Rapid Diagnostics to tackle AMRWhat we have learned recently

Till T. BachmannDivision of Infection and Pathway Medicine,

Edinburgh Medical School: Biomedical Sciences, University of Edinburgh

BSAC Spring Conference 2019Global views, local problems: Innovative solutions to AMR and infection challenges

21 - 22 March 2019, International Convention Center, Birmingham

#BSAC2019

Introduction & Contact

Till T. Bachmann, PhD FRSB• Deputy Head of Infection Medicine• Reader in Personalised Medicine in Infectious Diseases• Programme Director Clinical Microbiology and Infectious Diseases• University of Edinburgh Programme Director Zhejiang University –

University of Edinburgh Institute Dual PhD

Infection MedicineUniversity of Edinburgh Medical SchoolChancellor's Building49 Little France CrescentEdinburgh EH16 4SB

T: +44 (0)131 242 9438till.bachmann@ed.ac.ukwww.pathwaymedicine.ed.ac.uk@BachmannTill@AMR_DxC @EdinCMID 2

Variability of Antibiotic Prescription for Febrile Children

Antibiotic prescription for febrile children in European emergency departments: a cross-sectional, observational study. van de Maat J, van de Voort E, Mintegi S, Gervaix A, Nieboer D, Moll H, Oostenbrink R; Research in European Pediatric Emergency Medicine study group. Lancet Infect Dis. 2019 Feb 28. pii: S1473-3099(18)30672-8

https://www.theguardian.com/society/2013/jun/25/a-and-e-emergency-medicine

Diagnostics and Drivers of AMR

Quantifying drivers of antibiotic resistance in humans: a systematic review. Chatterjee A, Modarai M, Naylor NR, Boyd SE, Atun R, Barlow J, Holmes AH, Johnson A, Robotham JV. Lancet Infect Dis. 2018 Dec;18(12):e368-e378.

Unmet Need in Clinical Microbiology

5

Pathogen Drug Resistance

Therapy

Rapid Diagnostic• Therapy Decision Support• Patient Management• Surveillance• Drug Development

http://amr-review.org

“I call on the governments of the richest countries to

mandate now that by 2020, all antibiotic prescriptions will need to be informed by up-to-date surveillance information

and a rapid diagnostic test wherever one exists.”

AMR Review May 19, 2016 – Tackling Drug-Resistant Infections Globally: final report and

recommendations For Dx: UK AMR Diagnostics Collaborative

“… be able to report on the percentage of

prescriptions supported by a

diagnostic test or decision support tool

by 2024.“

The Diagnostic Spectrum in Clinical Microbiology

Phenotypic • Gram staining• Culture• Biochemistry

Non phenotypic• Immunoassays• Molecular• Mass Spec• Imaging• Sequencing

Host Response • Biomarkers• Gene expression

Specimen - CultureWhole Blood - Blood Culture

Automation, Integration, Sample to AnswerID, ID/AST, AMR

Lab - POCT

Systematic Review of Existing AMR Diagnostic Technologies

• Overview of the diagnostic technologies that improve the appropriate prescribing of antibiotics

• Comprehensive search of the literature and is divided into applications relevant to primary and secondary care settings

• 69 technologies were assessed in detail

• Lack of progress in developing robust evidence that will impact on practice

Position Paper on Anti-Microbial Resistance Diagnostics, June 2015, Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford

WHO Essential Diagnostics List

http://www.who.int/news-room/detail/15-05-2018-first-ever-who-list-of-essential-diagnostic-tests-to-improve-diagnosis-and-treatment-outcomes

I EDL for primary health careI.a General IVDs for PHC– Haematology– Clinical Chemistry and immunoassays– Blood transfusions– Serology– Microbiology, mycology and parasitologyI.b Disease-specific IVDs for PHC– Hepatitis B– Hepatitis C– HIV– Malaria– Tuberculosis– Syphilis

