Transcript Common misconceptions in medical mycology

Malassezia spp

Lipophilic yeast; at least 8 species


Commensal on skin


Cultured on olive oil agar
Selenium and tar extract shampoos
Typically harmless but can be systemic
in immunocompromised patients
M. furfur
M. pachydermatis
http://www.doctorfungus.org/thefungi/Malassezia.htm
http://dermnetnz.org/
dermatitis/seborrhoeicdermatitis.html
Piedra hortae

Superficial hair dermatophyte
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/Therapy/intro_t.htm
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
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
Systemic antifungal drugs
http://www.chclibrary.org/micromed/00037850.html
Toxicity of polyene and azole
antifungal drugs
Azole antifungals inhibit ergosterol synthesis
Ketaconazole
Itraconazole
Triaconazole
Fluoconazole
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 1990;12:308-29.


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
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
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/moldinfections.html
N-myristoylation factors and fungal
growth
Drug resistant fungal infections

Typically become
invasive/systemic




Current treatment include
combinatorial therapy
ABC drug transporters
Typical ‘cure’ ~ 6 months


Poor prognosis
Treatment may exceed 12
months
Cost exceeds US$30k
Posaconazole

Standard dosage


Contraindications


Posaconazole increased concentrations of rifabutin and decreased cyclosporine
concentrations. Rifabutin, phenytoin, and cimetidine decrease serum
concentrations of posaconazole
Main side effects


Hypersensitivity to related compounds.
Main drug interactions


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.
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