Diagnostic solutions for antimicrobial resistance MartinLlewelyn

BrightonandSussexUniversityHospitalsNHSTrustBrightonandSussexMedicalSchool

GailHaywardNIHRCommunityHealthcareMedTechandInvitroDiagnosticsCo-operative

UniversityofOxford

Antibiotic resistance and antibiotic use

• Antibioticresistance-aglobal,urgentthreattohumanhealth• Antibioticoveruseinhumansisakeydriverofantibioticresistance• Antibioticstewardship-means

• Or

• Prescribersandpatientsstrugglewithantimicrobialtreatmentdecisions

”asetofcoordinatedstrategiestoimprovetheuseofantimicrobialmedicationswiththegoaltoenhancepatienthealthoutcomes,reduceantibioticresistance,anddecreaseunnecessarycosts”

“…thelong-termeffectsofantimicrobialselection,dosage,anddurationoftreatmentonresistancedevelopmentshouldbeapartofeveryantimicrobialtreatmentdecision”1

1.McGowan,JEJr,;GerdingD."Doesantibioticrestrictionpreventresistance?"NewHorizon.1996.4(3):370–6.

A time-line of stewardship in the UK

Hospital antibiotic use in England

2010 2011 2012 2013 2014Piperacillin-tazobactam 100.0% 112.8% 130.4% 145.9% 161.7%Carbapenem(inpatients) 100.0% 113.6% 120.4% 130.6% 141.3%Totalantibiotics(inpatients) 100.0% 103.2% 107.8% 111.9% 115.3%

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

120.0%

140.0%

160.0%

180.0%

%CHANGEINDDDSPER1000INHABITANTS

PERDAYRELATIVETOYEAR2010

http://ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/esac-net-database/Pages/Antimicrobial-consumption-rates-by-country.aspx

ConsumptionofsystemicantibacterialsinthehospitalsectorinEurope2014

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/477962/ESPAUR_Report_2015.pdf

Totalandbroad-spectrumantibioticprescribingNHSEngland2010-2014

UK

CourtesyofDrKieranHand

A diagnostic solution?

Tacklingdrugresistantinfectionsglobally:anoverviewofourwork.ThereviewonAntimicrobialResistance.ChairedbyJimO’Neill

The current secondary care reality

The current secondary care reality

•  403consecutivepatientsprescribedantibioticsinacutemedicine

56(14%)hadapotentiallypathogenicorganismidentifiedinasamplesenttolab16oftheseresultswhichchangedantibiotictherapy10changedagent(6‘narrower’)5addedagent(inc1prolongedcourse)1increaseddoseInnoinstance,didpositivediagnostictestingreduceDDDantibioticexposure.

XXXXXXX

HamiltonW,PiresS-M,LippettS,GudkaV,CrossE,LlewelynM.FIS2017

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But only one part of the picture…

The Longitude Prize is a £10m prize fund that will reward a competitor that can develop a point–of–care diagnostic test that will conserve antibiotics for future generations and revolutionise the delivery of global healthcare. The test must be accurate, rapid, affordable and easy to use anywhere in the world.

Global drive for new diagnostics

Developer Sample,Technology Measurement Answer1 Becton,Dickinson Blood

DigitalimmunoassayPanelofcirculatinghostimmunebiomarkers Bacterialvsviralinfection

2 BrighamandWomen'sHospital

BreathGaschromatography

Volatilemetabolites Identificationofpneumoniaaetiology

3 FirstLightBiosciences

MultipleFluorescentimaging

Cellularandmoleculartargets Identificationofmicro-organisms,antibioticsusceptibility

4 DukeUniversity,Durham,

BloodGenetranscription

Immuneresponsegeneexpression Bacterialvsviralinfectionvsnon-infectiousaetiologies

5 PhilipsNorthAmerica

Blood(skinprick)Biomarker

NeutrophilLipocalin Bacterialvsviralinfection

6 ClickDiagnostics MultiplePCR

MultiplexPCRcartridge Identificationofmicro-organisms,antibioticsusceptibility

7 SpectralPlatforms BloodorurineProteinchemistry

Pathogeninteractionwithalbumin Bacterialvsviralinfection

8 AffinityBiosensor BloodCulture&rapidgrowthdetection

Microfluidicsensorthatcountsandweighsindividualmicrobes

IdentificationofkeyAMRpathogens,antibioticsusceptibility

9 UniversityofRochester

BloodGenetranscription

Respiratorytractspecific‘bio-signatures’ Bacterialvsviralinfection

10 YaleUniversity Nose/throatswabGenetranscription

Airwaycellresponsetoinfection Identificationofviralinfection

NIH Antimicrobial Resistance Diagnostic Test Challenge Semifinalists 2017

But there is a huge gap…

The case of Procalcitonin •  1980s Discoveredaspotentialbiomarkerofsmallcelllungcancer

•  1991 Investigatedasmarkerofacutelunginjury

•  1993 Firstreportofuseasbiomarkerofsepsis1

•  Subsequently…3000peer-reviewarticles,manyRCTs25meta-analysessince2009>300reviewarticles

•  NICEdiagnosticsguidance(2015):•  ‘….notenoughevidencetorecommendthatthesetestsareusedintheNHS.ButNICEhasrecommendedfurtherresearch…’

•  Currently(quite)widelyusedincriticalcaretoguidestopdecisionsinHAP/VAP1.AssicotMetalLancet1993;Feb27;341(8844):515-8.

