Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 28, Number 5—May 2022
CME ACTIVITY - Research

Genomic Epidemiology of Global Carbapenemase-Producing Escherichia coli, 2015–2017

Author affiliations: University of Calgary, Calgary, Alberta, Canada (G. Peirano, T.J. Finn, R. DeVinney, J.D.D. Pitout); Alberta Precision Laboratories, Calgary (G. Peirano, J.D.D. Pitout); Hackensack Meridian School of Medicine, Nutley, New Jersey, USA (L. Chen, B.N. Kreiswirth); University of Guelph, Guelph, Ontario, Canada (D. Nobrega); University of Pretoria, Pretoria, South Africa (J.D.D. Pitout)

Cite This Article

Introduction

CME Logo

Medscape CME ACTIVITY

In support of improving patient care, this activity has been planned and implemented by Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at https://www.medscape.org/journal/eid; and (4) view/print certificate.

Release date: April 15, 2022; Expiration date: April 15, 2023
Learning Objectives

Upon completion of this activity, participants will be able to:

  • Assess the global distribution of different carbapenemase genes, based on a genome sequencing study of 229 carbapenemase-producing Escherichia coli (2015–17) from 36 countries

  • Evaluate antimicrobial resistance determinants and plasmid replicon types, virulence-associated factors, and carbapenemase gene flanking regions and plasmid analysis, based on a genome sequencing study of 229 carbapenemase-producing Escherichia coli (2015–17) from 36 countries

  • Determine the public health implications of the global distribution of different carbapenemase genes and associated factors, based on a genome sequencing study of 229 carbapenemase-producing Escherichia coli (2015–17) from 36 countries

CME Editor

Jude Rutledge, BA, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Jude Rutledge has disclosed no relevant financial relationships.

CME Author

Laurie Barclay, MD, freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has disclosed the following relevant financial relationships: stocks, stock options, or bonds from AbbVie (former).

Authors

Gisele Peirano, PhD; Liang Chen, PhD; Diego Nobrega, PhD; Thomas J. Finn, PhD; Barry N. Kreiswirth, PhD; Rebekah DeVinney, PhD; and Johann D.D. Pitout, MD.

Top

Abstract

We describe the global molecular epidemiology of 229 carbapenemase-producing Escherichia coli in 36 countries during 2015–2017. Common carbapenemases were oxacillinase (OXA) 181 (23%), New Delhi metallo-β-lactamase (NDM) 5 (20%), OXA-48 (17%), Klebsiella pneumoniae carbapenemase 2 (15%), and NDM-1 (10%). We identified 5 dominant sequence types (STs); 4 were global (ST410, ST131, ST167, and ST405), and 1 (ST1284) was limited to Turkey. OXA-181 was frequent in Jordan (because of the ST410-B4/H24RxC subclade) and Turkey (because of ST1284). We found nearly identical IncX3-blaOXA-181 plasmids among 11 STs from 12 countries. NDM-5 was frequent in Egypt, Thailand (linked with ST410-B4/H24RxC and ST167-B subclades), and Vietnam (because of ST448). OXA-48 was common in Turkey (linked with ST11260). Global K. pneumoniae carbapenemases were linked with ST131 C1/H30 subclade and NDM-1 with various STs. The global carbapenemase E. coli population is dominated by diverse STs with different characteristics and varied geographic distributions, requiring ongoing genomic surveillance.

Carbapenems are effective options available for treating serious infections caused by multidrug-resistant (MDR) Enterobacterales bacteria (1). The emergence of carbapenem resistance is a major public health concern, and the World Health Organization has identified carbapenem-resistant Enterobacterales as critical-priority bacteria (2).

Carbapenemases are important causes of carbapenem resistance (3). Carbapenemase genes can be transferred between Enterobacterales species. The most common carbapenemases among Enterobacterales are Klebsiella pneumoniae carbapenemases (KPCs), imipenemases (IMPs), Verona integron–encoded metallo-β-lactamases (VIMs), New Delhi metallo-β-lactamases (NDMs), and oxacillinase (OXA) 48–like enzymes. Escherichia coli is the second most common carbapenemase-producing Enterobacterales species (4,5).

Because E. coli is mainly responsible for human community-associated infections (6), it evades conventional hospital-based infection-prevention measures (7). E. coli is an important One Health (i.e., human, animal, environmental health) reservoir for antimicrobial resistance (AMR) genes (8). Tracking global mobile genetic elements and E. coli clones associated with carbapenemase genes is a public health priority (9) and aids in designing management and prevention strategies.

Comprehensive epidemiology data about carbapenemase-producing E. coli is limited to institutional, regional, or countrywide surveys (10). We used short-read whole-genome sequencing (WGS) to describe the molecular characteristics and international distribution of carbapenemase-producing E. coli. We describe the geographic distribution of different carbapenemase genes (including their associations with dominant sequence types [STs], clades and underlying mobile genetic elements), other β-lactamases, AMR genes, and virulence factors.

