Fungal Research Trust 20th Anniversary Meeting June 2011 - Professor David Denning
Upcoming SlideShare
Loading in...5
×
 

Like this? Share it with your network

Share

Fungal Research Trust 20th Anniversary Meeting June 2011 - Professor David Denning

on

  • 1,596 views

Talk given to the 20th Anniversary Meeting entitled "Development of New Antifungal Drugs adn Combination Therapy" by Director of the National Aspergillosis Centre, Professor David Denning

Talk given to the 20th Anniversary Meeting entitled "Development of New Antifungal Drugs adn Combination Therapy" by Director of the National Aspergillosis Centre, Professor David Denning

Statistics

Views

Total Views
1,596
Views on SlideShare
1,592
Embed Views
4

Actions

Likes
0
Downloads
45
Comments
0

2 Embeds 4

http://www.nacpatients.org.uk 3
http://www.linkedin.com 1

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

Fungal Research Trust 20th Anniversary Meeting June 2011 - Professor David Denning Presentation Transcript

  • 1. 20th Anniversary Meeting of the Fungal Research Trust
    Development of new antifungal drugs & combination therapy
    Professor David Denning
    June 2011
    London, UK
  • 2. Development of new antifungal drugs & combination therapy
    Professor David Denning
    Scientific Advisor
    Fungal Research Trust
    The University of Manchester
    The National Aspergillosis Centre
  • 3. Priorities for novel antifungal agents for the treatment of invasive fungal infections
     Oral agent for treatment of systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).
     Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system
     Parenteral and oral agent with potent activity against Aspergillus spp., including triazole resistant species. Ideally there should be few drug interactions and safety in patients with renal or hepatic impairment.
     Parenteral and oral agent active against rare, but medically important moulds (e.g. Mucorales, Scedosporium spp.).
     Oral agent(s) for the treatment of chronic pulmonary and allergic aspergillosis, with few drug interactions (especially corticosteroids) and favourable intrapulmonary pharmacokinetics.
  • 4. The echinocandins
  • 5. The azoles
  • 6. Amphotericin B and its formulations
    AmBisome
    Abelcet
    Amphocil
  • 7. Priorities for novel antifungal agents for the treatment of invasive fungal infections
     Oral agent for treatment of systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).
     Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system
     Parenteral and oral agent with potent activity against Aspergillus spp., including triazole resistant species. Ideally there should be few drug interactions and safety in patients with renal or hepatic impairment.
     Parenteral and oral agent active against rare, but medically important moulds (e.g. Mucorales, Scedosporium spp.).
     Oral agent(s) for the treatment of chronic pulmonary and allergic aspergillosis, with few drug interactions (especially corticosteroids) and favourable intrapulmonary pharmacokinetics.
  • 8. Mechanism of drug action
    Only 4 mechanisms of action
    and only the azoles and flucytosine are oral
  • 9. Priorities for novel antifungal agents for the treatment of invasive fungal infections
    • New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).
  • Early treatment critical to good outcome in candidaemia
    25%
    25%
    Morrell, Antimicrob Agents Chemother 2005;49:3640. Garey, Clin Infect Dis 2006;43:25
  • 10. Importance of getting treatment right in candidaemia
    100
    P=0.02
    73
    Survival (%)
    44
    Yes No
    Empirical therapy correct?
    Parkins, J Antimicrob Chemother 2007;60:613.
  • 11. Micafungin versus Ambisome randomised study
    Important to monitor blood cultures during therapy
    Unpublished data Kuse, Lancet 2007;369:1519
  • 12. Laboratory surveillance of invasive fungal infections England 1990-2004
    * provisional data
  • 13. Laboratory surveillance of candidaemia age distribution 2008
    Voluntary surveillance of candidaemia in England, Wales, & N. Ireland: 2008
  • 14. Fluconazole insensitive or resistant
    Candidaemia - species distribution 2008
    Echinocandin insensitive or resistant
  • 15. Priorities for novel antifungal agents for the treatment of invasive fungal infections
