Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17: a nationwide, longitudinal, microbial population genomic study

Rebecca A. Gladstone; Alan McNally; Anna K. Pöntinen; Gerry Tonkin-Hill; John A. Lees; Kusti Skytén; François Cléon; Martin O.K. Christensen; Bjørg C. Haldorsen; Kristina K. Bye; Karianne W. Gammelsrud; Reidar Hjetland; Angela Kümmel; Hege E. Larsen; Paul Christoffer Lindemann; Iren H. Löhr; Åshild Marvik; Einar Nilsen; Marie T. Noer; Gunnar S. Simonsen; Martin Steinbakk; Ståle Tofteland; Marit Vattøy; Stephen D. Bentley; Nicholas J. Croucher; Julian Parkhill; Pål J. Johnsen; Ørjan Samuelsen; Jukka Corander

doi:10.1016/S2666-5247(21)00031-8

Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17: a nationwide, longitudinal, microbial population genomic study

Rebecca A. Gladstone^*, Alan McNally, Anna K. Pöntinen, Gerry Tonkin-Hill, John A. Lees, Kusti Skytén, François Cléon, Martin O.K. Christensen, Bjørg C. Haldorsen, Kristina K. Bye, Karianne W. Gammelsrud, Reidar Hjetland, Angela Kümmel, Hege E. Larsen, Paul Christoffer Lindemann, Iren H. Löhr, Åshild Marvik, Einar Nilsen, Marie T. Noer, Gunnar S. SimonsenMartin Steinbakk, Ståle Tofteland, Marit Vattøy, Stephen D. Bentley, Nicholas J. Croucher, Julian Parkhill, Pål J. Johnsen, Ørjan Samuelsen, Jukka Corander

^*Corresponding author for this work

Microbiology and Infection

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Abstract

Background: The clonal diversity underpinning trends in multidrug resistant Escherichia coli causing bloodstream infections remains uncertain. We aimed to determine the contribution of individual clones to resistance over time, using large-scale genomics-based molecular epidemiology.

Methods: This was a longitudinal, E coli population, genomic, cohort study that sampled isolates from 22 512 E coli bloodstream infections included in the Norwegian surveillance programme on resistant microbes (NORM) from 2002 to 2017. 15 of 22 laboratories were able to share their isolates, and the first 22·5% of isolates from each year were requested. We used whole genome sequencing to infer the population structure (PopPUNK), and we investigated the clade composition of the dominant multidrug resistant clonal complex (CC)131 using genetic markers previously reported for sequence type (ST)131, effective population size (BEAST), and presence of determinants of antimicrobial resistance (ARIBA, PointFinder, and ResFinder databases) over time. We compared these features between the 2002–10 and 2011–17 time periods. We also compared our results with those of a longitudinal study from the UK done between 2001 and 2011.

Findings: Of the 3500 isolates requested from the participating laboratories, 3397 (97·1%) were received, of which 3254 (95·8%) were successfully sequenced and included in the analysis. A significant increase in the number of multidrug resistant CC131 isolates from 71 (5·6%) of 1277 in 2002–10 to 207 (10·5%) of 1977 in 2011–17 (p<0·0001), was the largest clonal expansion. CC131 was the most common clone in extended-spectrum β-lactamase (ESBL)-positive isolates (75 [58·6%] of 128) and fluoroquinolone non-susceptible isolates (148 [39·2%] of 378). Within CC131, clade A increased in prevalence from 2002, whereas the global multidrug resistant clade C2 was not observed until 2007. Multiple de-novo acquisitions of both bla_CTX-M ESBL-encoding genes in clades A and C1 and gain of phenotypic fluoroquinolone non-susceptibility across the clade A phylogeny were observed. We estimated that exponential increases in the effective population sizes of clades A, C1, and C2 occurred in the mid-2000s, and in clade B a decade earlier. The rate of increase in the estimated effective population size of clade A (N_e=3147) was nearly ten-times that of C2 (N_e=345), with clade A over-represented in Norwegian CC131 isolates (75 [27·0%] of 278) compared with the UK study (8 [5·4%] of 147 isolates).