II EDL for health care facilities with clin laboratoriesII.a General IVDs for health care facilities with clinical laboratories – Clinical chemistry and immunoassay– Blood transfusion– Serology– Microbiology, mycology and parasitology– HaematologyII.b Disease-specific IVDs for HC facilities with clin. laboratories– Hepatitis B– Hepatitis C– HIV– Malaria– Tuberculosis– HPV– Syphilis

www.biocartis.com

Some Molecular Diagnostic Systems in Use or With Potential for Infectious Disease Dx

www.curetis.com

www.molecular.roche.com

www.enigmadiagnostics.com

www.epistem.co.uk

www.check-points.com

www.optigene.co.uk

www.micronics.net

www.rheonix.com

www.dnae.co.uk

www.meridianbioscience.co.ukwww.alere-i.com

www.optigene.co.uk www.alere.com

www.path.org

www.quantumdx.com

www.daktaridx.com www.quidel.com www.twistdx.co.uk www.fcubed.biz

www.me-med.comwww.atlasgenetics.com

www.stat-dx.com

www.cepheid.com www.chipcare.ca

www.xagenic.com

gbscience.com

www.bigteclabs.com

www.biomerieux-diagnostics.com

www.drw-ltd.com nanoporetech.com

spindiag.de

www.nanosphere.com

www.genmarkdx.com

www.bosch-vivalytic.com

Where are we today?

• Empiric treatment is the norm

• Lack of adoption of new diagnostics• Diagnostic stewardship

• Challenge Prizes• Public funding• Start-ups

Till

T. B

achm

ann,

The

Uni

vers

ity o

f Edi

nbur

gh 2

018

Runners Up:• ImmunoPoC (TNF-related apoptosis-inducing ligand (TRAIL) + Interferon gamma-

induced protein-10 (IP10)+ C-reactive protein (CRP)) (MeMed Diagnostics, Israel; University Medical Centre Utrecht, The Netherlands; Frog Design, Italy)

• PulmoCheck (Dr Andreas Paar kg, Austria; Synovo GmBH, Germany; StichtingMedisch Centrum Twente, The Netherlands)

Winner: Minicare HNL• Human Neutrophil Lipocalin (HNL) • Philips Electronics, Handheld Diagnostics, NL• P&M Venge AB

http://ec.europa.eu/research/horizonprize/index.cfm

A £8 million global prize that will reward a transformative, rapid, accurate, and affordable point-of-care diagnostic test that can significantly reduce antibiotic misuse or overuse, anywhere in the world.

£10 Million Prize Fund£8 Million payout

Ultimately 1 Winner

First past the post

Funded by Nesta & InnovateUK

What do competitors need to do to win?

A rapid, point-of-care diagnostic test to reduce inappropriate antibiotic prescribing that is accurate, affordable and impactful globally

Multiple

Sepsis

UTI

RTI TB Other

Figure: Till Bachmann

Antimicrobial Resistance Rapid, Point-of-Care Diagnostic Test Challenge Competition ($20 million) - Semi-Finalists (74à10) and Finalists (20à5)

• Antimicrobial Resistance Rapid, Point-of-Need Diagnostic Test ChallengeRichard Anderson, Becton, Dickinson and Company, Franklin Lakes, New Jersey

• Breath volatile metabolites for the rapid identification of pneumonia etiologySophia Koo, Brigham and Women's Hospital, Boston Massachusetts

• First Light's MultiPath platformDon Straus, First Light Biosciences, Inc., Bedford, Massachusetts

• Host gene expression to classify viral and bacterial infection using rapid multiplex PCREphraim Tsalik, Duke University, Durham, North Carolina

• Minicare HNL: Point-of-care detection of bacterial infections to curb unnecessary use of antibioticsJoe Frassica, Philips North America, Cambridge, Massachusetts

• Patient-side, disposable, molecular PCR diagnostic device for STI and Antimicrobial Resistance DetectionGregory Loney, Click Diagnostics, Inc., San Jose, California

• Rapid AMR Test using Spectral Platforms’ TechnologyRavi Kant Verma, Spectral Platforms, Monrovia, California

• Ultra-Rapid Phenotypical AST by Microbe Mass MeasurementKen Babock, Affinity Biosensor, Santa Barbara, California

• Transcriptional Profiling to Distinguish Bacterial and Viral Respiratory InfectionAnn Falsey, University of Rochester, Rochester, New York

• Yale's One Step, Rapid in vitro Diagnostic SystemEllen Foxman of Yale University, New Haven, Connecticut

• Fully automated pathogen ID and AST directly from whole blood and urineVincent G. Gau, GeneFluidics

• Single Cell Biometric Analysis for Rapid ID/ASTKyle Fieleke, Institution: Klaris Diagnostics

https://dpcpsi.nih.gov/AMRChallenge/Finalists

Joint Programming Initiative on AMR Transnational Working Group on Rapid Diagnostics

