Resistance Surveillance: Its Role in Drug Discovery and Development

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Resistance Surveillance Its Role in Drug
Discovery and Development

• Dr C.J. Thomson
• BSAC-Resistance Surveillance in the UK and
  Ireland
• 13th European Congress of Clinical Microbiology
  and Infectious Diseases
• 10 May 2003

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What are you trying to achieve?
Match a non existent compound with a future unmet
clinical need
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Attrition rate
CHEMICAL LAB 10,000 COMPOUNDS PHARMACOLOGY/TOX
ICOLOGY 1,000 CLINICAL DEVELOPMENT
10 N.D.A. SUBMISSION
1 COMPOUND RATE 10,0001
Impact of time e.g new compound today available
for clinical use 2009/10??
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What can surveillance tell us?

• Resistance/susceptibility data at a given time
• Trends over time-can be subtle (below the B.P.)
  but important
• evolution of TEM ?-lactamase- Clavulanic acid
  resistance (IRTS) and ESBLs
• accumulation of mutations in DNA gyrase and
  topoisomerase IV
• Mechanisms of Resistance
• Aetiology

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Where could surveillance data fit in the decision
making process?
Demographic data
Political Situation
Other Technical / Medical Advances
Surveillance Data
New data from Basic Research
Part of the overall Picture
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How can surveillance data be used in
antimicrobial discovery and development?
Research-discovery

• Long term planning
• Needs of the future Emerging pathogens,
  Resistance trends
• Short to mid term
• Modify pattern of use, Dosage, Class Resistance
• New Ways with Old Drugs
• New indications for agents

Clinical-development
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Long term planning Possible approaches
Full exploitation and development within a class
Nalidixic acid
Ciprofloxacin Ofloxacin / Levofloxacin
Gatifloxacin Moxifloxacin
Gemifloxacin
Increasing resistance in respiratory
pathogens Need to improve quinolone basic
activity against S. pneumoniae and decrease
potential for resistance
Scope to develop the class
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Long term planning Possible approaches
Full exploitation and development within a class
Tetracyclines widespread use in community
Increasing Resistance
Increasing resistance in hospital pathogens e.g
VRE tet genes only 2 basic mechanisms efflux r
ibosomal protection
Scope to develop the class
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Long term planning Possible Approaches
New class required
Trimethoprim use in UTI
New Inhibitors of DHFRs ?
Increasing Tp resistance in Urinary E. coli At
least 16 different plasmid mediated Tp R DHFRs
widespread.
Any new agent would need to be active against
normal DHFR and all resistant ones Unlikely
Tp clinical role will need to filled by a
different class New DHFR inhibitors for -Gram
positives ?
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Long term planning Possible Approaches
New class required ?
Cephalosporins
1st
2nd
3rd
4th...
Emergence of resistance mechanism ESBLs from
already prevalent ?-lactamases
Will a new class be required to take over the
general role of cephalosporins? Alternative
?-lactams - carbapenems Will new Cephalosporins
be developed to only fulfil specific roles e.g.
MRSA
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Long term planning Possible Approaches
Resistance Breakers
Stable prevalent resistance mechanism
compromising an existing agent ?-lactamse
inhibitors Clavulanic acid with
amoxycillin Tazobactam with piperacillin For
the future? Efflux pump inhibitors with
quinolones? Novel ?-lactamse inhibitors Carb
apenems Cephalosporins
Prevalence of ?-lactam resistance and responsible
mechanism in hospital and community isolates
Need Data to support these strategies
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Short to mid term
Class resistance the fate of the cephalosporin
class
Role of certain cephalosporins in selecting the
initial mutations that initiate the ESBL pathway
Impact for the whole class Dosage modification,
usage modification, further development?
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Short to mid termClass resistancepotential for
resistance inquinolones
Drivers for quinolone resistance well understood
S. pneumoniae
P. aeruginosa
Moxifloxacin Gatifloxacin Gemifloxacin
Ciprofloxacin
Ofloxacin/ Levofloxacin
Need to ensure a too generalist approach does not
compromise the class
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New ways with existing drugs
Resistance emergence threatens standard
treatment regimens
Scope to investigate new clinical areas
with existing compounds
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Industry Investment in surveillance related
activities

• Susceptibility surveillance programs
• LIBRA (Bayer)
• Alexander (GSK)
• SENTRY (BMS)
• PROTEKT (Aventis)
• Mystic (Astra- Zeneca)
• Local national approaches
• Joint initiatives
• BSAC Resistance Surveillance Working Groups
  Abbott, Aventis, Bayer, Cubist,
  Genesoft, GlaxoSmithKline, Merck Sharp
  Dohme, Pharmacia, Wyeth

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LIBRA Surveillance aims to be a key tool in

• Combating resistance
• Education on the existence of resistance
• Education on the importance of appropriate
  prescribing and use of antibiotics
• LIBRA Surveillance at www.librainitiative.com
  featuring
• Comprehensive information on Surveillance
• Interactive database comprising Surveillance data
  of pathogens relevant to both RTI and UTI
• Personalised analysis of Surveillance data
• The convenience of off-screen analysis of data

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Conclusions

• Surveillance data is critical to the drug
  discovery and development process
• Impact at a number of key decision points
• directing research effort
• appropriate use
• continuing clinical development
• Industry invests a considerable amount of
  resource in a wide variety of surveillance
  activities.