Materials and Methods

Bacterial Isolates

We obtained ethics approval for this study through the University of Calgary Conjoint Health Research Ethics Board (approval no. REB17-1010). We included 229 clinical, nonrepeat E. coli isolates collected from 2 global surveillance programs (SMART and INFORM) during 2015–2017 (Appendix). Isolates had undergone identification and susceptibility testing using Clinical Laboratory and Standards Institute guidelines (4,5,11). Carbapenem nonsusceptible isolates underwent molecular screening for blaKPC, blaVIM, blaNDM, blaOXA-48-like, blaIMP, and blaGES, as described previously (4,5). Overall, we collected 87,182 Enterobacterales for the period 2015–2017 from 62 countries: 27,444 were identified as E. coli and 275 (1%) tested nonsusceptible to >1 of the carbapenems. Most (229 [83%]) were positive for either blaKPC, blaOXA-48-like, blaNDM, blaVIM, or blaIMP and were included in this study. The remaining 46 were negative for blaKPC, blaVIM, blaNDM, blaOXA-48-like, blaIMP, and blaGES.

We defined major STs as representing >10% and minor STs as representing 5%–10% of the total E. coli carbapenemase population (12). Dominant STs were both major and minor STs.

Genomic Analysis

We subjected the carbapenemase-producing E. coli (n = 229) to short-read WGS by using NovoSeq (Illumina, https://www.illumina.com) with 151 × 2 paired-end reads (13,14). We obtained draft genomes by using SPAdes 3.15 (15). We used BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi) to determine AMR genes, plasmid replicons, and virulence genes against the following databases or typing schemes: National Center for Biotechnology Information Bacterial Antimicrobial Resistance Reference Gene Database (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA313047), ResFinder (16), PlasmidFinder (17), multilocus sequence typing (18), and virulence finder (19). We conducted multilocus sequence typing by using mlst 2.19 (https://github.com/tseemann/mlst). We identified ST410 and ST131 clades and subclades as described previously (20,21).

For phylogenetic analyses, we mapped trimmed raw reads from each genome to a reference genome sequence (EC958 [GenBank accession no. HG941718] for ST131, JS316 [GenBank accession no. CP058618] for ST410, WCHEC005237 [GenBank accession no. CP026580] for ST167, and AR_0015 [GenBank accession no. CP024862] for ST405) by using snippy (https://github.com/tseemann/snippy). We filtered single-nucleotide polymorphisms (SNPs) among prophages, repeated sequences, or insertion sequences as previously described (22), and we generated a maximum-likelihood phylogenetic tree inferred from the resulting SNP alignment by using RAxML 8.2.12 by using a general time-reversible model of nucleotide substitution and 4 discrete γ categories of rate heterogeneity (23). We identified phylogenetic clades by using hierarchical Bayesian analysis of the population structure in R by using RhierBAPS with 10 initial clusters at 2 clustering levels (24). We defined clades by using the first level of clustering and subclades at the second level of clustering (25). We annotated the phylogenetic trees in iTOL (26). We deposited all sequencing data in the National Center for Biotechnology Information database (BioProject PRJNA780590).

Statistical Analyses

We conducted all analyses in R 3.6.1 (27). Initially, we attempted to fit generalized linear mixed models with country-level random effects to summarize comparisons between dominant STs with respect to antimicrobial and virulence genes. Most models failed to converge, possibly because of the low number of isolates for some STs and the large number of countries involved. Thereafter, we attempted to use exact logistic regression models for clustered data, as previously described (28). Similarly, most models failed to converge, particularly for comparisons involving ST1284 where all isolates were obtained from a single country. We then used Fisher exact tests to perform pairwise comparisons of antimicrobial and virulence genes among dominant STs. We used Mann-Whitney tests for comparison of virulence scores between dominant STs. We adjusted p values for multiple comparisons within each outcome by using the false discovery rate (29). We defined statistical significance as p>0.05.

Results

Global Distribution of Carbapenemases

Overall, 218 isolates were positive for a single carbapenemase and 11 isolates were positive for 2 carbapenemases (Table). The OXA-48–like (n = 106) were the most common carbapenemases, followed by NDMs (n = 77), KPCs (n = 50), VIMs (n = 5), and IMPs (n = 2). The OXA-48–like carbapenemases consisted of OXA-48 (n = 41), OXA-181 (n = 55), OXA-244 (n = 3), and OXA-232 (n = 7). E. coli with OXA-48, OXA-181, and OXA-232 had a global distribution. OXA-244 was limited to Egypt (Table). The NDMs consisted of NDM-1 (n = 22), NDM-4 (n = 1), NDM-5 (n = 48), NDM-6 (n = 1), and NDM-7 (n = 5). E. coli with NDM-1 and NDM-5 had a global distribution. NDM-4 was limited to Vietnam and NDM-6 to Guatemala; NDM-7 was found in the Philippines and Vietnam (Table). The KPCs consisted of KPC-2 (n = 35), KPC-3 (n = 14), and KPC-18 (n = 1). E. coli with KPC-2 and KPC-3 had a global distribution, and KPC-18 was obtained from the United States (Table). E. coli with VIMs (VIM-1 and VIM-23) were found in Greece, Spain, Mexico, and Egypt; E. coli with IMP-59 were obtained from Australia (Table).

