Mechanism of action of Antifungals Flashcards
List the main fungal agents that infect humans and the disease entities that they cause.
1) Yeasts
○ Candida spp. → thrush, fungaemia (in immunocompromised patients)
○ Cryptococcus neoformans → meningitis, pneumonia, fungaemia
○ Pityriasis versicolor → Chronic skin infection
○ Systemic yeasts (e.g. Histoplasma capsulatum) → Pulmonary, pericardial, or disseminated infections
2) Filamentous fungi
• Aspergillus spp. → Pulmonary or ocular infection, farmer’s lung (inflammatory pneumonitis). Three main disease entities: aspergilloma (fungal mass growing in damaged part of lung), invasive aspergillosis, allergic bronchopulmonary aspergillosis
• Dematophytes → Chronic infections of skin, nails, kerion
Define the main kinds of aspergillosis.
“1) Allergic bronchopulmonary aspergillosis: spergillus causes inflammation in the lungs and allergy symptoms such as coughing and wheezing
2) Invasive aspergillosis: serious infection that usually affects people who have weakened immune systems, such as people who have had an organ transplant or a stem cell transplant. Can “spread rapidly from the lungs to the brain, heart, kidneys or skin”
3) Aspergilloma: ball of Aspergillus that grows in the lungs or sinuses, but usually does not spread to other parts of the body”
Describe symptoms treatment of aspergillosis.
Patients can be asymptomatic. If not, can develop haemoptysis, cough, SOB.
Corticosteroids, anti-fungals, lobectomy (if necessary)
List the main classes of anti-fungal agents.
-Triazoles
-Polyenes
-Flucytosine
-Echinocandins
-Terbinafine
-Griseofulvin
List the main examples of triazoles and describe the main clinical uses of each (including any cautions).
1) Fluconazole:
-Fungal meningitis (very well absorbed into oral administration + achieves good penetration in CSF)
-Candiduria because secreted largely unchanged in urine.
2) Itraconazole:
-Dematophytes (requires acid environment in the stomach for optimal absorption)
3) Posaconazole:
-Invasive fungal infections unresponsive to conventional treatment.
4) Voriconazole:
-broad spectrum antifungal, used in life-threatening infections.
FLUCONAZOLE
-Mechanism of action
MECHANISM OF ACTION
-“Inhibits the fungal cytochrome P450 enzyme 14α-demethylase in the cell wall
-This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane
-This results in increased cellular permeability causing leakage of cellular contents”
POLYENES
-List the main examples of polyenes and their clinical uses.
AMPHOTERICIN
-IV infusion, used for systemic fungal infections and is active against most fungi and yeasts. Highly protein bound and penetrates poorly into body fluids and tissues.
NYASTATIN
-Local application on skin, used for oral, oropharyngeal, and perioral infections.
POLYENES
-Mechanism of action
Binds to ergosterol in fungal membrane causing membrane to become
leaky (increases permeability)
FLUCYTOSINE
-Mechanism of action
-Clinical uses
-Mechanism of action: : Flucytosine (5-FC) enters the fungal cell through active transport on ATPases. Once inside cells, converted to active 5-fluorouracil (5FU) which is incorporated into RNA causing faulty RNA synthesis and thus inhibits protein synthesis.
-Clinical uses: systemic yeast and fungal infections; adjunct to amphotericin in cryptococcal or severe systemic candidiasis
ENCHINOCANDINS
-List examples
-Mechanism of action
-Clinical uses
♠ Anidulafungin
♠ Caspofungin
♠ Micafungin
-Mechanism of action: Act by inhibiting beta-(1,3)-D-glucan synthase (“to disturb fungal cell glucan synthesis”)
-Clinical uses: Fungicidal against candida spp. + fungistatic against Aspergillus spp. (but not used for aspergillosis treatment)
TERBINAFINE
-Mechanism of action
-Clinical uses
-Mechanism of action: Inhibitors of the
first step in ergosterol biosynthesis, the conversion of squalene to squalene-2,3-
epoxide by squalene epoxidase. The buildup of squalene in the cell membrane is toxic to the cell, causing pH imbalances and malfunction of membrane bound proteins.
-Clinical uses: dermatophyte infections of the nails, ringworm infections (including tinea pedis) where oral therapy appropriate (due to site, severity or extent)
GRISEOFULVIN
-Mechanism of action
-Clinical uses
-Mechanism of action: Fungistatic, causes disruption of mitotic spindle, inhibiting mitosis
-Clinical uses: dermatophyte infections of the skin, scalp, hair and nails where topical therapy has failed or is inappropriate
Define invasive candidiasis and the treatment for it.
Serious infection by candida spp. that can affect the blood, heart, brain, eyes, bones, and other parts of the body.
TREATMENT:
♦ Echinocandin
♦ Fluconazole- alternative for Candida albicans infections in clinically stable patients who have not receive an azole antifungal recently
♦ Amphotericin- other alternative when echinocandin or fluonazole cannot be used+ should be considered for initial treatment for CNS candidiasis
♦ Voriconazole- alternative for infections by fluconazole-resistant Candida spp. when oral therapy is required, or in patients intolerant of amphotericin or an echinocandin.
How is superficial candidiasis treated ?
♣ Miconazole (local treatment) for most superficial candidal infections including infections of the skin
♣ Widespread or intractable infections are treated with systemic anti-fungal treatment (e.g. fluconazole)
♣ Resistant organisms treated with oral itraconazole.
♣ Oropharyngeal candidiasis treated with topical therapy (nystatin mouthwashes)
How is aspergillosis treated ?
• Voriconazole (first line)
• Liposomal amphotericin (first line) if ^cannot be used
• Itraconazole can be used in patients who are refractory to, or intolerant of, voriconazole and liposoma amphotericin
• Itraconazole also used for treatment of chronic pulmonary aspergillosis or as an adjunct in the treatment of allergic bronchopulmonary aspergillosis