• Coordinator Till Bachmann, University of Edinburgh

• 50 partners globally, 2017/18

• Identify barriers for development and implementation of rapid diagnostic tests to tackle AMR

http://www.jpiamr.eu/ http://www.ed.ac.uk/pathway-medicine/antimicrobial-resistance/jpiamr-amrrdt

van Belkum A, Bachmann TT, Lüdke G, Lisby JG, Kahlmeter G, Mohess A, Becker K, Hays JP, Woodford N, Mitsakakis K, Moran-Gilad J, Vila J, Peter H, Rex JH, Dunne WM Jr; JPIAMR AMR-RDT Working Group on Antimicrobial Resistance and Rapid Diagnostic Testing. Nat Rev Microbiol. 2019 Jan;17(1):51-62.https://www.nature.com/articles/s41579-018-0098-9 https://www.nature.com/articles/d41586-018-07031-7 https://www.jpiamr.eu/in-nature-developmental-roadmap-for-antimicrobial-susceptibility-testing-systems/

Developmental roadmap for antimicrobial susceptibility testing systems

‘The successful uptake and sustainability of rapid infectious disease

and antimicrobial resistance point-of-care testing requires a complex

‘mix-and-match’ implementation package’

Hays JP, Mitsakakis K, Luz S, van Belkum A, Becker K, van den Bruel A, Harbarth S, Rex JH, Simonsen GS, Werner G, Di Gregori V, Lüdke G, van Staa T, Moran-Gilad J, Bachmann TT; JPIAMR AMR-RDT consortium, Eur J Clin Microbiol Infect Dis. 2019 Feb 2

http://www.pulsetoday.co.uk/news/commissioning/commissioning-topics/prescribing/pharmacies-to-offer-strep-throat-swab-testing-and-on-the-spot-antibiotics/20037824.article https://www.nice.org.uk/advice/mib145

Are new, better tests possible?

Evaluation of Performance of Direct from Blood Testing

Substantial diagnostic impact of blood culture independent molecular methods in bloodstream infections: Superior performance of PCR/ESI-MS. Makristathis A, Harrison N, Ratzinger F, Kussmann M, Selitsch B, Forstner C, Hirschl AM, Burgmann H. Sci Rep. 2018 Oct 30;8(1):16024.

cfDNA as Novel Markers for UTIs

Urinary cell-free DNA is a versatile analyte for monitoring infections of the urinary tract. Burnham P, Dadhania D, Heyang M, Chen F, Westblade LF, Suthanthiran M, Lee JR, De Vlaminck I. Nat Commun. 2018 Jun 20;9(1):2412.

Target Amplification Free Molecular Detection

• EIS - Electrochemical Impedance Spectroscopy

• How easily can an electroactive substance reach electrode surface?

• Label free & Amplification free• Small AC potential at different

frequencies à current response àimpedance

• Functionalisation introduces specificity

• Platform technology

Electrode

Amplification Free Detection of Plasmid encoded NDM

Amplification-free direct detection of NDM-1 plasmid DNA. Online EIS detection assay plotshowing Rct change on P7 functionalised electrodes normalised to Rct change onnegative control PNA functionalised electrode over time.

0 10 20 30 40 50

1.0

1.5

2.0

2.5

3.0

3.5

dRct

ND

M-1

PN

A/ d

Rct

Neg

ativ

e C

ontro

l PN

A

Time [min]

20 nM NDM-1 Plasmid 50 nM NDM-1 Plasmid 92 nM NDM-1 plasmid

• Direct amplification-free detection of NDM-1 plasmid DNA extracted fromCitrobacter freundii clinical isolate

• DNase treatment• First example of direct EIS-based plasmid detection

Huang JM, Henihan G, Macdonald D, Michalowski A, Templeton K, Gibb AP, Schulze H, Bachmann TT (2015) Rapid Electrochemical Detection of New Delhi Metallo-beta-lactamase Genes To Enable Point-of-Care Testing of Carbapenem-Resistant Enterobacteriaceae. Anal. Chem. 87 (15), 7738-7745.

Electrochemical Impedance Spectroscopy for POCTOne Detection Technology – Many Targets

mecA, NDM-1 PCR products

MRSA gDNA Pathogen rRNA[http://www.bio.nite.go.jp/dogan/]

Corrigan, D. K.; Schulze, H.; Henihan, G.; Hardie, A.; Ciani, I.; Giraud, G.; Terry, J. G.; Walton, A. J.; Pethig, R.; Ghazal, P.; Crain, J.; Campbell, C. J.; Templeton, K. E.; Mount, A. R.; Bachmann, T. T. Development of a PCR-free electrochemical point of care test for clinical detection of methicillin resistant Staphylococcus aureus (MRSA). Analyst 2013, 138 (22), 6997-7005.

