fungal infections Flashcards
what are the three types of anti fungals
- polyenes
- Azoles
- Others
What are Polyenes and give an example
They Bind to ergosterol in membranes promoting:
- Leakage of intracellular ions
- Disruption of membrane active transport mechanisms
Examples
- Amphotericin B, nystatin
Resistance is rare
Amphotericin B
- Active against almost all fungi causing systemic infection
- Poorly absorbed by the gut
IV administration
Lipid formulations
E.g. liposomal amphotericin B (AmBisome)
Adverse effects
- Many, some serious
- Nephrotoxicity (Monitor renal function
what are Azoles ?
Inhibit ergosterol synthesis
- Inhibit key cytochrome P450 step
- Inhibit 14α-demethylase which converts lanosterol to ergosterol
Accumulation of sterol precursors
Cell membrane with altered structure and function
Split into:
- Imidazoles
- Triazoles
Imidazoles
- Active against a wide variety of fungi and yeasts
- Miconazole, clotrimazole, ketoconazole
- Topical application for superficial infection
Ketoconazole
Better absorbed by mouth than other imidazoles
Oral preparation
Hepatotoxicity (LFTs)
Triazoles
-Similar spectrum of activity to the imidazoles
-Inhibit human cytochrome P450 enzymes ∴ drug interactions e.g. statins, warfarin
Examples
- Fluconazole
- Itraconazole
- Voriconazole
- Posaconazole
Other antifungals
- Caspofungin
- Flucytosine
- Terbinafine
- Griseofulvin
- Amorolfine
see Power point for more information
Resistance to antifungals
- Mutations in target gene - Resistance to flucytosine
- Overexpression of efflux pumps
- Overexpression of drug target - Resistance to azoles
- Upregulation of genes in ergosterol synthesis pathway
- Mutations in target enzyme -Resistance to caspofungin
- Alternate sterols used in membrane
- Resistance to polyenes - Altered cell membrane permeability - Resistance to polyenes
what are the causes of fungal disease
Mycotoxicoses
Hypersensitivities
Colonisation and disease
- Superficial mycoses
Colonise outermost layers of the skin and hair shaft
Rarely illicit an immune response since they colonise non-living tissue
No physical discomfort to the host, largely cosmetic
e.g. Pityriasis (tinea) versicolor
Common causative organism: Malassezia furfur
Treatment:
- Antifungals e.g miconazole
- Keratolytic agents
- Often simply improving personal hygiene
- Cutaneous mycoses
- Involve the keratinised layer of skin - will illicit an immune response
- Dermatophytosis or tinea
- Can affect skin (ringworm), nails, hair
- Treatable, but impact on patient’s quality of life can be severe
- Risk of developing into invasive disease in immunosuppressed patients
- Common causative organisms: Trichophyton spp.
treatment
- Topically: Imidazoles (e.g. clotrimazole, miconazole) or Terbinafine
- Orally: Griseofulvin, Terbinafine, Itraconazole
- Subcutaneous mycoses
- Rare e.g. chromoblastomycosis
- Usually site of trauma where the organism is planted in tissue, e.g. thorns or splinters
- Normally involves fungi found in soil or decaying vegetation
- Infections initially involve deeper layers of skin, before eventually presenting as lesions on skin surface
- Common causative organisms: Fonsecaea pedrosoi, Cladophialophora carrionii
treatment
- Depends on causative agents
- Amphotericin B
- Potassium iodide given orally
- Systemic fungal infection a. Primary pathogens
- Histoplasmosis – mould found in the soil
- Blastomycosis
- Not normally commensal fungi
- Can cause disease in a healthy individual
- Focus of infection normally lungs, unless infection is severe
- Most infections are short and cause immunity to a second infection
- Can be life threatening if immunocompromised
Treatment:
Amphotericin B (although toxic)
Ketoconazole
- Systemic fungal infection b. Opportunistic pathogens
- These fungi have low inherent virulence
- Take advantage of the host’s debilitated condition
- Immunocompromised are susceptible and if not treated rapidly and aggressively, the condition will become life threatening
-Incidence increasing due to:
HIV/AIDS
Invasive medical procedures
Number of immunocompromised patients