Global Distribution of Dominant E. coli Sequence Types and Clades

We identified 2 major STs (ST410 [20%] and ST131 [12%]) and 3 minor STs (ST1284 [8%], ST167 [7%], and ST405 [5%]) among this collection. The next most common STs did not fulfill the definition of a dominant ST: ST38 (n = 10 [4%]), ST354 (n = 7 [3%]), ST361 (n = 9 [4%]), ST648 (n = 8 [4%]), and ST11260 (n = 6 [3%]).

ST410 was the most common ST (n = 45/229 [20%]) and was positive for KPC-2 (7%), NDM-5 (27%), NDM-7 (2%), OXA-48 (4%), OXA-181 (47%), and VIM-23 [4%]) (Appendix Table 1). ST410 belonged to 2 subclades: B3/H24Rx (n = 10) and B4/H24RxC (n = 35) (21).

ST131 was the second most common ST (n = 26/229 [12%]) and was positive for KPC-2 (n = 8), KPC-3 (n = 7), KPC-18 (n = 1), NDM-1 (n = 5), NDM-5 (n = 1), OXA-48 (n = 2), OXA-181 (n = 1), and OXA-232 (n = 1). One NDM-1 isolate was also positive for VIM-1. ST131 belonged to clade A/H41 (n = 2) and subclades C1_nonM27 (n = 10), C1_M27 (n = 4), and C2 (n = 10). We also note the global distribution of different minor STs (ST1284, ST167, ST405) and their clades (Appendix).

AMR Determinants and Plasmid Replicon Types

We determined quinolone resistance–determining regions mutations, β-lactamases (noncarbapenemases), aminoglycoside modifying enzymes, and plasmid replicon types among the different E. coli STs (Appendix Table 1). TEM-1, CTX-M-15, aac(6')-Ib-cr, and sul1 were common among isolates.

Virulence Associated Factors

We assessed the presence of 37 putative virulence factors among the different dominant STs (Appendix Table 2). The following factors were present among most of isolates: fimH (100%), fyuA (55%), traT (64%), and iss (52%). Some virulence factors were associated with certain STs: papA (81%), iha (77%), sat (81%), fyuA (100%) usp (100%), ompT (100%), and malX (100%) with ST131, and astA (100%) and iutA (100%) with ST1284. ST131 had the highest overall number of virulence genes (n = 11), and ST410 had the lowest number of virulence genes (n = 2) (Appendix Table 2).

Carbapenemase Gene Flanking Regions and Plasmid Analysis

Because of the limitations of short-read sequencing (30), analyses of the immediate carbapenemase gene flanking regions and plasmids harboring carbapenemase genes were insufficient, especially for blaOXA-48 and blaVIMs. We obtained results for 20/22 of blaNDM-1, 2/2 of blaNDM-4, 46/48 of blaNDM-5, 1/1 of blaNDM-6, 4/5 of blaNDM-7, 34/35 of blaKPC-2, 14/14 of blaKPC-3, 1/1 of blaKPC-18, 1/41 blaOXA-48, 55/55 of blaOXA-181, 3/3 of blaOXA-244, and 7/7 of blaOXA-232.

Among blaKPC-2, 15 were situated in Tn4401 elements (Tn4401a [n = 4] in ST131 and ST46, Tn4401b [n = 9] in 7 STs, and Tn4401e [n = 2] in ST131 and ST1193). Nineteen were associated with non-Tn4401 mobile elements (NTMKPC) (31), including 4 ST131 and 3 ST405 strains. The blaKPC-3 genes were associated with Tn4401a (n = 9), Tn4401b (n = 3), and Tn4401d (n = 2). The blaKPC-18 was located on a novel Tn4401 variant (186 bp deletion). The blaNDMs were located on truncated Tn125 elements, and the blaNDM upstream regions showed substantial diversities with various IS element insertions (e.g., IS630, ISAba125, IS1, and IS903 with blaNDM-1; ISEcp1 and IS1 with blaNDM-5; and IS5 with blaNDM-7).

All blaOXA-232 genes were located on the same 6.1 kb colKp3 plasmids (pOXA-232) (32). Sequence similarities (95%–100%) of blaKPC-3 isolates with previously sequenced plasmids in GenBank showed that most (n = 9) were harbored within IncFIBQil plasmids (33); 2 KPC-3 genes were within pKPC-CAV1193 (34), 1 blaKPC-3 was within the IncFIA plasmid pBK30683 (35), and 1 blaKPC-3 was in the IncI2 plasmid pBK15692 (36). The blaOXA-181 (n = 55) were situated within Tn2013 harbored on the identical IncX3 plasmids with 99%–100% similarities to plasmid p72_X3_OXA181 (37). p72_X3_ OXA181 contained the IncX3 and truncated ColKp3 replicons (13).

Discussion

A World Health Organization report showed the lack of adequate surveillance programs in many parts of the world, especially from lower- and middle-income countries (LMICs) (38). That report identified bacteria, including carbapenem-resistant E. coli, where global surveillance data are urgently required. LMICs bear a considerable share of the disease burden attributable to MDR E. coli but lack adequate genomic surveillance systems (39). Our study aimed to describe the global molecular epidemiology of 229 carbapenemase-producing E. coli obtained from 36 countries (including 20 LMICs) during 2015–2017. Isolates with multiple AMR genes dominated the population. The most common carbapenemase group was the OXA-48-like carbapenemases (44%), followed by NDMs (32%), KPCs (21%), VIMs (2%), and IMPs (1%). OXA-48-like carbapenemases were numerous in Egypt, Jordan, and Turkey; NDMs were numerous in Egypt, Thailand, and Vietnam, and KPCs were numerous in Colombia, Italy, and the United States.

