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

2. ‘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

3. 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)

4. 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:

5. 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

6. 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

7. 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 March 1998

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

9. 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

10. 70 Years of Antibiotics and Resistance
Development of new antibiotic Emergence of resistance
Lets Talk Antibiotic Resistance

12. 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

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

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

15. 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.

17. 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

18. 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

19. 75% of antibiotics are prescribed in general practice
ESPAUR Annual Report

20. http://fingertips. phe. org

21. http://fingertips. phe. org

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

23. Then Focus…
Review the clinical diagnosis and the continuing need for antibiotics by 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.

24. 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 -

25. Review of antibiotic prescriptions at 48-72h and documented ‘stop’ decision, NHS Trusts in England
Source -

26. FREE! eBook on antimicrobial stewardship

30. 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

31. 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.