Interpretation: The early and sustained establishment of predominantly antimicrobial susceptible CC131 clade A isolates, relative to multidrug resistant clade C2 isolates, suggests that resistance is not necessary for clonal success. However, even in the low antibiotic use setting of Norway, resistance to important antimicrobial classes has rapidly been selected for in CC131 clade A isolates. This study shows the importance of genomic surveillance in uncovering the complex ecology underlying multidrug resistance dissemination and competition, which have implications for the design of strategies and interventions to control the spread of high-risk multidrug resistant clones.

Funding: Trond Mohn Foundation, European Research Council, Marie Skłodowska-Curie Actions, and the Wellcome Trust.

Original language	English
Pages (from-to)	e331-e341
Number of pages	11
Journal	The Lancet Microbe
Volume	2
Issue number	7
Early online date	10 May 2021
DOIs	https://doi.org/10.1016/S2666-5247(21)00031-8
Publication status	Published - Jul 2021

Bibliographical note

Funding Information:
NJC reports grants from GlaxoSmithKline and personal fees from Antigen Discovery, outside the submitted work. JP reports grants from Wellcome Trust, during the study. All other authors declare no competing interest. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

This work was supported by a Trond Mohn Foundation (antimicrobial resistance grant TMS2019TMT04; to RAG, AKP, JC, ?S, and PJJ), Marie Skłodowska-Curie Actions (801133; to AKP), and European Research Council (grant 742158; to JC). Sequencing at the Wellcome Sanger Institute was supported by a core Wellcome Trust grant (206194). We are grateful for technical assistance from Ellen Josefsen, Miriam Nilsen, Lennart Maximillian van Ligtenberg, and all those that prepared and shipped isolates for the study, and thank the Wellcome Sanger Institute sequencing facility and the Wellcome Sanger Institute pathogens informatics team.

Publisher Copyright:
© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

ASJC Scopus subject areas

Infectious Diseases
Microbiology (medical)
Microbiology
Virology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Gladstone, R. A., McNally, A., Pöntinen, A. K., Tonkin-Hill, G., Lees, J. A., Skytén, K., Cléon, F., Christensen, M. O. K., Haldorsen, B. C., Bye, K. K., Gammelsrud, K. W., Hjetland, R., Kümmel, A., Larsen, H. E., Lindemann, P. C., Löhr, I. H., Marvik, Å., Nilsen, E., Noer, M. T., ... Corander, J. (2021). Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17: a nationwide, longitudinal, microbial population genomic study. The Lancet Microbe, 2(7), e331-e341. Advance online publication. https://doi.org/10.1016/S2666-5247(21)00031-8

@article{efbe361e649846e7b2ca5c2e0895ee28,

title = "Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17: a nationwide, longitudinal, microbial population genomic study",

abstract = "Background: The clonal diversity underpinning trends in multidrug resistant Escherichia coli causing bloodstream infections remains uncertain. We aimed to determine the contribution of individual clones to resistance over time, using large-scale genomics-based molecular epidemiology. Methods: This was a longitudinal, E coli population, genomic, cohort study that sampled isolates from 22 512 E coli bloodstream infections included in the Norwegian surveillance programme on resistant microbes (NORM) from 2002 to 2017. 15 of 22 laboratories were able to share their isolates, and the first 22·5% of isolates from each year were requested. We used whole genome sequencing to infer the population structure (PopPUNK), and we investigated the clade composition of the dominant multidrug resistant clonal complex (CC)131 using genetic markers previously reported for sequence type (ST)131, effective population size (BEAST), and presence of determinants of antimicrobial resistance (ARIBA, PointFinder, and ResFinder databases) over time. We compared these features between the 2002–10 and 2011–17 time periods. We also compared our results with those of a longitudinal study from the UK done between 2001 and 2011. Findings: Of the 3500 isolates requested from the participating laboratories, 3397 (97·1%) were received, of which 3254 (95·8%) were successfully sequenced and included in the analysis. A significant increase in the number of multidrug resistant CC131 isolates from 71 (5·6%) of 1277 in 2002–10 to 207 (10·5%) of 1977 in 2011–17 (p<0·0001), was the largest clonal expansion. CC131 was the most common clone in extended-spectrum β-lactamase (ESBL)-positive isolates (75 [58·6%] of 128) and fluoroquinolone non-susceptible isolates (148 [39·2%] of 378). Within CC131, clade A increased in prevalence from 2002, whereas the global multidrug resistant clade C2 was not observed until 2007. Multiple de-novo acquisitions of both blaCTX-M ESBL-encoding genes in clades A and C1 and gain of phenotypic fluoroquinolone non-susceptibility across the clade A phylogeny were observed. We estimated that exponential increases in the effective population sizes of clades A, C1, and C2 occurred in the mid-2000s, and in clade B a decade earlier. The rate of increase in the estimated effective population size of clade A (Ne=3147) was nearly ten-times that of C2 (Ne=345), with clade A over-represented in Norwegian CC131 isolates (75 [27·0%] of 278) compared with the UK study (8 [5·4%] of 147 isolates). Interpretation: The early and sustained establishment of predominantly antimicrobial susceptible CC131 clade A isolates, relative to multidrug resistant clade C2 isolates, suggests that resistance is not necessary for clonal success. However, even in the low antibiotic use setting of Norway, resistance to important antimicrobial classes has rapidly been selected for in CC131 clade A isolates. This study shows the importance of genomic surveillance in uncovering the complex ecology underlying multidrug resistance dissemination and competition, which have implications for the design of strategies and interventions to control the spread of high-risk multidrug resistant clones. Funding: Trond Mohn Foundation, European Research Council, Marie Sk{\l}odowska-Curie Actions, and the Wellcome Trust.",

