Diagnostic solutions for antimicrobial resistance Martin Llewelyn Brighton and Sussex University Hospitals NHS Trust Brighton and Sussex Medical School Gail Hayward NIHR Community Healthcare MedTech and In vitro Diagnostics Co-operative University of Oxford
Antibiotic resistance and antibiotic use Antibiotic resistance - a global, urgent threat to human health Antibiotic overuse in humans is a key driver of antibiotic resistance Antibiotic stewardship - means Or a set of coordinated strategies to improve the use of antimicrobial medications with the goal to enhance patient health outcomes, reduce antibiotic resistance, and decrease unnecessary costs the long-term effects of antimicrobial selection, dosage, and duration of treatment on resistance development should be a part of every antimicrobial treatment decision 1 Prescribers and patients struggle with antimicrobial treatment decisions 1. McGowan, JE Jr,; Gerding D. "Does antibiotic restriction prevent resistance?" New Horizon. 1996. 4 (3): 370 6.
A time-line of stewardship in the UK
Hospital antibiotic use in England Total and broad-spectrum antibiotic prescribing NHS England 2010-2014 Consumption of systemic antibacterials in the hospital sector in Europe 2014 180.0% 160.0% UK 140.0% % CHANGE IN DDDS PER 1000 INHABITANTS PER DAY RELATIVE TO YEAR 2010 120.0% 100.0% 80.0% 60.0% 40.0% 20.0% 0.0% 2010 2011 2012 2013 2014 Piperacillin-tazobactam 100.0% 112.8% 130.4% 145.9% 161.7% Carbapenem (inpatients) 100.0% 113.6% 120.4% 130.6% 141.3% Total antibiotics (inpatients) 100.0% 103.2% 107.8% 111.9% 115.3% https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/477962/ ESPAUR_Report_2015.pdf http://ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/esacnet-database/pages/antimicrobial-consumption-rates-by-country.aspx Courtesy of Dr Kieran Hand
A diagnostic solution? Tackling drug resistant infections globally: an overview of our work. The review on Antimicrobial Resistance. Chaired by Jim O Neill
The current secondary care reality
The current secondary care reality 403 consecutive patients prescribed antibiotics in acute medicine XXXXXXX 56 (14%) had a potentially pathogenic organism identified in a sample sent to lab XX 16 of these results which changed antibiotic therapy 10 changed agent (6 narrower ) 5 added agent (inc 1 prolonged course) 1 increased dose In no instance, did positive diagnostic testing reduce DDD antibiotic exposure. Hamilton W, Pires S-M, Lippett S, Gudka V, Cross E, Llewelyn M. FIS 2017
But only one part of the picture
Global drive for new diagnostics 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.
NIH Antimicrobial Resistance Diagnostic Test Challenge Semifinalists 2017 Developer Sample, Technology Measurement Answer 1 Becton, Dickinson Blood Panel of circulating host immune biomarkers Bacterial vs viral infection Digital immunoassay 2 Brigham and Women's Hospital Breath Gas chromatography Volatile metabolites Identification of pneumonia aetiology 3 First Light Biosciences Multiple Fluorescent imaging 4 Duke University, Blood Durham, Gene transcription 5 Philips North Blood (skin prick) America Biomarker 6 Click Diagnostics Multiple PCR 7 Spectral Platforms Blood or urine Protein chemistry 8 Affinity Biosensor Blood Culture & rapid growth detection 9 University of Rochester Blood Gene transcription 10 Yale University Nose / throat swab Gene transcription Cellular and molecular targets Immune response gene expression Neutrophil Lipocalin Multiplex PCR cartridge Pathogen interaction with albumin Microfluidic sensor that counts and weighs individual microbes Respiratory tract specific bio-signatures Airway cell response to infection Identification of micro-organisms, antibiotic susceptibility Bacterial vs viral infection vs non-infectious aetiologies Bacterial vs viral infection Identification of micro-organisms, antibiotic susceptibility Bacterial vs viral infection Identification of key AMR pathogens, antibiotic susceptibility Bacterial vs viral infection Identification of viral infection
But there is a huge gap
The case of Procalcitonin 1980s 1991 Discovered as potential biomarker of small cell lung cancer Investigated as marker of acute lung injury 1993 First report of use as biomarker of sepsis 1 Subsequently 3000 peer-review articles, many RCTs 25 meta-analyses since 2009 >300 review articles NICE diagnostics guidance (2015):. not enough evidence to recommend that these tests are used in the NHS. But NICE has recommended further research Currently (quite) widely used in critical care to guide stop decisions in HAP/VAP 1. Assicot M et al Lancet 1993; Feb 27;341(8844):515-8.
