title: Multi-institute analysis of carbapenem resistance reveals remarkable diversity, unexplained mechanisms, and limited clonal outbreaks.
abstract: Carbapenem-resistant Enterobacteriaceae (CRE) are among the most severe threats to the antibiotic era. Multiple different species can exhibit resistance due to many different mechanisms, and many different mobile elements are capable of transferring resistance between lineages. We prospectively sampled CRE from hospitalized patients from three Boston-area hospitals, together with a collection of CRE from a single California hospital, to define the frequency and characteristics of outbreaks and determine whether there is evidence for transfer of strains within and between hospitals and the frequency with which resistance is transferred between lineages or species. We found eight species exhibiting resistance, with the majority of our sample being the sequence type 258 (ST258) lineage of Klebsiella pneumoniae There was very little evidence of extensive hospital outbreaks, but a great deal of variation in resistance mechanisms and the genomic backgrounds carrying these mechanisms. Local transmission was evident in clear phylogeographic structure between the samples from the two coasts. The most common resistance mechanisms were KPC (K. pneumoniae carbapenemases) beta-lactamases encoded by blaKPC2, blaKPC3, and blaKPC4, which were transferred between strains and species by seven distinct subgroups of the Tn4401 element. We also found evidence for previously unrecognized resistance mechanisms that produced resistance when transformed into a susceptible genomic background. The extensive variation, together with evidence of transmission beyond limited clonal outbreaks, points to multiple unsampled transmission chains throughout the continuum of care, including asymptomatic carriage and transmission of CRE. This finding suggests that to control this threat, we need an aggressive approach to surveillance and isolation.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Cerqueira
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Ashlee M
authors.initials: AM
authors.lastname: Earl
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.|Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Ernst
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.|Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, MA 02115.|Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, CEP 31270, Belo Horizonte, Brazil.
authors.forename: Yonatan H
authors.identifier: 0000-0001-5646-1314
authors.initials: YH
authors.lastname: Grad
authors.affiliation: Massachusetts General Hospital, Boston, MA 02114.
authors.forename: John P
authors.initials: JP
authors.lastname: Dekker
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Michael
authors.initials: M
authors.lastname: Feldgarden
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Sinéad B
authors.initials: SB
authors.lastname: Chapman
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.|Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: João L
authors.initials: JL
authors.lastname: Reis-Cunha
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Shea
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Sarah
authors.initials: S
authors.lastname: Young
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Qiandong
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, CEP 31270, Belo Horizonte, Brazil.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Delaney
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of California, Irvine, CA 92617.
authors.forename: Diane
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Irvine, CA 92617.
authors.forename: Ellena M
authors.initials: EM
authors.lastname: Peterson
authors.affiliation: Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, CEP 31270, Belo Horizonte, Brazil.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: O'Brien
authors.affiliation: Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Ferraro
authors.affiliation: Massachusetts General Hospital, Boston, MA 02114.
authors.forename: David C
authors.initials: DC
authors.lastname: Hooper
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of California, Irvine, CA 92617.|Health Policy Research Institute, School of Medicine, University of California, Irvine, CA 92617.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Huang
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215.
authors.forename: James E
authors.initials: JE
authors.lastname: Kirby
authors.affiliation: Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, CEP 31270, Belo Horizonte, Brazil.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Onderdonk
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Birren
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.|Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Deborah T
authors.initials: DT
authors.lastname: Hung
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.|Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, CEP 31270, Belo Horizonte, Brazil.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cosimi
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Wortman
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Cheryl I
authors.initials: CI
authors.lastname: Murphy
authors.affiliation: Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, MA 02115; whanage@hsph.harvard.edu.
authors.forename: William P
authors.initials: WP
authors.lastname: Hanage
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics; D001900:Boston / Q000453:epidemiology; D015780:Carbapenems / Q000494:pharmacology*; D002999:Clone Cells; D003428:Cross Infection / Q000453:epidemiology / Q000382:microbiology / Q000635:transmission; D004251:DNA Transposable Elements / Q000235:genetics*; D004196:Disease Outbreaks; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D004756:Enterobacteriaceae Infections / Q000453:epidemiology / Q000382:microbiology* / Q000635:transmission; D014644:Genetic Variation; D016680:Genome, Bacterial; D006801:Humans; D011446:Prospective Studies; D011815:R Factors / Q000235:genetics*; D016415:Sequence Alignment; D014169:Transformation, Bacterial; D018440:beta-Lactam Resistance / Q000235:genetics* / Q000502:physiology; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D015780:Carbapenems; D004251:DNA Transposable Elements; D001618:beta-Lactamases
keywords: Enterobacteriaceae; carbapenem resistance; comparative genomics; molecular evolution; whole-genome sequencing