We identified 5 dominant STs and their respective clades and subclades; 4 were global: ST410 subclades B3/H24Rx and B4/H24RxC; ST131 clade A/H41, subclades C1_nonM27/H30, C1_M27/H30, and C2/H30; ST167 subclades B1, B2, and B3; and ST405 clades A and B (Appendix Figure). ST1284 (1 clade) was limited to Turkey, and the ST167-A clade was limited to Guatemala. Dominant STs and their respective clades and subclades were associated with different underlying mobile genetic elements: ST410 was linked with NDM-5 and OXA-181; ST131 was linked with KPCs, ST1284 was linked with OXA-181, ST167 was linked with NDM-5, and ST405 was linked with various carbapenemases.

A recent survey of global carbapenemase-producing E. coli for the period 2002–2017 included 343 carbapenem-resistant isolates obtained mainly from the United States (40). KPC (16%), NDM (16%), and OXA-48–like (13%) carbapenemases were common. The study screened for different E. coli phylogroups and certain STs (ST131, ST648, and ST405). Phylogroup B2 isolates were common, and phylogroup A was dominant in Asia. Global ST131 with blaKPCs was the most common ST, followed by ST648 with blaOXA-48-like and ST405 with blaNDMs.

The most frequent individual carbapenemases in our survey were OXA-181 (23%), NDM-5 (20%), OXA-48 (17%), KPC-2 (15%), and NDM-1 (10%). This result was different from carbapenemase-producing K. pneumoniae and Enterobacter cloacae complex with carbapenemases obtained from the same surveillance programs (14,41). The K. pneumoniae population was dominated by ST258 with KPC-2 from Greece and KPC-3 from the United States (41). The E. cloacae complex isolates (various STs) were dominated by VIM-1 from Greece and Italy (14). K. pneumoniae (42) and E. cloacae complex (43) are mainly hospital pathogens, whereas E. coli was mainly a community pathogen (6), which could partly be responsible for the different carbapenemase types among these species.

Molecular-based surveillance studies have shown that OXA-48–like enzymes are common among global carbapenemase-producing Enterobacterales (4,5). OXA-48 is currently the most common OXA-48–like derivative and OXA-181 the second most common derivative (44). OXA-48 is endemic in North Africa, Middle East, and Turkey (44). E. coli with blaOXA-48 is linked to various STs (44). In our study, OXA-48 was identified among 18 STs from 15 countries. E. coli with blaOXA-48 was common in Turkey, where it was linked with ST11260.

OXA-181 is linked with certain E. coli STs, especially ST410 (44). E. coli ST410 belongs to phylogroup A and is divided into 2 clades (A/H53 and B/H24). Clade B is divided into subclades B1/H24, B2/H24R, B3/H24Rx, and B4/H24RxC (21). The B2/H24R subclade is associated with fluroquinolone resistance, B3/H24Rx with blaCTX-M-15, and B4/H24RxC with blaOXA-181 (21). In our survey, OXA-181 was identified among 11 different STs obtained from 12 countries. All the OXA-181 genes were situated within Tn2013 harbored on near identical IncX3 plasmids (≈100% similarly to p72_X3_OXA181). K. pneumoniae ST307 with p72_X3_OXA181 was previously responsible for large outbreaks in South Africa (13,37). E. coli with blaOXA-181 was frequent in Jordan, Egypt (linked with ST410- B4/H24RxC subclade), and Turkey (linked with ST1284). The ST410-B4/H24RxC subclade with blaOXA-181 was also found in Thailand and South Korea. The ST410-B3/H24Rx subclade with blaOXA-181 was present in South Africa and Kuwait.

Molecular-based surveillance studies have shown that NDMs are often the most common carbapenemase in certain regions (e.g., the Indian subcontinent) (4,5). NDM-1 is the most frequent NDM enzyme and associated with various STs within diverse plasmid platforms (45). In our survey, NDM-1 was identified among 14 different STs obtained from 10 countries. E. coli with blaNDM-1 was not linked with a specific ST and was evenly distributed among the different countries.

E. coli with NDM-5 is numerous among E. coli with NDMs from India, China, and sub-Saharan Africa (45). NDM-5, in our survey, was found among 9 different STs from 9 countries. It was common in Egypt (linked with ST410 [B4/H24RxC] and ST167 [B1 and B3]), Thailand (linked with ST410 [B4/H24RxC] and ST167 [B2]), and Vietnam (linked with ST448). ST167 belongs to phylogroup A and is an emerging carbapenemase clone associated with blaNDM-5 (46). We divided ST167 into 2 clades (A and B) and 3 subclades (B1, B2, and B3). Subclade B3 was the most dominant clade and associated with blaNDM-5 obtained from Egypt and Italy. Other subclades were less common and linked with blaNDM-5, blaNDM-1, and blaOXA-181 obtained in Guatemala (clade A), Egypt (subclades B1 and B2), and Thailand (subclade B2).