author = "Gladstone, {Rebecca A.} and Alan McNally and P{\"o}ntinen, {Anna K.} and Gerry Tonkin-Hill and Lees, {John A.} and Kusti Skyt{\'e}n and Fran{\c c}ois Cl{\'e}on and Christensen, {Martin O.K.} and Haldorsen, {Bj{\o}rg C.} and Bye, {Kristina K.} and Gammelsrud, {Karianne W.} and Reidar Hjetland and Angela K{\"u}mmel and Larsen, {Hege E.} and Lindemann, {Paul Christoffer} and L{\"o}hr, {Iren H.} and {\AA}shild Marvik and Einar Nilsen and Noer, {Marie T.} and Simonsen, {Gunnar S.} and Martin Steinbakk and St{\aa}le Tofteland and Marit Vatt{\o}y and Bentley, {Stephen D.} and Croucher, {Nicholas J.} and Julian Parkhill and Johnsen, {P{\aa}l J.} and {\O}rjan Samuelsen and Jukka Corander",

note = "Funding Information: NJC reports grants from GlaxoSmithKline and personal fees from Antigen Discovery, outside the submitted work. JP reports grants from Wellcome Trust, during the study. All other authors declare no competing interest. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. This work was supported by a Trond Mohn Foundation (antimicrobial resistance grant TMS2019TMT04; to RAG, AKP, JC, ?S, and PJJ), Marie Sk{\l}odowska-Curie Actions (801133; to AKP), and European Research Council (grant 742158; to JC). Sequencing at the Wellcome Sanger Institute was supported by a core Wellcome Trust grant (206194). We are grateful for technical assistance from Ellen Josefsen, Miriam Nilsen, Lennart Maximillian van Ligtenberg, and all those that prepared and shipped isolates for the study, and thank the Wellcome Sanger Institute sequencing facility and the Wellcome Sanger Institute pathogens informatics team. Publisher Copyright: {\textcopyright} 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license ",

year = "2021",

month = jul,

doi = "10.1016/S2666-5247(21)00031-8",

language = "English",

volume = "2",

pages = "e331--e341",

journal = "The Lancet Microbe",

issn = "2666-5247",

publisher = "Elsevier",

number = "7",

}

Gladstone, RA, McNally, A, Pöntinen, AK, Tonkin-Hill, G, Lees, JA, Skytén, K, Cléon, F, Christensen, MOK, Haldorsen, BC, Bye, KK, Gammelsrud, KW, Hjetland, R, Kümmel, A, Larsen, HE, Lindemann, PC, Löhr, IH, Marvik, Å, Nilsen, E, Noer, MT, Simonsen, GS, Steinbakk, M, Tofteland, S, Vattøy, M, Bentley, SD, Croucher, NJ, Parkhill, J, Johnsen, PJ, Samuelsen, Ø & Corander, J 2021, 'Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17: a nationwide, longitudinal, microbial population genomic study', The Lancet Microbe, vol. 2, no. 7, pp. e331-e341. https://doi.org/10.1016/S2666-5247(21)00031-8

Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17: a nationwide, longitudinal, microbial population genomic study. / Gladstone, Rebecca A.; McNally, Alan; Pöntinen, Anna K. et al.
In: The Lancet Microbe, Vol. 2, No. 7, 07.2021, p. e331-e341.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17

T2 - a nationwide, longitudinal, microbial population genomic study

AU - Gladstone, Rebecca A.