Diagnostic tests or diagnostic strategies? How will diagnostics fit into key strategies to combat AMR? Avoiding unnecessary antibiotic use: Ø Tests to rule out bacterial or confirm viral infection Diagnostic strategies to combat AMR Identifying high-risk patients: Ø Tests to determine if an organism is causing disease Ø Prognostic markers Optimising antibiotic use (escalation/de-escalation) Ø Tests to identify specific pathogens, characterise susceptibility Improving drug development: Ø Tools to accurately identify patients for trials Regulatory and reimbursement factors Physician behaviour Patient attitudes Over a global landscape Four diagnostic strategies for better targeted antibiotic use. The Wellcome Trust 2016
Foresight Study on European Stakeholder Appraisal of Diagnostics to Manage Antimicrobial Resistance EU-wide study to assess priorities and drivers for AMR diagnostics Involving Policy makers Industry Academia Diagnosticians Hospital clinicians Primary care clinicians Patients Using Detailed expert interviews By multi-criteria mapping Web-based survey Patients Professional Groups discrete choice experiments 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.
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 highly expert individuals to appraise different system-wide levers to drive diagnostics A methodology used in social sciences to landscaping the range of opinions which exist Assesses strength of views Explores why different stakeholder groups hold different views Interviews with 49 individuals Appraising six policy options for diagnostic market development Enhance revenues pulling diagnostic firms into the market e.g. subsidies Fund R&D Government provides Incentivise use Make pathways Protect markets pushing technological advances state provision of diagnostic tools encourages demand e.g. pushing diagnostics in pathways through regulatory systems to preserve profitability over time
MCM asks key opinion leaders to appraise different system-wide levers to drive diagnostics Enhance revenues Fund R&D Government provides Incentivise use Make pathways opportunity Protect markets Pessimistic pulling industry into the market pushing technological advances state provision of diagnostic tools encourages demand pushing industry with evidence of market pulling industry into the market 3 2 Optimistic 1
DCE elicited public preferences for rapid diagnostic Strength of preference 60 3 3 3 3 1 2 1 1 2 1 2 2 1 2 2 1 2 1 3 0 Germany Spain France 3 Greece Italy 3 Netherlands UK Germany Spain France Greece Italy Netherlands UK Germany Spain France Greece Italy Netherlands UK Speed Convenience Confidence DE ES FR GR IT NL UK Willingness to pay n = 158 n = 142 n = 129 n = 127 n = 125 n = 125 n = 165 Mean 90.72 132.01 126.48 98.30 90.83 118.22 63.13
Physician behaviour / patient attitudes An 88 year old woman is admitted from a nursing home with hypoactive delirium. CRP 53,?crepes L-base. Started on antibiotics for LRTI. Sputum not available/sent for culture. Day 3 flu A positive. Improving. Discharged to complete 5/7 treatment. Avoiding unnecessary antibiotic use: Ø Tests to rule out bacterial or confirm viral infection Diagnostic strategies to combat AMR Identifying high-risk patients: Ø Tests to determine if an organism is causing disease Ø Prognostic markers Optimising antibiotic use (escalation/de-escalation) Ø Tests to identify specific pathogens, characterise susceptibility Improving drug development: Ø Tools to accurately identify patients for trials Which diagnostic strategy would avoid this antibiotic overuse?
Diagnostic solutions for antimicrobial resistance Vital to guide antibiotic treatment more precisely Currently much work focuses on R+D Little work on translation into diagnostic practice Development of demand and easing routes to market may be most important Views may vary between markets Realities of implementation into diagnostic pathways are very challenging given prescriber behaviour and patient expectations
Acknowledgements The Foresight Study team Michael Hopkins Frederique Bone Josie Coburn Grace Hampden Jorge Mestre Ferrandiz