1. Brielle Haas RISE Spring 2015 Dr. Gullo
Antifungal Therapies
Brielle Haas
RISE Spring 2015
Dr. Gullo

2. Deficits of Antifungal Therapies
Antifungal Problems
Growing clinical need
Lack of treatment options
Antifungal resistance
Low efficacy of current treatments

3. Fungal Cell Characteristics
Distinctive cell wall components
Chitinases
Glucanases
Ergosterol
Mannan
Hydrolytic enzymes
Growth as a filament
Hyphae

4. Fungal Hyphae
Hyphae growth
Fungal Sinusitis

5. Growing Susceptibility
Immunocompromised patients
Patients with HIV/AIDS and other autoimmune disorders
Patients taking certain medications
Cancer Patients
Chemotherapy and radiation lower immunity
Organ transplant patients
Anti-rejection medication lowers immunity
Stem cell transplant patients
Hospitalized patients

6. Common Invasive Fungal Infections
Aspergillus spp.
Aspergillosis (lung infections)
Candida spp.
Candidiasis (thrush and yeast infections)
Cryptococcus (C. neoformans and C. gatti )
Cryptococcosis (lung infections)
Cryptococcal meningitis (CNS infections)
Mucoromycotina
Mucoromycosis (skin, lung, and sinus infections)
Pneumocystis jirovecii
Pneumocystic pneumonia (PCP)

7. Current Antifungal Treatments
Polyenes
Azoles
Enchinocandins
Amphotericin B
Fluconazole
Voriconazole
Posaconazole
Itraconazole
Caspofungin
Micafungin
Anidulafungin

8. Polyenes Amphotericin B Under development Fungicidal
High toxicity (lower with lipid formulations)
Targets ergosterol on cell membrane
Used in combination with flucytosine
Used for cryptococcal meningitis and invasive mucormycotina
Under development
Nystatin
Amphotericin B cochleate formulation

9. Polyene Structures

10. Azoles All types Fluconazole Most broadly used class
Inhibits cytochrome P-450, which is responsible for ergosterol synthesis
Fungistatic,except for voriconazole
May interfere with other medication
Fluconazole
Used against yeasts such as Candida and Cryptococcus
Not active against molds
Used to treat cryptococcal meningitis in resource-poor regions where Amphotericin B is not available

11. Azoles Voriconazole Posaconazole Itraconazole Under development
Fungicidal
Active against yeasts and molds
Treats Aspergillus spp. infections
Posaconazole
Treats Mucor spp. infections
Itraconazole
Active against yeasts and molds
Treats superficial fungal infections
Under development
Albaconazole
Isavuconazole
Ravuconazole

12. Azole Structures

13. Enchinocandins General Caspofungin Anidulafungin Micafungin
Inhibit glucan synthesis
Used as secondary choice treatment options for Candida and Aspergillus
Caspofungin
Fungicidal toward A. fumigatus
Anidulafungin
Used as fluconazole alternative
Micafungin
Used as antifungal prophylaxis after stem cell transplant
Under development
Aminocandin
Enfumifungin

14. Enchinocandin Structures

15. Further Under Development
Nikkomycin Z
Inhibits chitin synthesis
Sordarins
Inhibits elongation factor 2 which prevents protein synthesis
Nanoparticle Formations
Attempt to solve toxicity and solubility issues of current treatments (Amphotericin B and Itraconazole)

16. Antifungal Drug Targets

17. Fungal CNS Infections Difficulty in diagnosis
CSF screenings
MRI
Passage of medication through blood-brain barrier
Need for surgical intervention
Risks of any invasive neurological procedure
Increased susceptibility to other fungal infections

18. Research Topics Why are there so few effective antifungal drugs?
What efforts are currently being made to “fix” the problems with antifungal therapies?
How do these problems manifest in the treatment of fungal infections of the CNS?

19. References http://mic.sgmjournals.org/content/150/7/2029.abstract
Roemer T, Krysan DJ. Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harbor perspectives in medicine 2014;4(5):a
McCarthy M, Rosengart A, Schuetz AN, Kontoyiannis DP, Walsh TJ. Mold Infections of the Central Nervous System. The New England Journal of Medicine 2014;371(2):