E. coli with blaKPC is associated with ST131 (47) on diverse plasmid platforms (48). E. coli ST131 is global MDR high-risk clone associated with fluoroquinolone resistance and blaCTX-Ms (49). ST131 belongs to clades A/H41, B/H22, and C/H30 (50). C/H30 is divided into subclades C0, C1_nonM27, C1_M27, and C2. In our survey, KPC genes were found among 26 different STs from 11 countries. E. coli with blaKPC was common in Colombia linked with various STs. ST131 was responsible for 32% of KPC isolates and obtained from Italy, Israel, Guatemala, Puerto Rico, and the United States (including Puerto Rico). ST131 with blaKPC was dominated by the C1_nonM27 subclade. This dominance is different from that observed by Johnson et al. study (40), where the C2 subclade was common. The ST131-C1_M27 subclade in our survey was positive for blaNDM-1 and blaOXA-232.

Among this study’s strengths is that it included a large global collection of recent isolates representing multiple LMICs. We characterized all isolates using short-read WGS and provided novel information regarding the geographic distribution and MDR determinants of dominant STs and their respective clades and subclades (e.g., global ST410 was linked with blaOXA-181, ST131 with blaKPCs, ST167 with blaNDM-5, and ST405 with various carbapenemases).

We showed that the underlying molecular epidemiology within the same carbapenemase groups were very different (e.g., NDM-1 was linked with various STs, including ST131-C2/H30, whereas NDM-5 was linked with ST167-B and ST410B4/H24Rx). The geographic distribution of isolates with NDM-1 and NDM-5 was different (e.g., NDM-1 showed global distribution whereas those with NDM-5 were numerous in Egypt, Thailand, and Vietnam). Similar differences were described for isolates with OXA-48 (various STs) and OXA-181 (linked with ST410B4/H24Rx). Future genomic surveys should use methodologies that characterize individual carbapenemases.

We also showed that global blaOXA-181 was harbored on near identical IncX3 plasmids (irrespective of the ST or geographic location). This finding suggests that highly similar IncX3 plasmids were mainly responsible for the global distribution of OXA-181 genes, the most common carbapenemase in this collection. The control of such IncX3 plasmids should be a public health priority.

Limitations of this study include the fact that flanking regions and plasmids harboring carbapenemases were not fully reconstructed because of the limitations of short-read sequencing (30). The characterization of plasmids is vital to fully comprehend the molecular epidemiology of global carbapenemase-producing E. coli, and a follow-up study using long-read sequencing is under way. Several countries included only few isolates (Table) and therefore may not be fully representative of what carbapenemase-producing E. coli dominates in that region.

In summary, the global carbapenemase-producing E. coli population is dominated by diverse STs with different characteristics and varied geographic distributions. This characterization was especially apparent within certain carbapenemases groups (i.e., NDM-1 vs. NDM-5 or OXA-48 vs. OXA-181). Ongoing genomic surveillance to characterize individual carbapenemases will assist in designing management and prevention strategies to help curtail the spread of AMR bacteria.

Top

Acknowledgments

We thank Merck and AstraZeneca for providing the SMART and INFORM isolates.

This work was supported by a research grant from the Joint Programming Initiative on Antimicrobial Resistance–Canadian Institute Health Research program (grant no. 10016015) and the US National Institutes of Health (grant no. 10028552).

