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Oxford University Lead: Nicole Stoesser

PHE co-lead: Matt Ellington

 

We aim to understand how healthcare associated and antimicrobial resistant infections can be affected by what happens on farms, and in both the general and hospital environment. Our strategy is to increase our understanding on what the important factors to drive AMR and HAI infections,  how these factors are influenced by different environments and how they are passed onto and disseminated in humans.  We hope this will provide understanding on how AMR genes are shared between humans, animals and the environment, identify what systems contribute to the to the spread of microbes in hospitals and work towards minimising this and optimise resistance prediction for certain microbes using whole genome sequencing and molecular techniques.

Project Updates 

Objectives – Contexts theme​

Short-term (years 1-2) 

Define AMR gene prevalence, dissemination and drivers amongst Enterobacterales

Medium-term (years 3-4) 

Design interventions to reduce the impact of the healthcare environment on AMR gene amplification and transmission​

​Define AMR genotype-phenotype correlations in Enterobacterales

Long-term (years 4-5) 

Combine genomic and epidemiological data to monitor key AMR gene reservoirs and transmission pathways and impact of interventions

Strategy/Aims – Contexts theme​

“Inside & outside” and “One Health” emphasis:​

  • Humans​
  • Farms and livestock​
  • External water/wastewater environments in general​
  • Hospital ward and wastewater environments​

Tackling Antimicrobial Resistance 2019-2024: The UK’s 5-year national action plan​

  • Better how AMR spreads between and among humans, the animals and the environment, and minimise its spread​
  • Improving Infection Prevention and Control (IPC)​

 

Project title 12:

AMR gene transmission in Enterobacterales Oxfordshire  

Project Leads: Katie Hopkins (PHE), Nicole Stoesser (OU), Researchers: Samuel Lipworth, Will Matlock, Manal AbuOun, Bede Constantinides 

Projected start date: April 2020 

We have now established unique datasets via the REHAB project to complete the analyses of both clonal and mobile genetic element-mediated AMR gene transmission across human (bloodstream infection), livestock and wastewater/lotic reservoirs in Oxfordshire, including: 828 complete Enterobacterales genomes and 2293 plasmids for the non-human compartments and ~1000 complete Enterobacterales genomes and ~2500 plasmids for the human compartment.

We plan to: 

  • Complete the development of a bioinformatics tool which provides a pipeline for the iterative evaluation of the genetic context around AMR genes from assembled genomes (“Flanker”), using a mash-based measure of similarity to assess relatedness in the flanking regions around AMR gene variants between sequenced isolates. 
  • Complete the comparative analysis, write-up and submission for publication of a sequencing analysis comparing the sequence data from the REHAB study with the Oxford Gram-negative bacteraemia surveillance programme. 
  • Complete the comparative analysis, write-up and submission for publication of a sequencing analysis comparing the Oxford Gram-negative bacteraemia surveillance programme isolates/plasmids with isolates/metagenomics derived from sinks in the John Radcliffe (JR) Hospital, Oxford. 

Results will inform plans for further sequencing of isolates from healthcare and/or natural environments in years 3-4. 

Key milestones and timescales: 

Mar 2021 - Write-up and submission for publication of the analysis of JR sink metagenomes/isolates and human BSI infection isolates  

Apr 2021 - Write-up and submission for publication of bioinformatics tool enabling comparison of flanking contexts of AMR genes and relatedness 

Jun 2021 - Write-up and submission for publication of comparison between human BSI sequence data and REHAB datasets 

 

Project title 13:

AMR gene transmission in Enterobacterales nationally and internationally  

Project Leads: Muna Anjum (APHA lead), Katie Hopkins (PHE), Nicole Stoesser (OU), Researchers: Samuel Lipworth, Will Matlock, Manal AbuOun, Bede Constantinides 

Expanding on project 12 above, we will pursue similar analyses to investigate AMR gene/strain transmission nationally and internationally by:  

  • Comparing the REHAB and Oxfordshire Gram-negative hybrid isolate assemblies, and short-read data for the Oxfordshire bacteraemia isolates, with existing isolate sequence collections from livestock across the UK; this work has been delayed due to the secondment of staff at APHA to SARS-CoV-2-related work. APHA is responsible for implementing EU AMR monitoring in zoonotic and indicator bacteria from healthy livestock (pig and poultry) on behalf of the UK government (includes both phenotypic and genotypic characterisation). WGS available from isolates in the national collection will be compared with those from livestock in REHAB to detect any similarities or differences that may occur in AMR profiles and resistance harbouring plasmids between national and regional levels. 
  • Completing an analysis comparing the genomic epidemiology, overlap and AMR gene sharing amongst Oxfordshire Gram-negative bloodstream infection sequences, national bacteraemia collections (BSAC, Cambridge University Hospitals) and publicly available global sequencing datasets. 
  • Completing an analysis comparing hospital environmental isolates in two different healthcare settings (Manchester and Oxford)  