Diagnostic tests or diagnostic strategies? • HowwilldiagnosticsfitintokeystrategiestocombatAMR?

DiagnosticstrategiestocombatAMR

Avoidingunnecessaryantibioticuse:Ø  Teststoruleoutbacterialorconfirmviral

infection

Identifyinghigh-riskpatients:Ø  TeststodetermineifanorganismiscausingdiseaseØ  Prognosticmarkers

Optimisingantibioticuse(escalation/de-escalation)Ø  Teststoidentifyspecificpathogens,characterise

susceptibility

Improvingdrugdevelopment:Ø  Toolstoaccuratelyidentifypatientsfortrials

PhysicianbehaviourPatientattitudes

RegulatoryandreimbursementfactorsOveragloballandscape

Fourdiagnosticstrategiesforbettertargetedantibioticuse.TheWellcomeTrust2016

Foresight Study on European Stakeholder Appraisal of Diagnostics

to Manage Antimicrobial Resistance

Antimicrobial Resistance Cross-Council Initiative (Grant Ref: MR/N014316/1) by the UK’s Biotechnology and Biological Sciences Research Council, Medical Research Council, and the Economic and Social Research Council.

InvolvingPolicymakersIndustryAcademiaDiagnosticiansHospitalcliniciansPrimarycarecliniciansPatients

EU-widestudytoassessprioritiesanddriversforAMRdiagnostics

UsingDetailedexpertinterviewsBy‘multi-criteriamapping’Web-basedsurvey

PatientsProfessionalGroups

’discretechoiceexperiments’

MCM asks highly expert individuals to appraise different system-wide levers to drive diagnostics

Enhancerevenues pullingdiagnosticfirmsintothemarkete.g.subsidiesFundR&D pushingtechnologicaladvancesGovernmentprovides stateprovisionofdiagnostictoolsIncentiviseuse encouragesdemande.g.pushingdiagnosticsinpathwaysMakepathways throughregulatorysystemsProtectmarkets topreserveprofitabilityovertime

•  Amethodologyusedinsocialsciencestolandscapingtherangeofopinionswhichexist•  Assessesstrengthofviews

•  Exploreswhydifferentstakeholdergroupsholddifferentviews•  Interviewswith49individuals•  Appraisingsixpolicyoptionsfordiagnosticmarketdevelopment

Bellamy, R., Chilvers, J., Vaughan, N. E., & Lenton, T. M. (2013). “Opening up” geoengineering appraisal: Multi-Criteria Mapping of options for tackling climate change. Global Environmental Change, 23(5), 926–937. doi:10.1016/j.gloenvcha.2013.07.011

MCM asks key opinion leaders to appraise different system-wide levers to drive diagnostics Enhancerevenues pullingindustryintothemarketFundR&D pushingtechnologicaladvancesGovernmentprovides stateprovisionofdiagnostictoolsIncentiviseuse encouragesdemandMakepathways pushingindustrywithevidenceofmarketopportunityProtectmarkets pullingindustryintothemarket

Pessimistic Optimistic

1

2

3

DCE elicited public preferences for rapid diagnostic

Germ

any

Spain

France

Greece

Italy

Nethe

rland

s

UK

Germ

any

Spain

France

Greece

Italy

Nethe

rland

s

UK

Germ

any

Spain

France

Greece

Italy

Nethe

rland

s

UK

Speed Convenience Confidence

Strengthofp

reference

0

60

11

1 11

11

2

2

2

2

22

2

33 3

3

3

3

3

Mean €90.72 €132.01 €126.48 €98.30 €90.83 €118.22 £63.13

DE ES FR GR IT NL UK

Willingnesstopay n=158 n=142 n=129 n=127 n=125 n=125 n=165

Physician behaviour / patient attitudes •  An88yearoldwomanisadmittedfromanursinghomewithhypoactivedelirium.CRP53,?crepesL-base.StartedonantibioticsforLRTI.Sputumnotavailable/sentforculture.Day3‘fluApositive.Improving.Dischargedtocomplete5/7treatment.

DiagnosticstrategiestocombatAMR

Avoidingunnecessaryantibioticuse:Ø  Teststoruleoutbacterialorconfirmviral

infection

Identifyinghigh-riskpatients:Ø  TeststodetermineifanorganismiscausingdiseaseØ  Prognosticmarkers

Optimisingantibioticuse(escalation/de-escalation)Ø  Teststoidentifyspecificpathogens,characterise

susceptibility

Improvingdrugdevelopment:Ø  Toolstoaccuratelyidentifypatientsfortrials

• Whichdiagnosticstrategywouldavoidthisantibioticoveruse?

Diagnostic solutions for antimicrobial resistance • Vitaltoguideantibiotictreatmentmoreprecisely• CurrentlymuchworkfocusesonR+D•  Littleworkontranslationintodiagnosticpractice

•  Developmentofdemandandeasingroutestomarketmaybemostimportant

•  Viewsmayvarybetweenmarkets

• Realitiesofimplementationintodiagnosticpathwaysareverychallenginggivenprescriberbehaviourandpatientexpectations

Acknowledgements

•  TheForesightStudyteam• MichaelHopkins•  FrederiqueBone•  JosieCoburn• GraceHampden•  JorgeMestreFerrandiz