were associated with a significantly increased risk of sustained carriage (median duration 75 days, 95% CI 48-102, p=0·0001). Onward transmission was found in 13 (7·7%) of 168 household members. The probability of transmitting ESBL-E to another household member was 12% (95% CI 5-18).
  
  
  
  Acquisition and spread of ESBL-E during and after international travel was substantial and worrisome. Travellers to areas with a high risk of ESBL-E acquisition should be viewed as potential carriers of ESBL-E for up to 12 months after return.
  
  
  
  Netherlands Organisation for Health Research and Development (ZonMw).
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Maris S
authors.initials: MS
authors.lastname: Arcilla
authors.affiliation: Department of Medical Microbiology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Jarne M
authors.initials: JM
authors.lastname: van Hattem
authors.affiliation: Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, Netherlands.
authors.forename: Manon R
authors.initials: MR
authors.lastname: Haverkate
authors.affiliation: Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, Netherlands; Department of Mathematics, Faculty of Science, Utrecht University, Utrecht, Netherlands.
authors.forename: Martin C J
authors.initials: MCJ
authors.lastname: Bootsma
authors.affiliation: Institute for Tropical Diseases, Havenziekenhuis, Rotterdam, Netherlands.
authors.forename: Perry J J
authors.initials: PJJ
authors.lastname: van Genderen
authors.affiliation: Centre of Tropical Medicine and Travel Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Abraham
authors.initials: A
authors.lastname: Goorhuis
authors.affiliation: Centre of Tropical Medicine and Travel Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Grobusch
authors.affiliation: School for Public Health and Primary Care (Caphri), Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, Netherlands.
authors.forename: Astrid M Oude
authors.initials: AMO
authors.lastname: Lashof
authors.affiliation: Institute for Tropical Diseases, Havenziekenhuis, Rotterdam, Netherlands.
authors.forename: Nicky
authors.initials: N
authors.lastname: Molhoek
authors.affiliation: Department of Medical Microbiology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Constance
authors.initials: C
authors.lastname: Schultsz
authors.affiliation: School for Public Health and Primary Care (Caphri), Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, Netherlands.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Stobberingh
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Henri A
authors.initials: HA
authors.lastname: Verbrugh
authors.affiliation: Department of Medical Microbiology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Menno D
authors.initials: MD
authors.lastname: de Jong
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Damian C
authors.initials: DC
authors.lastname: Melles
authors.affiliation: School for Public Health and Primary Care (Caphri), Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, Netherlands; School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre, Maastricht, Netherlands. Electronic address: j.penders@maastrichtuniversity.nl.
authors.forename: John
authors.initials: J
authors.lastname: Penders
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D003967:Diarrhea / Q000209:etiology; D004755:Enterobacteriaceae / Q000201:enzymology*; D004756:Enterobacteriaceae Infections / Q000453:epidemiology* / Q000635:transmission; D005243:Feces / Q000382:microbiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D011795:Surveys and Questionnaires; D013997:Time Factors; D014195:Travel; D001618:beta-Lactamases
chemical_list: D000900:Anti-Bacterial Agents; D001618:beta-Lactamases