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

View ORCID ProfileTimothy J. Davies, Nicole Stoesser, Anna E Sheppard, Manal Abuoun, Philip Fowler, Jeremy Swann, T. Phuong Quan, David Griffiths, Alison Vaughan, Marcus Morgan, Hang TT Phan, Katie J Jeffery, Monique Andersson, Matt J Ellington, Oskar Ekelund, Neil Woodford, Amy J. Mathers, Robert A. Bonomo, Derrick W. Crook, Tim E.A. Peto, Muna F Anjum, A. Sarah Walker
doi: https://doi.org/10.1101/511402
Timothy J. Davies
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
bNational Institute for Health Research (NIHR) Health Protection Research Unit on Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, UK
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  • ORCID record for Timothy J. Davies
  • For correspondence: timothy.davies@ndm.ox.ac.uk
Nicole Stoesser
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
bNational Institute for Health Research (NIHR) Health Protection Research Unit on Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, UK
cOxford University Hospitals NHS Foundation Trust, Oxford, UK
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Anna E Sheppard
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
bNational Institute for Health Research (NIHR) Health Protection Research Unit on Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, UK
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Manal Abuoun
dBacteriology, Animal and Plant Health Agency, Surrey UK
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Philip Fowler
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
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Jeremy Swann
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
bNational Institute for Health Research (NIHR) Health Protection Research Unit on Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, UK
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T. Phuong Quan
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
bNational Institute for Health Research (NIHR) Health Protection Research Unit on Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, UK
eNIHR Biomedical Research Centre, Oxford, UK
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David Griffiths
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
eNIHR Biomedical Research Centre, Oxford, UK
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Alison Vaughan
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
eNIHR Biomedical Research Centre, Oxford, UK
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Marcus Morgan
cOxford University Hospitals NHS Foundation Trust, Oxford, UK
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Hang TT Phan
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
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Katie J Jeffery
cOxford University Hospitals NHS Foundation Trust, Oxford, UK
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Monique Andersson
cOxford University Hospitals NHS Foundation Trust, Oxford, UK
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Matt J Ellington
fAntimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, London UK
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Oskar Ekelund
gDepartment of Clinical Microbiology and the EUCAST Development Laboratory, Kronoberg Region, Central Hospital, Växjö, Sweden
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Neil Woodford
bNational Institute for Health Research (NIHR) Health Protection Research Unit on Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, UK
fAntimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, London UK
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Amy J. Mathers
hDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia, USA Clinical Microbiology, Department of Pathology, University of Virginia Health System, Charlottesville, Virginia, USA
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Robert A. Bonomo
iLouis Stokes Cleveland Veterans Affairs Medical Centre, Research Service, Cleveland, OH; Case Western Reserve University, Departments of Medicine, Biochemistry, Molecular Biology and Microbiology, Pharmacology, and Proteomics and Bioinformatics; CWRU-Cleveland VAMC Centre for Antimicrobial Resistance and Epidemiology (Case VA CARES); and Geriatric Research Education and Clinical Centers (GRECC), Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, OH
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Derrick W. Crook
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
bNational Institute for Health Research (NIHR) Health Protection Research Unit on Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, UK
cOxford University Hospitals NHS Foundation Trust, Oxford, UK
eNIHR Biomedical Research Centre, Oxford, UK
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Tim E.A. Peto
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
bNational Institute for Health Research (NIHR) Health Protection Research Unit on Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, UK
cOxford University Hospitals NHS Foundation Trust, Oxford, UK
eNIHR Biomedical Research Centre, Oxford, UK
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Muna F Anjum
dBacteriology, Animal and Plant Health Agency, Surrey UK
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A. Sarah Walker
aNuffield Department of Medicine, Oxford University, Oxford, United Kingdom
bNational Institute for Health Research (NIHR) Health Protection Research Unit on Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford, UK
eNIHR Biomedical Research Centre, Oxford, UK
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Abstract

Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 E. coli bloodstream infection isolates from Oxfordshire, UK, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity 23% (78/339)) but improved when genetic features associated with penicillinase hyper-production (e.g. promoter mutations, copy number estimates) were considered (sensitivity 82% (277/339); p<0.0001). Most discrepancies occurred in isolates with peri-breakpoint MICs. We investigated two potential causes; the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions.

Footnotes

  • Rewording of text and clarifications. Adding github repository for MIC data and code

  • https://github.com/TimothyJDavies/reconciling_the_potentially_irreconcilable/

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 06, 2020.
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Reconciling the potentially irreconcilable? Genotypic and phenotypic amoxicillin-clavulanate resistance in Escherichia coli
Timothy J. Davies, Nicole Stoesser, Anna E Sheppard, Manal Abuoun, Philip Fowler, Jeremy Swann, T. Phuong Quan, David Griffiths, Alison Vaughan, Marcus Morgan, Hang TT Phan, Katie J Jeffery, Monique Andersson, Matt J Ellington, Oskar Ekelund, Neil Woodford, Amy J. Mathers, Robert A. Bonomo, Derrick W. Crook, Tim E.A. Peto, Muna F Anjum, A. Sarah Walker
bioRxiv 511402; doi: https://doi.org/10.1101/511402
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Reconciling the potentially irreconcilable? Genotypic and phenotypic amoxicillin-clavulanate resistance in Escherichia coli
Timothy J. Davies, Nicole Stoesser, Anna E Sheppard, Manal Abuoun, Philip Fowler, Jeremy Swann, T. Phuong Quan, David Griffiths, Alison Vaughan, Marcus Morgan, Hang TT Phan, Katie J Jeffery, Monique Andersson, Matt J Ellington, Oskar Ekelund, Neil Woodford, Amy J. Mathers, Robert A. Bonomo, Derrick W. Crook, Tim E.A. Peto, Muna F Anjum, A. Sarah Walker
bioRxiv 511402; doi: https://doi.org/10.1101/511402

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