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

20th Anniversary Meeting of the Fungal Research Trust
Development of new antifungal drugs & combination therapy
Professor David Denning
June 2011
London, UK

Development of new antifungal drugs & combination therapy
Professor David Denning
Scientific Advisor
Fungal Research Trust
The 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
AmBisome
Abelcet
Amphocil

 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 action
and only the azoles and flucytosine are oral

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

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.

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
* provisional data

Laboratory surveillance of candidaemia age distribution 2008
Voluntary surveillance of candidaemia in England, Wales, & N. Ireland: 2008

Fluconazole insensitive or resistant
Candidaemia - species distribution 2008
Echinocandin insensitive or resistant

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

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
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

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
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

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

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

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”.

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.

Patient LT

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
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

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

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

by Graham Atherton on Jul 27, 2011

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