Corrigan, D. K.; *, Schulze, H.; *, Henihan, G.; Ciani, I.; Giraud, G.; Terry, J. G.; Walton, A. J.; Pethig, R.; Ghazal, P.; Crain, J.; Campbell, C. J.; Mount, A. R.; Bachmann, T. T. Impedimetric detection of single-stranded PCR products derived from methicillin resistant Staphylococcus aureus (MRSA) isolates. Biosens. Bioelectron. 2012, 34 (1), 178-184.Huang JM, Henihan G, Macdonald D, Michalowski A, Templeton K, Gibb AP, Schulze H, Bachmann TT. Rapid Electrochemical Detection of New Delhi Metallo-beta-lactamase Genes To Enable Point-of-Care Testing of Carbapenem-Resistant Enterobacteriaceae. Anal. Chem. 2015, 87 (15), 7738-7745.

[Behrens S. et al. (2003) Appl.Env.Microbiol. 69, 1748-58]

Grace Henihan*, Holger Schulze*, Ilenia Ciani, Damion Corrigan, Gerard Giraud, Jonathan G. Terry, Colin J. Campbell, Anthony J. Walton, Jason Crain, Ronald Pethig, Peter Ghazal, Andrew R. Mount and Till T. Bachmann. Label- and amplification-free electrochemical detection of bacterial ribosomal RNA. Biosens. Bioelectron. 2016 DOI: http://dx.doi.org/10.1016/j.bios.2016.03.037.

TREM-1, MMP9 protein infection biomarker

Ciani, I.; Schulze, H.; Corrigan, D. K.; Henihan, G.; Giraud, G.; Terry, J. G.; Walton, A. J.; Pethig, R.; Ghazal, P.; Crain, J.; Campbell, C. J.; Bachmann, T. T.; Mount, A. R. Development of immunosensors for direct detection of three wound infection biomarkers at point of care using electrochemical impedance spectroscopy. Biosens. Bioelectron. 2012, 31 (1), 413-418.

microRNAOngoing, In collaboration with James W. Dear, University of Edinburgh

Homo Serine Lactone (HSL) quorum sensing biomarker

Ciani, I.; Schulze, H.; Corrigan, D. K.; Henihan, G.; Giraud, G.; Terry, J. G.; Walton, A. J.; Pethig, R.; Ghazal, P.; Crain, J.; Campbell, C. J.; Bachmann, T. T.; Mount, A. R. Development of immunosensors for direct detection of three wound infection biomarkers at point of care using electrochemical impedance spectroscopy. Biosens. Bioelectron. 2012, 31 (1), 413-418.

Phenotypic AST by Hydrodynamic Trapping

Multiparameter antibiotic resistance detection based on hydrodynamic trapping of individual E. coli. Pitruzzello G, Thorpe S, Johnson S, Evans A, Gadêlha H, Krauss TF. Lab Chip. 2019

Phenotypic AST by Deep Learning

Phenotypic Antimicrobial Susceptibility Testing with Deep Learning Video Microscopy. Yu H, Jing W, Iriya R, Yang Y, Syal K, Mo M, Grys TE, Haydel SE, Wang S, Tao N. Anal Chem. 2018 May 15;90(10):6314-6322

Phenotypic AST and Detection of Heteroresistance

AU Lyu, FJ Pan, M Patil, S Wang, JH Matin, AC Andrews, JR Tang, SKYAF Lyu, Fengjiao Pan, Ming Patil, Sunita Wang, Jing-Hung Matin, A. C. Andrews, Jason R. Tang, Sindy K. Y.TI Phenotyping antibiotic resistance with single-cell resolution for the detection of heteroresistanceSO SENSORS AND ACTUATORS B-CHEMICAL

Detection of Antibiotics - Towards simpler TDM?

Ultratrace antibiotic sensing using aptamer/graphene-based field-effect transistors. Chen X, Liu Y, Fang X, Li Z, Pu H, Chang J, Chen J, Mao S. Biosens Bioelectron. 2019 Feb 1;126:664-671.

Summary

• Diagnostics is urgently needed to tackle AMR

• Many great technology solutions• Implementation barriers

• Challenge Prizes• Academic Research• Innovation tomorrow

“Without diagnostics, medicine is blind”Alain Mérieux, President, Fondation Mérieux

http://www.kiwimagonline.com/2013/01/keep-an-eye-out-for-these-common-health-problems/

Many Thanks for Your Attention

Questions?