Top

References

  1. Tompkins  K, van Duin  D. Treatment for carbapenem-resistant Enterobacterales infections: recent advances and future directions. Eur J Clin Microbiol Infect Dis. 2021;40:205368. DOIPubMedGoogle Scholar
  2. Tacconelli  E, Carrara  E, Savoldi  A, Harbarth  S, Mendelson  M, Monnet  DL, et al.; WHO Pathogens Priority List Working Group. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18:31827. DOIPubMedGoogle Scholar
  3. Pitout  JD, Nordmann  P, Poirel  L. Carbapenemase-producing Klebsiella pneumoniae, a key pathogen set for global nosocomial dominance. Antimicrob Agents Chemother. 2015;59:587384. DOIPubMedGoogle Scholar
  4. Karlowsky  JA, Lob  SH, Kazmierczak  KM, Young  K, Motyl  MR, Sahm  DF. In vitro activity of imipenem/relebactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples: SMART Surveillance United States 2015-2017. J Glob Antimicrob Resist. 2020;21:2238. DOIPubMedGoogle Scholar
  5. Kazmierczak  KM, Karlowsky  JA, de Jonge  BLM, Stone  GG, Sahm  DF. Epidemiology of carbapenem resistance determinants identified in meropenem-nonsusceptible Enterobacterales collected as part of a global surveillance program, 2012 to 2017. Antimicrob Agents Chemother. 2021;65:e0200020. DOIPubMedGoogle Scholar
  6. Pitout  JD. Extraintestinal pathogenic Escherichia coli: an update on antimicrobial resistance, laboratory diagnosis and treatment. Expert Rev Anti Infect Ther. 2012;10:116576. DOIPubMedGoogle Scholar
  7. Pitout  JDD. Population dynamics of Escherichia coli causing bloodstream infections over extended time periods. MSphere. 2021;6:e0095621. DOIPubMedGoogle Scholar
  8. Léger  A, Lambraki  I, Graells  T, Cousins  M, Henriksson  PJG, Harbarth  S, et al. Characterizing social-ecological context and success factors of antimicrobial resistance interventions across the One Health spectrum: analysis of 42 interventions targeting E. coli. BMC Infect Dis. 2021;21:873. DOIPubMedGoogle Scholar
  9. Nordmann  P, Poirel  L. The difficult-to-control spread of carbapenemase producers among Enterobacteriaceae worldwide. Clin Microbiol Infect. 2014;20:82130. DOIPubMedGoogle Scholar
  10. Manges  AR, Geum  HM, Guo  A, Edens  TJ, Fibke  CD, Pitout  JDD. Global extraintestinal pathogenic Escherichia coli (ExPEC) lineages. Clin Microbiol Rev. 2019;32:e0013518. DOIPubMedGoogle Scholar
  11. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Twenty-fifth information supplement (M100–S25). Wayne (PA): The Institute; 2015.
  12. Holland  MS, Nobrega  D, Peirano  G, Naugler  C, Church  DL, Pitout  JDD. Molecular epidemiology of Escherichia coli causing bloodstream infections in a centralized Canadian region: a population-based surveillance study. Clin Microbiol Infect. 2020;26:1554.e18. DOIPubMedGoogle Scholar
  13. Lowe  M, Kock  MM, Coetzee  J, Hoosien  E, Peirano  G, Strydom  KA, et al. Klebsiella pneumoniae ST307 with blaOXA-181, South Africa, 2014-2016. Emerg Infect Dis. 2019;25:73947. DOIPubMedGoogle Scholar
  14. Peirano  G, Matsumura  Y, Adams  MD, Bradford  P, Motyl  M, Chen  L, et al. Genomic epidemiology of global carbapenemase-producing Enterobacter spp., 2008–2014. Emerg Infect Dis. 2018;24:10109. DOIPubMedGoogle Scholar
  15. Nurk  S, Bankevich  A, Antipov  D, Gurevich  AA, Korobeynikov  A, Lapidus  A, et al. Assembling single-cell genomes and mini-metagenomes from chimeric MDA products. J Comput Biol. 2013;20:71437. DOIPubMedGoogle Scholar
  16. Zankari  E, Hasman  H, Cosentino  S, Vestergaard  M, Rasmussen  S, Lund  O, et al. Identification of acquired antimicrobial resistance genes. J Antimicrob Chemother. 2012;67:26404. DOIPubMedGoogle Scholar
  17. Carattoli  A, Zankari  E, García-Fernández  A, Voldby Larsen  M, Lund  O, Villa  L, et al. In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing. Antimicrob Agents Chemother. 2014;58:3895903. DOIPubMedGoogle Scholar
  18. Zhou  Z, Alikhan  NF, Mohamed  K, Fan  Y, Achtman  M; Agama Study Group. The EnteroBase user’s guide, with case studies on Salmonella transmissions, Yersinia pestis phylogeny, and Escherichia core genomic diversity. Genome Res. 2020;30:13852. DOIPubMedGoogle Scholar
  19. Joensen  KG, Scheutz  F, Lund  O, Hasman  H, Kaas  RS, Nielsen  EM, et al. Real-time whole-genome sequencing for routine typing, surveillance, and outbreak detection of verotoxigenic Escherichia coli. J Clin Microbiol. 2014;52:150110. DOIPubMedGoogle Scholar
  20. Matsumura  Y, Pitout  JDD, Peirano  G, DeVinney  R, Noguchi  T, Yamamoto  M, et al. Rapid identification of different Escherichia coli sequence type 131 clades. Antimicrob Agents Chemother. 2017;61:e0017917. DOIPubMedGoogle Scholar
  21. Roer  L, Overballe-Petersen  S, Hansen  F, Schønning  K, Wang  M, Røder  BL, et al. Escherichia coli sequence type 410 is causing new international high-risk clones. MSphere. 2018;3:e0033718. DOIPubMedGoogle Scholar
  22. Wang  M, Earley  M, Chen  L, Hanson  BM, Yu  Y, Liu  Z, et al. Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study. Lancet Infect Dis. 2021; [Epub ahead of print].PubMedGoogle Scholar
  23. Stamatakis  A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics. 2014;30:13123. DOIPubMedGoogle Scholar
  24. Tonkin-Hill  G, Lees  JA, Bentley  SD, Frost  SDW, Corander  J. RhierBAPS: An R implementation of the population clustering algorithm hierBAPS. Wellcome Open Res. 2018;3:93. DOIPubMedGoogle Scholar
