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.
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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