AU - McNally, Alan

AU - Pöntinen, Anna K.

AU - Tonkin-Hill, Gerry

AU - Lees, John A.

AU - Skytén, Kusti

AU - Cléon, François

AU - Christensen, Martin O.K.

AU - Haldorsen, Bjørg C.

AU - Bye, Kristina K.

AU - Gammelsrud, Karianne W.

AU - Hjetland, Reidar

AU - Kümmel, Angela

AU - Larsen, Hege E.

AU - Lindemann, Paul Christoffer

AU - Löhr, Iren H.

AU - Marvik, Åshild

AU - Nilsen, Einar

AU - Noer, Marie T.

AU - Simonsen, Gunnar S.

AU - Steinbakk, Martin

AU - Tofteland, Ståle

AU - Vattøy, Marit

AU - Bentley, Stephen D.

AU - Croucher, Nicholas J.

AU - Parkhill, Julian

AU - Johnsen, Pål J.

AU - Samuelsen, Ørjan

AU - Corander, Jukka

N1 - Funding Information: NJC reports grants from GlaxoSmithKline and personal fees from Antigen Discovery, outside the submitted work. JP reports grants from Wellcome Trust, during the study. All other authors declare no competing interest. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. This work was supported by a Trond Mohn Foundation (antimicrobial resistance grant TMS2019TMT04; to RAG, AKP, JC, ?S, and PJJ), Marie Skłodowska-Curie Actions (801133; to AKP), and European Research Council (grant 742158; to JC). Sequencing at the Wellcome Sanger Institute was supported by a core Wellcome Trust grant (206194). We are grateful for technical assistance from Ellen Josefsen, Miriam Nilsen, Lennart Maximillian van Ligtenberg, and all those that prepared and shipped isolates for the study, and thank the Wellcome Sanger Institute sequencing facility and the Wellcome Sanger Institute pathogens informatics team. Publisher Copyright: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

PY - 2021/7

Y1 - 2021/7

N2 - Background: The clonal diversity underpinning trends in multidrug resistant Escherichia coli causing bloodstream infections remains uncertain. We aimed to determine the contribution of individual clones to resistance over time, using large-scale genomics-based molecular epidemiology. Methods: This was a longitudinal, E coli population, genomic, cohort study that sampled isolates from 22 512 E coli bloodstream infections included in the Norwegian surveillance programme on resistant microbes (NORM) from 2002 to 2017. 15 of 22 laboratories were able to share their isolates, and the first 22·5% of isolates from each year were requested. We used whole genome sequencing to infer the population structure (PopPUNK), and we investigated the clade composition of the dominant multidrug resistant clonal complex (CC)131 using genetic markers previously reported for sequence type (ST)131, effective population size (BEAST), and presence of determinants of antimicrobial resistance (ARIBA, PointFinder, and ResFinder databases) over time. We compared these features between the 2002–10 and 2011–17 time periods. We also compared our results with those of a longitudinal study from the UK done between 2001 and 2011. Findings: Of the 3500 isolates requested from the participating laboratories, 3397 (97·1%) were received, of which 3254 (95·8%) were successfully sequenced and included in the analysis. A significant increase in the number of multidrug resistant CC131 isolates from 71 (5·6%) of 1277 in 2002–10 to 207 (10·5%) of 1977 in 2011–17 (p<0·0001), was the largest clonal expansion. CC131 was the most common clone in extended-spectrum β-lactamase (ESBL)-positive isolates (75 [58·6%] of 128) and fluoroquinolone non-susceptible isolates (148 [39·2%] of 378). Within CC131, clade A increased in prevalence from 2002, whereas the global multidrug resistant clade C2 was not observed until 2007. Multiple de-novo acquisitions of both blaCTX-M ESBL-encoding genes in clades A and C1 and gain of phenotypic fluoroquinolone non-susceptibility across the clade A phylogeny were observed. We estimated that exponential increases in the effective population sizes of clades A, C1, and C2 occurred in the mid-2000s, and in clade B a decade earlier. The rate of increase in the estimated effective population size of clade A (Ne=3147) was nearly ten-times that of C2 (Ne=345), with clade A over-represented in Norwegian CC131 isolates (75 [27·0%] of 278) compared with the UK study (8 [5·4%] of 147 isolates). Interpretation: The early and sustained establishment of predominantly antimicrobial susceptible CC131 clade A isolates, relative to multidrug resistant clade C2 isolates, suggests that resistance is not necessary for clonal success. However, even in the low antibiotic use setting of Norway, resistance to important antimicrobial classes has rapidly been selected for in CC131 clade A isolates. This study shows the importance of genomic surveillance in uncovering the complex ecology underlying multidrug resistance dissemination and competition, which have implications for the design of strategies and interventions to control the spread of high-risk multidrug resistant clones. Funding: Trond Mohn Foundation, European Research Council, Marie Skłodowska-Curie Actions, and the Wellcome Trust.

