L12 - Treatment of Fungal Diseases Flashcards
What are the four main classes of antifungals? - Give an example
Polyenes (Amphotericin B)
Azoles (Voriconazole)
Echinocandins (Caspofungin)
Allylamines (Terbinafine)
What is the MoA of Polyenes?
Polyenes bind to Ergosterol in the cell membrane, weakening it
What is the MoA of Azoles?
Azoles inhibit the conversion of Lanosterol to Ergosterol (c14a-demthylase)
What is the MoA of Allylamines?
Allylamines inhibit the conversion of Squalene to Lanosterol (Squalene epoxide)
What is the MoA of Echinocandins?
Echinocandins inhibit glucan synthesis in the cell wall (B-1,3-D-glucan synthase)
What is the MoA of 5-Flucytosine?
5-Flucytosine is an antimetabolite pyrimidine analogue
Define selective toxicity
The ability to be toxic to microbial cells but not host cells
What are the problems with selective toxicity?
Sterols (cholesterol) are present in host plasma membranes
CYP450 system in host hepatocytes
Nucleic acids in host cells
How can we achieve selective toxicity?
Topical application
Target specificity
Describe Amphotericin B toxicity - Acute reactions
30 mins post infusion
Chills, fever, SoB, drop in BP, aches
Peaks @ 1h, lasts <4h
Induction of Prostaglandin E2
How can we treat for Amphotericin B toxicity? - Acute reactions
Test doses and escalate slowly
Pre-medicate (NSAIDs/steroids)
Describe Amphotericin B toxicity - Renal toxicity
Vasoconstriction of afferent renal aa
K, Mg, HCO3- loss
Decreased EPO
Loss of nephrons
How can we treat for Amphotericin B toxicity? - Renal toxicity
Regular renal monitoring
Electrolyte replacement
Amiloride
Describe Amphotericin B toxicity - Rarer symptoms
Anorexia, nausea, vomiting
Phlebitis
Gradual anaemia (decreased EPO)
Thrombocytopaenia, leucopenia, coagulopathy
Tinnitus, vertigo, seizures, encephalopathy
Anaphylaxis/allergy
What is an appropriate dose of AmB?
3-5mg/kg
What are the three lipid formulations of Amphotericin B?
Liposomal AmB (L-AmB)
AmB colloidal dispersion (ABCD)
AmB lipid complexes (ABLC)
Describe L-AmB
60-70nm vesicles
Describe ABCD
~115nm diameter discs
What is the disadvantage of lipid formulations of AmB?
Expense
Why do we use lipid formulations of Amphotericin B?
AmB is released by preferential affinity to Ergosterol/action of phospholipase, avoiding toxicity
Describe ABLC
1600-11000nm ribbons
Describe the Antifungal spectrum
AmB - Largely effective (Scedosporium)
Fluc - Rarely effective
Itra - Somewhat effective
Vori - Largely effective
How does resistance to AmB arise?
Alteration of Ergosterol (reduces fungal fitness)
How does resistance to Azoles arise?
Altered c14a demthylase
Efflux mechanisms
How does resistance to 5-Flucytosine arise?
Decreased permeability
Altered phosphorylation
Resistance only common in monotherapy
Describe the formulation of Echinocadins
Lipopetide side chains determine solubility
i.v. route only
What is the activity of Echinocandins restricted to?
Candida spp (cidal) Aspergillus spp (static)
What are the side effects of Echinocandins?
Phlebitis Fever Headache Hepatotoxicity Haemolysis
Define mycoses
Mild to severe infections with fungi
Give examples of the superficial mycoses
Skin - Dermatophytosis
Nails - Onychomycosis
Mucous Membranes - Candidasis
Give examples of the deep mycoses
Invasive candidasis
Aspergillosis
Cryptococcosis
What moulds cause dermatophytosis? - Tineas
Trichophyton
Microsporum
Epidermophyton
What yeasts cause dematophytosis?
Malassezia
What predisposes patients to invasive candidasis?
Indwelling devices
Damaged mucosae
Immunocompromised
What antifungals are used to treat invasive candidasis?
AmB
Fluconazole
Caspofungin
Micafungin
What antifungals are used to treat aspergillosis?
AmB
Itraconazole
Voriconazole
Caspofungin
What problem does cryptococcus cause in HIV?
Meningitis
What antifungals are used to treat cryptococcus?
AmB +/- 5-Flucytosine
What antifungals are used to treat endemic mycoses?
AmB
Itraconazole