Key milestones and timescales: 

Feb 2021 - Write-up and submission for publication of the comparative analysis of Oxfordshire, national and global bloodstream infection isolate sequencing datasets 

Jun 2021 - Write-up and submission for publication of the analysis of environmental isolates in two different healthcare settings 

Dec 2021 - Write-up and submission for publication of the comparative analyses of animal isolate datasets 

 

Project title 14:

Impact of sink design and wastewater infrastructure in hospitals on AMR gene dissemination in humans 

Project Leads: Ginny Moore (PHE lead), Nicole Stoesser (OU), Derrick Crook (OUResearchers: OU Post-doctoral Research Assistant, PHE DPhil student 

Several pilot projects are underway/planned to explore the potential for hospital wastewater sites/management to contribute to resistance dissemination in humans.

We will:  

  • Survey sink design across the entirety of all four Oxfordshire hospitals (including the geographically separated hospital at Banbury) to develop a sink design classification system, then test it in low and high CPE-prevalence hospitals nationally. 
  • Complete work sampling nine hospitals (sink waste trap water and drain swabs) in different regions of England - includes culture-based analyses and sequencing of samples to evaluate prevalence of Enterobacterales and carbapenem resistance genes (new component) 
  • Complete work evaluating the impact of a novel clinical handwash basin design (with anti-splash “fin” and redesigned drainage outlet) can reduce contaminated droplet dispersal from colonised waste traps/drains (new component) 
  • Submit data (culture/sequencing) that demonstrate that blockage events can result in transfer of drug resistant Enterobacterales from one sink to another (new component) 

These data will feed into controlled studies that will be evaluated in PHE’s model ward system (expected to be functioning in the second half of 2021) - a simulated ward environment where organism/AMR gene dissemination can be assessed in conjunction with possible interventions (e.g. cleaning, flushing strategies). 

Key milestones and timescales: 

May 2021 - Submission for publication of the evaluation on sink blockage 

Aug 2021 - Write-up and submission for publication of the analysis of novel handwash basin design 

Nov 2021 - Write-up and submission for publication of the analysis of sampling of nine hospitals 

Dec 2021 - Completion of survey of Oxfordshire hospitals and the sink design classification system, write-up, and publication 

 

Contexts Theme Publications

A genomic epidemiological study shows that prevalence of antimicrobial resistance in Enterobacterales is associated with the livestock host, as well as antimicrobial usage

AbuOun M, Jones H, Stubberfield E, Gilson D, Shaw LP, Hubbard ATM, Chau K, Sebra R, Peto TEA, Crook DW, Read DS, Gweon HS, Walker AS, Stoesser N, Smith RP, Anjum MF

https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.000630

 

Migration of Escherichia coli and Klebsiella pneumoniae Carbapenemase (KPC)-Producing Enterobacter cloacae through Wastewater Pipework and Establishment in Hospital Sink Waste Traps in a Laboratory Model System

Aranega-Bou P, Ellaby N, Ellington M, Moore G

https://www.mdpi.com/2076-2607/9/9/1868

 

A splash-reducing clinical handwash basin reduces droplet-mediated dispersal from a sink contaminated with Gram-negative bacteria in a laboratory model system

Aranega-Bou P, Cornbill C, Verlander N, Moore G

Please contact crookpm@ndm.ac.ox.uk for a copy of the paper.

 

Population-level faecal metagenomic profiling as a tool to predict antimicrobial resistance in Enterobacterales isolates causing invasive infections: An exploratory study across Cambodia, Kenya, and the UK

Auguet O, Niehus R, Gweon HS, Berkley JA, Waichungo J, Njim T, Edgeworth JD, Batra R, Chau K, Swann J, Walker AS, Peto TE, Crook DW, Lamble S, Turner P, Cooper BS, Stoesser N

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00190-5/fulltext

 

Genomic surveillance of Escherichia coli and Klebsiella spp. in hospital sink drains and patients