    • New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).
    • 16. Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system
  • Cryptococcal meningitis treatment
    Nussbaum et al, Clin Infect Dis 2010;50:338
  • 17. Priorities for novel antifungal agents for the treatment of invasive fungal infections
    • New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).
    • 18. IV & oral antifungal with activity against Cryptococcus and penetration into the central nervous system
    • 19. IV & oral antifungal with potent activity against Aspergillus spp., including triazole resistant species. Ideally there should be few drug interactions and safety in patients with renal or hepatic impairment.
  • Impact of voriconazole in real life for invasive aspergillosis
    Nivoix et al, Clin Infect Dis 2008;47:1176
  • 20. Combination therapy – invasive aspergillosis
    Retrospective
    AmB failures
    Most HSCT
    30/47 proven IA
    Multivariate analysis
    P=0.008 for combination and survival
    Curves came together later
    Marr et al, Clin Infect Dis 2004:39:797
  • 21. Priorities for novel antifungal agents for the treatment of invasive fungal infections
    • New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).
    • 22. IV & oral antifungal with activity against Cryptococcus and penetration into the central nervous system
    • 23. IV & oral antifungal with potent activity against Aspergillus spp., including triazole resistant species. Ideally there should be few drug interactions and safety in patients with renal or hepatic impairment.
    • 24. Oral agent(s) for the treatment of chronic pulmonary and allergic aspergillosis, with few drug interactions (especially corticosteroids), excellent safety and favourable intrapulmonary pharmacokinetics.
  • Chronic pulmonary aspergillosis and posaconazole
    DC (♂, age 73) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole and voriconazole. CPA had developed on a background of asthma and ABPA.
    Oct 2008
    Jan 2010
    Unpublished
  • 25. Acneiform rash with posaconazole
    Within 48hrs of commencing posaconazole he developed a severe acne-like rash, typical of folliculitis, across his face.
    His treatment had to stop, and we have n more oral treatments available for him.
    Unpublished
  • 26. Patient LT
    LT (♀, age 49) lifelong asthma and atopy, with ABPA diagnosed in 1993.
    Recognised to have CPA complicating ABPA in 2001, but the CPA diagnosis was apparent in 1993.
    www.aspergillus.org.uk
  • 27. Patient LT
    Better pulmonary status on voriconazole initially, but then slow deterioration, On 4l/min oxygen dependent 24 hours a day. Mild photosensitivity on voriconazole, even with little sun exposure. As wheelchair bound very little outside time, so mostly indoor light. She developed rough scaly patches over her face, neck and lower arms. Dermatological review indicated “multiple solar keratoses”.
    www.aspergillus.org.uk
  • 28. Patient LT
    Skin biopsy from the right forearm showed low grade premalignant change. She was treated with local 5-fluorouracil cream (Efudix) (3 cycles) to the affected lesions.
    www.aspergillus.org.uk
  • 29. Patient LT
    www.aspergillus.org.uk
  • 30. Patient LT
    www.aspergillus.org.uk
  • 31. Patient LT
    These photos were taken when her skin was at its worst. The inflammation resolved after discontinuing the cream. This reaction is expected with application of this mild chemotherapy agent. Following treatment her skin was much softer and considerably improved. Voriconazole has been stopped, and posaconazole substituted.
  • 32. Patient LT
    18 months later, new lesion on her forearm. Biopsy showed squamous cell carcinoma in situ.
    So voriconazole is a potent photosensitising drug with malignant potential
  • 33. What is coming?
    • Isavuconazole [similar to voriconazole with fewer drug interactions and photosensitivity. Once daily, phase 3]
    • 34. Nikkomycin Z [oral, coccidioidomycosis, phase 2]
    • 35. Candida vaccine [to prevent invasive candididiasis and MRSA, phase 1/2]
    • 36. FG3409 series [New mode of action, Aspergillus and moulds, IV & oral, phase 1]
    • 37. Nanoparticle preparations of amphotericin B [oral, preclinical]
    • 38. Others
  • Thank you for supporting the work of
    the Fungal Research Trust