Malassezia spp

1
Malassezia spp

• Lipophilic yeast at least 8 species
• Cultured on olive oil agar
• Commensal on skin
• Selenium and tar extract shampoos
• Typically harmless but can be systemic in
  immunocompromised patients

http//dermnetnz.org/dermatitis/seborrhoeic-dermat
itis.html
M. furfur
M. pachydermatis
http//www.doctorfungus.org/thefungi/Malassezia.ht
m
2
Piedra hortae

• Superficial hair dermatophyte

3
Antifungal drugs

• Targets
• Ergosterol / ergosterol biosynthesis
• Chitin biosynthesis
• Other wall components
• Lysine biosynthesis (DAP/AAA)
• Fungal growth regulators

http//www.doctorfungus.org/cme/oppfungi/html/Ther
apy/intro_t.htm
4
Classical antifungals

• Potassium iodide since 1903 only for
  sporotrichosis
• Context
• 1953 first effective antifungal drugs
• 1941 bacteriocidal drugs
• 1932 bacteriostatic (sulfa) drugs
• 1936 Nigeria meningitis deaths 11 ? 75
• 1953 Hazen and Brown polyene antibiotics from
  Streptomyces Nystatin
• 1957 Ampotericin B

5
Current and investigational classes of antifungal
agents

• Azoles Inhibition production of ergosterol
• Polyenes Bind to ergosterol in the cell membrane
  
• Echinocandins Inhibit synthesis of b-1, 3-glucan
• Allylamines Interrupt ergosterol synthesis
• Nikkomycins Inhibit chitin synthase in the fungal
  cell wall
• Sphingolipid synthesis inhibitors Fungal cell
  membrane
• Sodarins Inhibit protein synthesis via EF2a
• N-myristoyltransferase inhibitors ADP-ribosylation

www.treatment-options.com/article.cfm
6
Systemic antifungal drugs
http//www.chclibrary.org/micromed/00037850.html
7
Toxicity of polyene and azole antifungal drugs
8
Azole antifungals inhibit ergosterol synthesis
Ketaconazole Itraconazole Triaconazole Fluoconazol
e
9
Amphotericin B

• Forms a membrane ion channel
• Selective for inserting near ergosterol rich
  regions
• Fungal membranes are ergosterol rich compared to
  animal membranes
• Gallis HA, Drew RH, Pickard WW. Amphotericin B
  30 years of clinical experience. Rev Infect Dis
  199012308-29.

10
Treatments for superficial fungal infections

• Nystatin pore former
• like amphotericin B
• Nocodazole and benomyl antimicrotubule drugs
  with affinity for fungal microtubules
• highly toxic when used systemically
• Chloramphenicol mitochondrial function also
  used as antibacterial

http//micro.magnet.fsu.edu/pharmaceuticals/pages/
nystatin.html
11
Echinocandins inhibit cell wall matrix components
Cyclic peptide acylated at the N-terminus by
linoleic acid Inhibits fungal (1,3)-B-D-glucan
synthase 0,1,2,5,10,20 mg/kg/d LY (A-E) vs 1
mg/kg/d AmB (F) Difficulty estimating total
biomass vs viable biomass in filamentous fungi
Petraitis et al 1998 Antifungal Efficacy, Safety,
and Single-Dose Pharmacokinetics of LY303366, a
Novel Echinocandin B, in Experimental Pulmonary
Aspergillosis in Persistently Neutropenic
Rabbits. Antimicrobial Agents 42, 2898-2905
12
More antifungals

• Ergosterol synthesis inhibitors
• Bind to squalene epoxidase
• Fungal specific antimicrotubule agents (topical)

Benomyl (plants only) Nocodazole (not shown)
http//www.njmoldinspection.com/mycoses/moldinfect
ions.html
13
N-myristoylation factors and fungal growth
14
Drug resistant fungal infections

• Typically become invasive/systemic
• Poor prognosis
• Current treatment include combinatorial therapy
• ABC drug transporters
• Typical cure 6 months
• Treatment may exceed 12 months
• Cost exceeds US30k

15
Posaconazole

• Standard dosage
• The optimal dosage has not been established.
  However, an oral dosage of 200 mg four times
  daily or 400 mg twice daily is being investigated
  in clinical studies.
• Contraindications
• Hypersensitivity to related compounds.
• Main drug interactions
• Posaconazole increased concentrations of
  rifabutin and decreased cyclosporine
  concentrations. Rifabutin, phenytoin, and
  cimetidine decrease serum concentrations of
  posaconazole
• Main side effects
• None reported.
• Special points
• Spectrum of activity includes azole-susceptible
  and azole-resistant Candida species, Cryptococcus
  neoformans, Aspergillus species, Histoplasma
  capsulatum, and Coccidioides immitis. May be
  active against various zygomycetes.

http//www.treatment-options.com/article.cfm