20th Anniversary Meeting of the Fungal Research Trust<br />Development of new antifungal drugs & combination therapy <br /...
Development of new antifungal drugs & combination therapy<br />Professor David Denning<br />Scientific Advisor<br />Fungal...
Priorities for novel antifungal agents for the treatment of invasive fungal infections<br />	Oral agent for treatment of ...
The echinocandins<br />
The azoles<br />
Amphotericin B and its formulations<br />AmBisome<br />Abelcet<br />Amphocil<br />
Priorities for novel antifungal agents for the treatment of invasive fungal infections<br />	Oral agent for treatment of ...
Mechanism of drug action<br />Only 4 mechanisms of action<br />and only the azoles and flucytosine are oral<br />
Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /><ul><li> New treatment for sys...
Importance of getting treatment right in candidaemia<br />100<br />P=0.02<br />73<br />Survival (%)<br />44<br />Yes			No<...
Micafungin versus Ambisome randomised study<br />Important to monitor blood cultures during therapy<br />Unpublished data ...
Laboratory surveillance of invasive fungal infections England 1990-2004<br />* provisional data<br />
Laboratory surveillance of candidaemia age distribution 2008<br />Voluntary surveillance of candidaemia in England, Wales,...
Fluconazole insensitive or resistant<br />Candidaemia - species distribution 2008<br />Echinocandin insensitive or resista...
Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /><ul><li> New treatment for sys...
 Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system</li>...
Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /><ul><li> New treatment for sys...
 IV & oral antifungal with activity against Cryptococcus and penetration into the central nervous system
 IV & oral antifungal with potent activity against Aspergillus spp., including triazole resistant species.  Ideally there ...
Combination therapy – invasive aspergillosis<br />Retrospective<br />AmB failures<br />Most HSCT<br />30/47 proven IA<br /...
Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /><ul><li> New treatment for sys...
 IV & oral antifungal with activity against Cryptococcus and penetration into the central nervous system
 IV & oral antifungal with potent activity against Aspergillus spp., including triazole resistant species.  Ideally there ...
 Oral agent(s) for the treatment of chronic pulmonary and allergic aspergillosis, with few drug interactions (especially c...
Acneiform rash with posaconazole<br />Within 48hrs of commencing posaconazole he developed a severe acne-like rash, typica...
Patient LT<br />LT (♀, age 49) lifelong asthma and atopy, with ABPA diagnosed in 1993. <br />Recognised to have CPA compli...
Patient LT<br />Better pulmonary status on voriconazole initially, but then slow deterioration, On 4l/min oxygen dependent...
Patient LT<br />Skin biopsy from the right forearm showed low grade premalignant change. She was treated with local 5-fluo...
Patient LT<br />www.aspergillus.org.uk<br />
Patient LT<br />www.aspergillus.org.uk<br />
Patient LT<br />These photos were taken when her skin was at its worst. The inflammation resolved after discontinuing the ...
Patient LT<br />18 months later, new lesion on her forearm. Biopsy showed squamous cell carcinoma in situ.<br />So voricon...
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Fungal Research Trust 20th Anniversary Meeting June 2011 - Professor David Denning

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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

