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

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

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

18. IV & oral antifungal with activity against Cryptococcus and penetration into the central nervous system

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

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.

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

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]