AB - Background: The clonal diversity underpinning trends in multidrug resistant Escherichia coli causing bloodstream infections remains uncertain. We aimed to determine the contribution of individual clones to resistance over time, using large-scale genomics-based molecular epidemiology. Methods: This was a longitudinal, E coli population, genomic, cohort study that sampled isolates from 22 512 E coli bloodstream infections included in the Norwegian surveillance programme on resistant microbes (NORM) from 2002 to 2017. 15 of 22 laboratories were able to share their isolates, and the first 22·5% of isolates from each year were requested. We used whole genome sequencing to infer the population structure (PopPUNK), and we investigated the clade composition of the dominant multidrug resistant clonal complex (CC)131 using genetic markers previously reported for sequence type (ST)131, effective population size (BEAST), and presence of determinants of antimicrobial resistance (ARIBA, PointFinder, and ResFinder databases) over time. We compared these features between the 2002–10 and 2011–17 time periods. We also compared our results with those of a longitudinal study from the UK done between 2001 and 2011. Findings: Of the 3500 isolates requested from the participating laboratories, 3397 (97·1%) were received, of which 3254 (95·8%) were successfully sequenced and included in the analysis. A significant increase in the number of multidrug resistant CC131 isolates from 71 (5·6%) of 1277 in 2002–10 to 207 (10·5%) of 1977 in 2011–17 (p<0·0001), was the largest clonal expansion. CC131 was the most common clone in extended-spectrum β-lactamase (ESBL)-positive isolates (75 [58·6%] of 128) and fluoroquinolone non-susceptible isolates (148 [39·2%] of 378). Within CC131, clade A increased in prevalence from 2002, whereas the global multidrug resistant clade C2 was not observed until 2007. Multiple de-novo acquisitions of both blaCTX-M ESBL-encoding genes in clades A and C1 and gain of phenotypic fluoroquinolone non-susceptibility across the clade A phylogeny were observed. We estimated that exponential increases in the effective population sizes of clades A, C1, and C2 occurred in the mid-2000s, and in clade B a decade earlier. The rate of increase in the estimated effective population size of clade A (Ne=3147) was nearly ten-times that of C2 (Ne=345), with clade A over-represented in Norwegian CC131 isolates (75 [27·0%] of 278) compared with the UK study (8 [5·4%] of 147 isolates). Interpretation: The early and sustained establishment of predominantly antimicrobial susceptible CC131 clade A isolates, relative to multidrug resistant clade C2 isolates, suggests that resistance is not necessary for clonal success. However, even in the low antibiotic use setting of Norway, resistance to important antimicrobial classes has rapidly been selected for in CC131 clade A isolates. This study shows the importance of genomic surveillance in uncovering the complex ecology underlying multidrug resistance dissemination and competition, which have implications for the design of strategies and interventions to control the spread of high-risk multidrug resistant clones. Funding: Trond Mohn Foundation, European Research Council, Marie Skłodowska-Curie Actions, and the Wellcome Trust.

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Gladstone RA, McNally A, Pöntinen AK, Tonkin-Hill G, Lees JA, Skytén K et al. Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17: a nationwide, longitudinal, microbial population genomic study. The Lancet Microbe. 2021 Jul;2(7):e331-e341. Epub 2021 May 10. doi: 10.1016/S2666-5247(21)00031-8

Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17: a nationwide, longitudinal, microbial population genomic study

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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