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

  1. 1. 20th Anniversary Meeting of the Fungal Research Trust<br />Development of new antifungal drugs & combination therapy <br />Professor David Denning<br />June 2011<br />London, UK<br />
  2. 2. Development of new antifungal drugs & combination therapy<br />Professor David Denning<br />Scientific Advisor<br />Fungal Research Trust<br />The University of Manchester<br />The National Aspergillosis Centre<br />
  3. 3. Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /> Oral agent for treatment of systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).<br /> Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system<br /> 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.<br /> Parenteral and oral agent active against rare, but medically important moulds (e.g. Mucorales, Scedosporium spp.). <br /> Oral agent(s) for the treatment of chronic pulmonary and allergic aspergillosis, with few drug interactions (especially corticosteroids) and favourable intrapulmonary pharmacokinetics.<br />
  4. 4. The echinocandins<br />
  5. 5. The azoles<br />
  6. 6. Amphotericin B and its formulations<br />AmBisome<br />Abelcet<br />Amphocil<br />
  7. 7. Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /> Oral agent for treatment of systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).<br /> Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system<br /> 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.<br /> Parenteral and oral agent active against rare, but medically important moulds (e.g. Mucorales, Scedosporium spp.). <br /> Oral agent(s) for the treatment of chronic pulmonary and allergic aspergillosis, with few drug interactions (especially corticosteroids) and favourable intrapulmonary pharmacokinetics.<br />
  8. 8. Mechanism of drug action<br />Only 4 mechanisms of action<br />and only the azoles and flucytosine are oral<br />
  9. 9. Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /><ul><li> New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).</li></li></ul><li>Early treatment critical to good outcome in candidaemia<br />25%<br />25%<br />Morrell, Antimicrob Agents Chemother 2005;49:3640. Garey, Clin Infect Dis 2006;43:25<br />
  10. 10. Importance of getting treatment right in candidaemia<br />100<br />P=0.02<br />73<br />Survival (%)<br />44<br />Yes No<br />Empirical therapy correct?<br />Parkins, J Antimicrob Chemother 2007;60:613. <br />
  11. 11. Micafungin versus Ambisome randomised study<br />Important to monitor blood cultures during therapy<br />Unpublished data Kuse, Lancet 2007;369:1519<br />
  12. 12. Laboratory surveillance of invasive fungal infections England 1990-2004<br />* provisional data<br />
  13. 13. Laboratory surveillance of candidaemia age distribution 2008<br />Voluntary surveillance of candidaemia in England, Wales, & N. Ireland: 2008<br />
  14. 14. Fluconazole insensitive or resistant<br />Candidaemia - species distribution 2008<br />Echinocandin insensitive or resistant<br />
  15. 15. Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /><ul><li> New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).
  16. 16. Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system</li></li></ul><li>Cryptococcal meningitis treatment<br />Nussbaum et al, Clin Infect Dis 2010;50:338<br />
  17. 17. Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /><ul><li> New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).
  18. 18. IV & oral antifungal with activity against Cryptococcus and penetration into the central nervous system
  19. 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.</li></li></ul><li>Impact of voriconazole in real life for invasive aspergillosis<br />Nivoix et al, Clin Infect Dis 2008;47:1176<br />
  20. 20. Combination therapy – invasive aspergillosis<br />Retrospective<br />AmB failures<br />Most HSCT<br />30/47 proven IA<br />Multivariate analysis<br />P=0.008 for combination and survival<br />Curves came together later<br />Marr et al, Clin Infect Dis 2004:39:797<br />
  21. 21. Priorities for novel antifungal agents for the treatment of invasive fungal infections<br /><ul><li> New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).
  22. 22. IV & oral antifungal with activity against Cryptococcus and penetration into the central nervous system
  23. 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. 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.</li></li></ul><li>Chronic pulmonary aspergillosis and posaconazole<br />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.<br />Oct 2008<br />Jan 2010<br />Unpublished<br />
  25. 25. Acneiform rash with posaconazole<br />Within 48hrs of commencing posaconazole he developed a severe acne-like rash, typical of folliculitis, across his face.<br />His treatment had to stop, and we have n more oral treatments available for him.<br />Unpublished<br />
  26. 26. Patient LT<br />LT (♀, age 49) lifelong asthma and atopy, with ABPA diagnosed in 1993. <br />Recognised to have CPA complicating ABPA in 2001, but the CPA diagnosis was apparent in 1993.<br />www.aspergillus.org.uk<br />
  27. 27. Patient LT<br />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”.<br />www.aspergillus.org.uk<br />
  28. 28. Patient LT<br />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.<br />www.aspergillus.org.uk<br />
  29. 29. Patient LT<br />www.aspergillus.org.uk<br />
  30. 30. Patient LT<br />www.aspergillus.org.uk<br />
  31. 31. Patient LT<br />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.<br />
  32. 32. Patient LT<br />18 months later, new lesion on her forearm. Biopsy showed squamous cell carcinoma in situ.<br />So voriconazole is a potent photosensitising drug with malignant potential<br />
  33. 33. What is coming?<br /><ul><li> Isavuconazole [similar to voriconazole with fewer drug interactions and photosensitivity. Once daily, phase 3]
  34. 34. Nikkomycin Z [oral, coccidioidomycosis, phase 2]
  35. 35. Candida vaccine [to prevent invasive candididiasis and MRSA, phase 1/2]
  36. 36. FG3409 series [New mode of action, Aspergillus and moulds, IV & oral, phase 1]
  37. 37. Nanoparticle preparations of amphotericin B [oral, preclinical]
  38. 38. Others </li></li></ul><li>Thank you for supporting the work of <br />the Fungal Research Trust<br />
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