  25. Cheng  L, Connor  TR, Sirén  J, Aanensen  DM, Corander  J. Hierarchical and spatially explicit clustering of DNA sequences with BAPS software. Mol Biol Evol. 2013;30:12248. DOIPubMedGoogle Scholar
  26. Letunic  I, Bork  P. Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Res. 2016;44(W1):W242-5. DOIPubMedGoogle Scholar
  27. R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2017.
  28. Troxler  S, Lalonde  T, Wilson  JR. Exact logistic models for nested binary data. Stat Med. 2011;30:86676. DOIPubMedGoogle Scholar
  29. Benjamini  Y, Hochberg  Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289300. DOIGoogle Scholar
  30. Arredondo-Alonso  S, Willems  RJ, van Schaik  W, Schürch  AC. On the (im)possibility of reconstructing plasmids from whole-genome short-read sequencing data. Microb Genom. 2017;3:e000128. DOIPubMedGoogle Scholar
  31. Chen  L, Mathema  B, Chavda  KD, DeLeo  FR, Bonomo  RA, Kreiswirth  BN. Carbapenemase-producing Klebsiella pneumoniae: molecular and genetic decoding. Trends Microbiol. 2014;22:68696. DOIPubMedGoogle Scholar
  32. Potron  A, Rondinaud  E, Poirel  L, Belmonte  O, Boyer  S, Camiade  S, et al. Genetic and biochemical characterisation of OXA-232, a carbapenem-hydrolysing class D β-lactamase from Enterobacteriaceae. Int J Antimicrob Agents. 2013;41:3259. DOIPubMedGoogle Scholar
  33. García-Fernández  A, Villa  L, Carta  C, Venditti  C, Giordano  A, Venditti  M, et al. Klebsiella pneumoniae ST258 producing KPC-3 identified in italy carries novel plasmids and OmpK36/OmpK35 porin variants. Antimicrob Agents Chemother. 2012;56:21435. DOIPubMedGoogle Scholar
  34. Sheppard  AE, Stoesser  N, Sebra  R, Kasarskis  A, Deikus  G, Anson  L, et al. Complete genome sequence of KPC-producing Klebsiella pneumoniae strain CAV1193. Genome Announc. 2016;4:e0164915. DOIPubMedGoogle Scholar
  35. Chen  L, Chavda  KD, Melano  RG, Hong  T, Rojtman  AD, Jacobs  MR, et al. Molecular survey of the dissemination of two blaKPC-harboring IncFIA plasmids in New Jersey and New York hospitals. Antimicrob Agents Chemother. 2014;58:228994. DOIPubMedGoogle Scholar
  36. Chen  L, Chavda  KD, Al Laham  N, Melano  RG, Jacobs  MR, Bonomo  RA, et al. Complete nucleotide sequence of a blaKPC-harboring IncI2 plasmid and its dissemination in New Jersey and New York hospitals. Antimicrob Agents Chemother. 2013;57:501925. DOIPubMedGoogle Scholar
  37. Strydom  KA, Chen  L, Kock  MM, Stoltz  AC, Peirano  G, Nobrega  DB, et al. Klebsiella pneumoniae ST307 with OXA-181: threat of a high-risk clone and promiscuous plasmid in a resource-constrained healthcare setting. J Antimicrob Chemother. 2020;75:896902. DOIPubMedGoogle Scholar
  38. World Health Organization. Antimicrobial resistance: global report on surveillance 2014. Geneva: World Health Organization; 2014. p. 257.
  39. Acharya  KP, Subramanya  SH, Pitout  JDD. Inclusion of next-generation leaders and cost-effective precision diagnostic techniques are vital in combatting antimicrobial resistance in low- and middle-income countries. JAC Antimicrob Resist. 2020 Jun 23 [Epub ahead of print].
  40. Johnston  BD, Thuras  P, Porter  SB, Anacker  M, VonBank  B, Vagnone  PS, et al. Global molecular epidemiology of carbapenem-resistant Escherichia coli (2002-2017). Eur J Clin Microbiol Infect Dis. 2021; Epub ahead of print. DOIPubMedGoogle Scholar
  41. Peirano  G, Bradford  PA, Kazmierczak  KM, Chen  L, Kreiswirth  BN, Pitout  JD. Importance of clonal complex 258 and IncFK2-like plasmids among a global collection of Klebsiella pneumoniae with blaKPC. Antimicrob Agents Chemother. 2017;61:e026106. DOIPubMedGoogle Scholar
  42. Peirano  G, Chen  L, Kreiswirth  BN, Pitout  JDD. Emerging antimicrobial-resistant high-risk Klebsiella pneumoniae clones ST307 and ST147. Antimicrob Agents Chemother. 2020;64:e0114820. DOIPubMedGoogle Scholar
  43. Stokes  W, Peirano  G, Matsumara  Y, Nobrega  D, Pitout  JDD. Population-based surveillance of Enterobacter cloacae complex causing blood stream infections in a centralized Canadian region. [Epub ahed of print]. Eur J Clin Microbiol Infect Dis. 2021.PubMedGoogle Scholar
  44. Pitout  JDD, Peirano  G, Kock  MM, Strydom  KA, Matsumura  Y. The global ascendency of OXA-48-type carbapenemases. Clin Microbiol Rev. 2019;33:e0010219. DOIPubMedGoogle Scholar
  45. Wu  W, Feng  Y, Tang  G, Qiao  F, McNally  A, Zong  Z. NDM metallo-β-lactamases and their bacterial producers in health care settings. Clin Microbiol Rev. 2019;32:e001158. DOIPubMedGoogle Scholar
  46. Cummins  EA, Snaith  AE, McNally  A, Hall  RJ. The role of potentiating mutations in the evolution of pandemic Escherichia coli clones. [Epub of print]. Eur J Clin Microbiol Infect Dis. 2021. DOIPubMedGoogle Scholar
  47. Peirano  G, Bradford  PA, Kazmierczak  KM, Badal  RE, Hackel  M, Hoban  DJ, et al. Global incidence of carbapenemase-producing Escherichia coli ST131. Emerg Infect Dis. 2014;20:192831. DOIPubMedGoogle Scholar
  48. Stoesser  N, Sheppard  AE, Peirano  G, Anson  LW, Pankhurst  L, Sebra  R, et al. Genomic epidemiology of global Klebsiella pneumoniae carbapenemase (KPC)-producing Escherichia coli. Sci Rep. 2017;7:5917. DOIPubMedGoogle Scholar
  49. Mathers  AJ, Peirano  G, Pitout  JD. The role of epidemic resistance plasmids and international high-risk clones in the spread of multidrug-resistant Enterobacteriaceae. Clin Microbiol Rev. 2015;28:56591. DOIPubMedGoogle Scholar
  50. Pitout  JDD, Finn  TJ. The evolutionary puzzle of Escherichia coli ST131. Infect Genet Evol. 2020;81:104265. DOIPubMedGoogle Scholar

