20th Anniversary Meeting of the Fungal Research Trust
Development of new antifungal drugs & combination therapy
Professor David Denning
June 2011London, UK
Development of new antifungal drugs & combination therapy
Professor David DenningScientific Advisor
Fungal Research TrustThe University of Manchester
The National Aspergillosis Centre
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.
The echinocandins
The azoles
Amphotericin B and its formulations
Abelcet Amphocil AmBisome
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.
Mechanism of drug action
Only 4 mechanisms of actionand only the azoles and flucytosine are oral
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
Morrell, Antimicrob Agents Chemother 2005;49:3640. Garey, Clin Infect Dis 2006;43:25
Mortality rate from time of blood draw that later turns positive
Rx in <12 hrs
Rx in 12-24 hrs
Rx in 24-48 hrs
Rx >48 hrs Rx >72 hrs
Morell, 2005 11.1% 30% 32.6% 34.5% -
Garey, 2006 15.4% 23.7% 36.4% 41.4%
25%
25%
Importance of getting treatment right in candidaemia
Parkins, J Antimicrob Chemother 2007;60:613.
Su
rviv
al (%
)
Empirical therapy correct?Yes No
100
73
44
P=0.02
Micafungin versus Ambisome randomised study
Important to monitor blood cultures during therapy
Unpublished data Kuse, Lancet 2007;369:1519
Laboratory surveillance of invasive fungal infections England 1990-
2004
0
400
800
1200
1600
2000
1990
1992
1994
1996
1998
2000
2002
2004
*
nu
mb
er o
f re
po
rts
invasive candidosis
invasive aspergillosis
* provisional data
Laboratory surveillance of candidaemia age distribution 2008
Voluntary surveillance of candidaemia in England, Wales, & N. Ireland: 2008
Candidaemia - species distribution 2008
Fluconazole insensitive or resistant
Echinocandin insensitive or resistant
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).• 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
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).• 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 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
Combination therapy – invasive aspergillosis
RetrospectiveAmB failuresMost HSCT30/47 proven IA
Multivariate analysisP=0.008 for combination and survival
Curves came together later
Marr et al, Clin Infect Dis 2004:39:797
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).• 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 should be few drug interactions and safety in patients with renal or hepatic impairment.• 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
Unpublished
Jan 2010 Oct 2008
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.
Acneiform rash with posaconazole
Unpublished
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.
Patient LT
www.aspergillus.org.uk
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.
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
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
Patient LT
www.aspergillus.org.uk
Patient LT
www.aspergillus.org.uk
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.
Patient LT
So voriconazole is a potent photosensitising drug with malignant potential
18 months later, new lesion on her forearm. Biopsy showed squamous cell carcinoma in situ.
What is coming?
• Isavuconazole [similar to voriconazole with fewer drug interactions and photosensitivity. Once daily, phase 3]•Nikkomycin Z [oral, coccidioidomycosis, phase 2] • Candida vaccine [to prevent invasive candididiasis and MRSA, phase 1/2]• FG3409 series [New mode of action, Aspergillus and moulds, IV & oral, phase 1]• Nanoparticle preparations of amphotericin B [oral, preclinical]• Others
Thank you for supporting the work of the Fungal Research Trust