Constantinides B, Chau KK, Quan TP, Rodger G, Andersson MI, Jeffery K, Lipworth S, Hyun S, Peniket A, Pike G, Millo J, Byukusenge M, Holdaway M, Gibbons C, Mathers A, Crook D, Peto T, Walker A, Stoesser N

https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.000391

 

Reconciling the potentially irreconcilable? Genotypic and phenotypic amoxicillin-clavulanate resistance in Escherichia coli

Davies T, Stoesser N, Sheppard A, Abuoun M, Fowler P, Swann J, Quan P, Griffiths D, Vaugahn A, Morgan M, Phan H, Jeffery K, Andersson M, Ellington M, Ekelund O, Woodford N, Mathers A, Bonomo R, Crook D, Peto T, Anjum M, Walker S

Reconciling the Potentially Irreconcilable? Genotypic and Phenotypic Amoxicillin-Clavulanate Resistance in Escherichia coli | Antimicrobial Agents and Chemotherapy (asm.org)

 

Genomic dynamics of species and mobile genetic elements in a prolonged blaIMP-4-associated carbapenemase outbreak in an Australian hospital

Kizny GA, Phan H, Lipworth S, Cheong E, Gottlieb T, George S, Peto T, Mathers A, Walker A, Crook D, Stoesser N

https://academic.oup.com/jac/article/75/4/873/5710700

 

Ten years of population-level genomic Escherichia coli and Klebsiella pneumoniae serotype surveillance informs vaccine development for invasive infections

Lipworth S, Vihta K, Chau K, Kavanagh J, Davies T, George S,  Barker L, Vaughan A,  Anderson M, Jeffrey K, Oakley S, Morgan M, Peto T, Crook D, Walker A, Stoesser N

https://academic.oup.com/cid/article/73/12/2276/6067638

 

Ten-year longitudinal molecular epidemiology study of Escherichia coli and Klebsiella species bloodstream infections in Oxfordshire, UK

Lipworth S, Vihta K, Chau K, Barker L, George S, Kavanagh J, Davies T, Vaughan A, Andersson M, Jeffery K, Oakley S, Morgan M, Hopkins S, Peto TEA, Crook DW, Walker AS, Stoesser N

https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-021-00947-2

 

Epidemiology of Mycobacterium abscessus in England: an observational study

Lipworth S, Hough N, Weston N, Muller-Pebody B, Phin N, Myers R, Chapman S, Flight W, Alexander E, Smith E, Robinson E, Peto T, Crook D, Walker A, Hopkins S, Eyre D, Walker T

https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00128-2/fulltext

 

Optimized use of Oxford Nanopore flowcells for hybrid assemblies

Lipworth S, Pickford H, Sanderson N, Chau K, Kavanagh J, Barker L, Vaughan A, Swann J, Anderson M, Jeffery K, Morgan M, Peto T, Crook D, Stoesser N, Walker A

https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.000453

 

Antimicrobial resistance genes and clonal success in Escherichia coli isolates causing bloodstream infection

Lipworth S, Peto T, Crook D, Walker A, Stoesser N

https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00151-8/fulltext

 

Genomic network analysis of environmental and livestock F-type plasmid populations

Matlock W, Chau K, AbuOun M, Stubberfield E, Barker L, Kavanagh J, Pickford H, Gilson D, Smith R, Gweon H, Hoosdally S, Swann J, Sebra R, Bailey M, Peto T, Crook D, Anjum M, Read D, Walker A, Stoesser N, Shaw L, REHAB Consortium

https://www.nature.com/articles/s41396-021-00926-w

 

Flanker: a tool for comparative genomics of gene flanking regions

Matlock W, Lipworth S, Constantinides B, Peto T, Walker A, Crook D, Stoesser N

https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.000634

 

Risk factors associated with carbapenemase-producing Enterobacterales (CPE) positivity in the hospital wastewater environment

Park S, Parikh H, Vegesana K, Stoesser N, Barry K, Kotay S, Dudley S, Peto T, Crook D, Walker A, Mathers A

https://journals.asm.org/doi/10.1128/AEM.01715-20

 

Niche and local geography shape the pangenome of wastewater- and livestock-associated Enterobacteriaceae

Shaw L, Chau K, Kavanagh J, Abuoun M, Stubberfield E, Gweon HS, Barker L, Rodger G, Bowes MJ, Hubbard ATM, Pickford H, Swann J, Gilson D, Smith RP, Hoosdally SJ, Sebra R, Brett H, Peto TEA, Bailey MJ, Crook DW, Read DS, Anjum MF, Walker AS, Stoesser N

https://www.science.org/doi/10.1126/sciadv.abe3868