Dr Nick Brown 17 November 2018 It is not difficult to make microbes resistant to penicillin in the Laboratoryand the same thing has occasionally happened in the body The time may come when penicillin can be bought by anyone in the ID: 739883
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Slide1
Where are we with AMR? – the human perspective
Dr Nick Brown17 November 2018Slide2
‘
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 FlemingNobel Lecture, 11 December 1945Slide3
Resistant organism
in susceptible
population
Susceptible
cells killed
by antibiotic
Resistant progeny
grow
Darwinian ‘survival of the fittest’
Antibiotics kill susceptible bacteria; resistant ones survive
Level of antibiotic use affects the prevalence of resistance
Slide: US Centers for Disease Control & Prevention (CDC)Slide4
Bulger
Ann Int Med 1968; 69: 1099-1108
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
Resistance surveillance
1959Slide5
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 diagnosticsPROMOTE the development of new antimicrobials, new approaches
and better di
agnostics.
Underpinned by:
Surveillance
Research and Development
Education, training and awareness
International collaborationSlide6
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 prescribingReduce
antimicrobial use in animals, particularly for prophylaxis or metaphylaxisAntimicrobials and the environment - establish safe systems for disposal Slide7
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
House of Lords
http://www.parliament.the-stationery-office.co.ukSlide8
Methicillin-resistant Staphylococcus
aureus
(MRSA)
bacteraemia reports (mandatory reporting scheme): England
Source: Public Health EnglandSlide9
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 programmeDiscovery & Development 2011 (US & EU) FDA & EMA
A steady stream of new guidance 2012: (US) GAIN Act2013: (EU) Chatham House Conference “Antimicrobial resistance: Incentivising Change Towards a Global Solution”
2014: (US) PCAST Report
2016: UN General Assembly resolutionSlide10
70 Years of Antibiotics and Resistance
10
Lets Talk Antibiotic Resistance
Development of new antibiotic
Emergence of resistanceSlide11Slide12
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 Slide13
Key factors impacting the net present value (NPV) of a pharmaceutical product
LOSSESSlide14
Characteristics of a commercially successful antibiotic versus those required
Broad spectrum
Large volume
Primary care
Targeted
Small volume
Specialty/secondary careSlide15
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.Slide16Slide17
Artesunate-
mefloquine
Cipla
Artefenomel/
Ferroquine
Sanofi
MMV-supported projects
Translational
Product development
Access
Preclinical
Patient confirmatory
Approved/
ERP
Human volunteers
Patient exploratory
Regulatory review
Research
Candidate profiling
Lead optimization
Injectable Prodrug
Calibr
OZ609
Nebraska/Monash/ STPHI
Miniportfolio
3 series
GSK
SFK59 Series
H3D Cape Town
DHODH Backups
UTSW/UW/Monash
Open Source Series
University of Sydney
Purines
Celgene
DHODH
Broad/Eisai
Phenotypic Lead
Eisai
Phe tRNA lygase
Broad Institute/Eisai
Pantothenates
TropIQ/RUMC
P218
Janssen
(Biotec Thailand)
MMV253Zydus Cadila
M5717Merck KGaA
AN13762
UCT943
H3D Cape Town
MMV048
(UCT)Cipargamin Novartis
Tafenoquine GlaxoSmithKline
Dihydroartemisinin
- piperaquine dispersibleAlfasigma/Pierre Fabre
Rectal artesunateStridesDihydroartemisinin- piperaquine
Alfasigma/Pierre FabreArtesunate for Injection
Guilin Pyronaridine-artesunateShin Poong
Artesunate- amodiaquine SanofiPyronaridine-
artesunate granulesShin Poong3
24Artemether-
lumefantrineDispersible Novartis6
Sulfadoxine- pyrimethamine+amodiaquine *Guilin 4
13
SAR121
Sanofi
Phenotypic LeadDaiichi-SankyoMolecular Target
DDU DundeeDSM265Takeda(UTSW)5
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
Rectal artesunate
Cipla6
Sulfadoxine- pyrimethamine+amodiaquine ** Guilin
Sulfadoxine-
pyrimethamine+
amodiaquine dispersibleS Kant6
SJ733Kentucky/EisaiKAF156/
Lumefantrine NovartisSlide18
Limitations of current antibiotic prescribing
Remains empirical
Diagnostic uncertainty compounded by antibiotic resistance
Potential consequences:Wrong organism targetedWrong antimicrobial agent selected
Unnecessary exposure to side effectsExpenditure without benefit
Adapted from Finch, EU Interdepartmental conference 2005 Slide19
ESPAUR Annual Report
75% of antibiotics are prescribed in general practiceSlide20
http://fingertips.phe.org.uk/profile/amr-local-indicators/data#page/0Slide21
http://fingertips.phe.org.uk/profile/amr-local-indicators/data#page/0Slide22
Kumar et al
Crit
Care Med 2006Duration of hypotension before initiation of effective antimicrobial therapy in human septic shockSlide23
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 infection2. Switch antibiotics from IV to oral3. 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-focusSlide24
Review of antibiotic prescriptions at 48-72h and documented ‘stop’ decision, NHS Trusts in England, Q4 2017/18
Source - https://fingertips.phe.org.uk/
Review and Stop decision (%)
Antibiotic prescription reviewed (%)
Median
100
908070
60
0
10
20
30
4050Slide25
Review of antibiotic prescriptions at 48-72h and documented ‘stop’ decision, NHS Trusts in England
Source - https://fingertips.phe.org.uk/Slide26
FREE! eBook on antimicrobial stewardship
http://www.bsac.org.uk Slide27Slide28
http://www.catchshortfilm.com Slide29Slide30
10 areas, 29 recommendations
Progress in:R&D and investment in AMREarly development of new compoundsLack of progress in:Big Pharma
engagement and investmentDiagnostics
O’Neill update July 2018Slide31
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.