Where are we with AMR? – the human perspective Dr Nick Brown 17 November 2018

‘It is not difficult to make microbes resistant to penicillin in the Laboratory…and the same thing has occasionally happened in the body. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.’ Alexander Fleming Nobel Lecture, 11 December 1945

Darwinian ‘survival of the fittest’ Resistant organism in susceptible population Susceptible cells killed by antibiotic Resistant progeny grow Antibiotics kill susceptible bacteria; resistant ones survive Level of antibiotic use affects the prevalence of resistance Slide: US Centers for Disease Control & Prevention (CDC)

Resistance surveillance 1959 Staphylococcus aureus, Seattle 40% isolates resistant to 4 or more antibiotics 85% resistant to penicillin and streptomycin 60% resistant to tetracycline 43% resistant to erythromycin 28% resistant to chloramphenicol Bulger Ann Int Med 1968; 69: 1099-1108

The UK AMR Strategy: a tripartite approach A One Health approach: PREVENT infection prevention and control PRESERVE existing antibiotics through stewardship programmes that promote rational prescribing and better use of existing and new rapid diagnostics PROMOTE the development of new antimicrobials, new approaches and better diagnostics. Underpinned by: Surveillance Research and Development Education, training and awareness International collaboration

Tackling Antimicrobial Resistance needs to be firmly established as a 'top five policy priority' for the Government Pharmaceutical market failure in antimicrobial development Rapid review and withdrawal of clinically unnecessary secondary care prescribing Reduce antimicrobial use in animals, particularly for prophylaxis or metaphylaxis Antimicrobials and the environment - establish safe systems for disposal

Committee on Science and Technology - Seventh Report House of Lords Committee on Science and Technology - Seventh Report ‘This enquiry has been an alarming experience, which leaves us convinced that resistance to antibiotics and other anti-infective agents constitutes a major threat to public health, and ought to be recognised as such more widely than it is at present.’ Lord Soulsby of Swaffham Prior Chairman 17 March 1998 http://www.parliament.the-stationery-office.co.uk

Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia reports (mandatory reporting scheme): England Source: Public Health England

Lots of ‘stuff’ going on 2003 IDSA: “Bad Bugs, No Drugs” 2009: (EU) Swedish presidency “Innovative Incentives for Effective Antibacterials” 2011: WHO World Health day on AMR “No action today, no cure tomorrow” 2011: (EU) ND4BB programme Discovery & Development 2011 (US & EU) FDA & EMA A steady stream of new guidance 2012: (US) GAIN Act 2013: (EU) Chatham House Conference “Antimicrobial resistance: Incentivising Change Towards a Global Solution” 2014: (US) PCAST Report 2016: UN General Assembly resolution

70 Years of Antibiotics and Resistance Development of new antibiotic Emergence of resistance Lets Talk Antibiotic Resistance

The are only around 40 candidate antibiotics in clinical development The are only around 40 candidate antibiotics in clinical development. Only 6 are expected to be licenced before 2024 In contrast, over 170 diabetes drugs and 700 cancer drugs are in various stages of development https://www.newstatesman.com/sites/default/files/ns_msd_supplement_nov_2017.pdf

Key factors impacting the net present value (NPV) of a pharmaceutical product LOSSES

Characteristics of a commercially successful antibiotic versus those required Broad spectrum Large volume Primary care Targeted Small volume Specialty/secondary care

De-linkage as a key principle Pipeline coordinators: governmental or non-profit organizations that closely track the antibiotic pipeline, identify gaps, and actively support R&D projects both financially and technically. Market entry rewards: payments to an antibiotic developer for successfully achieving regulatory approval that meets pre-defined criteria, with obligations for sustainable use, equitable availability and supply. Long-term supply continuity model: a delinked payment to create a predictable supply of important generic antibiotics.