Top

Figure
Table

Top

Follow Up

Earning CME Credit

To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions (with a minimum 75% passing score) and earn continuing medical education (CME) credit, please go to https://www.medscape.org/journal/eid. Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers.

You must be a registered user on http://www.medscape.org. If you are not registered on http://www.medscape.org, please click on the “Register” link on the right hand side of the website.

Only one answer is correct for each question. Once you successfully answer all post-test questions, you will be able to view and/or print your certificate. For questions regarding this activity, contact the accredited provider, CME@medscape.net. For technical assistance, contact CME@medscape.net. American Medical Association’s Physician’s Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activities. For further information on this award, please go to https://www.ama-assn.org. The AMA has determined that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA Category 1 Credits™. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit may be acceptable as evidence of participation in CME activities. If you are not licensed in the US, please complete the questions online, print the AMA PRA CME credit certificate, and present it to your national medical association for review.

Article Title: 
Genomic Epidemiology of Global Carbapenemase-Producing Escherichia coli, 2015–2017
CME Questions
  • You are advising a large hospital system about emerging antibiotic resistance of Escherichia coli. On the basis of the genome sequencing study of 229 carbapenemase-producing E. coli (2015–17) from 36 countries by Peirano and colleagues, which one of the following statements about global distribution of different carbapenemase genes is correct?

    • KPC-2 and NDM-1 were the 2 most common carbapenemases

    • Of 5 dominant sequence types (STs), ST410 and ST131 were limited to Turkey

    • OXA-181 was frequent in Jordan (because of ST410-B4/H24RxC subclade) and Turkey (because of ST1284)

    • OXA-48 was frequent in Egypt, Thailand, and Vietnam

  • According to the genome sequencing study of 229 carbapenemase-producing E. coli (2015–17) from 36 countries by Peirano and colleagues, which one of the following statements about antimicrobial resistance determinants and plasmid replicon types, virulence-associated factors, and carbapenemase gene flanking regions and plasmid analysis is correct?

    • Among antimicrobial resistance determinants, this study examined only carbapenemase genes

    • The investigators found nearly identical IncX3-blaOXA-181 plasmids among 11 STs from 12 countries

    • Most isolates had papA and iha virulence factors

    • All NDM genes were situated within Tn2013 harbored on near-identical IncX3 plasmids

  • On the basis of the genome sequencing study of 229 carbapenemase-producing E. coli (2015–17) from 36 countries by Peirano and colleagues, which one of the following statements about public health implications of global distribution of different carbapenemase genes and associated factors is correct?

    • A World Health Organization (WHO) report showed adequate surveillance for carbapenem-resistant E. coli in most lower- and middle-income countries

    • Global multidrug-resistant surveillance does not require characterization of individual carbapenemases

    • The most frequent individual carbapenemases in this survey were similar to those in carbapenemase-producing Klebsiella pneumoniae and Enterobacter cloacae complex

    • A public health priority should be control of IncX3 plasmids, which were mainly responsible for global distribution of OXA-181 genes, the most common carbapenemase in this study

Top

Cite This Article

DOI: 10.3201/eid2805.212535

Original Publication Date: April 15, 2022

Related Links

Table of Contents – Volume 28, Number 5—May 2022

EID Search Options
presentation_01 Advanced Article Search – Search articles by author and/or keyword.
presentation_01 Articles by Country Search – Search articles by the topic country.
presentation_01 Article Type Search – Search articles by article type and issue.

Top

Comments

Please use the form below to submit correspondence to the authors or contact them at the following address:

Johann D.D. Pitout, University of Calgary, #9, 3535 Research Rd NW, Calgary, AB T2L 2K8, Canada

Send To

10000 character(s) remaining.

Top

Page created: March 10, 2022
Page updated: April 15, 2022
Page reviewed: April 15, 2022
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external