MMV-supported projects Research Translational Product development Access Lead optimization Candidate profiling Human volunteers Patient exploratory Patient confirmatory Regulatory review Approved/ ERP Preclinical Injectable Prodrug Calibr OZ609 Nebraska/Monash/ STPHI M5717 Merck KGaA P218 Janssen (Biotec Thailand) Artefenomel/ Ferroquine Sanofi Tafenoquine GlaxoSmithKline Rectal artesunate Strides Artemether- lumefantrine Dispersible Novartis 1 Miniportfolio 3 series GSK MMV253 Zydus Cadila SJ733 Kentucky/Eisai KAF156/ Lumefantrine Novartis Dihydroartemisinin- piperaquine dispersible Alfasigma/Pierre Fabre Artesunate for Injection Guilin 3 2 SFK59 Series H3D Cape Town AN13762 Cipargamin Novartis Sulfadoxine- pyrimethamine+ amodiaquine dispersible S Kant Dihydroartemisinin- piperaquine Alfasigma/Pierre Fabre 6 3 DHODH Backups UTSW/UW/Monash UCT943 H3D Cape Town DSM265 Takeda (UTSW) Pyronaridine- artesunate Shin Poong 4 Pantothenates TropIQ/RUMC SAR121 Sanofi MMV048 (UCT) Pyronaridine- artesunate granules Shin Poong 4 Phenotypic Lead Daiichi-Sankyo Artesunate- amodiaquine Sanofi 5 Open Source Series University of Sydney Artesunate- mefloquine Cipla Phe tRNA lygase Broad Institute/Eisai Sulfadoxine- pyrimethamine+ amodiaquine * Guilin 6 MMV support to projects may include financial, in-kind, and advisory activities. Footnotes: Included in MMV portfolio after product approval and/or development. DNDi and partners completed development and registration of ASMQ and ASAQ. WHO TDR completed PhaseIII trials of rectal artesunate. │ Global Fund Expert Review Panel (ERP) reviewed product – permitted for time-limited procurement, while regulatory/WHO prequalification review is ongoing. │ WHO Prequalified OR approved/positive opinion by regulatory bodies who are ICH members/observers. │ Paediatric formulation. │ * For children 13 – 60 months; ** For infants 3 – 12 months. Brand names 1: Coartem® Dispersible; 2: Artesun®; 3: Eurartesim®; 4: Pyramax® tablets or granules; 5: ASAQ Winthrop®; 6: SPAQ-COTM Purines Celgene Sulfadoxine- pyrimethamine+ amodiaquine ** Guilin 6 DHODH Broad/Eisai Rectal artesunate Cipla Phenotypic Lead Eisai Molecular Target DDU Dundee

Limitations of current antibiotic prescribing Remains empirical Diagnostic uncertainty compounded by antibiotic resistance Potential consequences: Wrong organism targeted Wrong antimicrobial agent selected Unnecessary exposure to side effects Expenditure without benefit Adapted from Finch, EU Interdepartmental conference 2005

75% of antibiotics are prescribed in general practice ESPAUR Annual Report

http://fingertips. phe. org http://fingertips.phe.org.uk/profile/amr-local-indicators/data#page/0

http://fingertips. phe. org http://fingertips.phe.org.uk/profile/amr-local-indicators/data#page/0

Duration of hypotension before initiation of effective antimicrobial therapy in human septic shock Kumar et al Crit Care Med 2006

Then Focus… Review the clinical diagnosis and the continuing need for antibiotics by 48-72 hours and make a clear plan of action - the ‘antimicrobial prescribing decision’ The five ‘antimicrobial prescribing decision’ options: 1. Stop antibiotics if there is no evidence of infection 2. Switch antibiotics from IV to oral 3. Change antibiotics – ideally to a narrower spectrum – or broader if required. 4. Continue and document next review or stop date 5. Outpatient Parenteral Antibiotic Therapy (OPAT) Document the review and any subsequent decision clearly in the clinical notes and on the drug chart. https://www.gov.uk/government/publications/antimicrobial-stewardship-start-smart-then-focus

Review of antibiotic prescriptions at 48-72h and documented ‘stop’ decision, NHS Trusts in England, Q4 2017/18 Review and Stop decision (%) Antibiotic prescription reviewed (%) Median 100 90 80 70 60 10 20 30 40 50 Source - https://fingertips.phe.org.uk/

Review of antibiotic prescriptions at 48-72h and documented ‘stop’ decision, NHS Trusts in England Source - https://fingertips.phe.org.uk/

FREE! eBook on antimicrobial stewardship http://www.bsac.org.uk

http://www.catchshortfilm.com

O’Neill update July 2018 10 areas, 29 recommendations Progress in: R&D and investment in AMR Early development of new compounds Lack of progress in: Big Pharma engagement and investment Diagnostics

Use of antibiotics – conundrums Most use of antibiotics in humans is to treat an infection that they haven’t got; Worldwide, more people die because they cannot get an antibiotic than as a result of antibiotic resistance.