Antifungal Flashcards
Systemic drugs for subcutaneous and systemic mycoses?
Amphotericin B
Flucytosine
Azoles
Echinocandins
Amphotericin B
Polyene Antibiotic, Broad spectrum to treat all life-threatening fungal infections, esp during pregnancy
Binds ergosterol, forming pores in the cell membrane. These pores allow leakage of intracellular ions and macromolecules, leading to cell death.
Amphoteracin B is insoluble and therefore formulated as deoxycholate colloidal suspension and administered via IV. This formulation penetrates the CSF very slowly therefore an intrathecal therapy may be necessary. Intrathecal admin may cause seizures and serious neurological damage.
**used as initial induction regimen to rapidly reduce current fungal infection, then you move to a better tolerated drug, can be used topically for cutaneous candidiasis
Infusion-related toxicity - universal presenting with fever, chills, muscle spasms, vomiting, headache, hypotension. Premedicate pt with antihistamines, glucocorticoids, antipyretics or meperidine OR slow infusion rate/decrease daily dose.
Renal toxicity - amphotericin B binds to cholesterol and forms pores in mammalian cell membranes. Azotemia, decreased GFR, magnesium and potassium wasting. – this can be attenuated with the administer with saline infusion (sodium loading). With renal toxicity this also causes a decrease in EPO production therefore hypochromic normocytic anemia. Also measure liver function to be safe.
**By packing amphotericin B in to lipid carriers there is a reduced exposure to the nephron so decreased NEPHROTOXICITY
Lipid formulation of amphotericin B
• Liposomal amphotericin B (L-AMB)
• Amphotericin B lipid complex (ABLC)
• Amphotericin B colloidal dispersion (ABCD)
Flucytosine?
Synthetic pyrimidine antimetabolite (Cytosine, Flucytosine, 5-fluorouracil), narrow spectrum used with other agents to avoid development of resistance
- 5-FC is taken into fungal cells via cytosine permease
- 5-FC to 5-FU via cytosine deaminase
- 5-FU to FdUMP
- FdUMP inhibits thymidylate synthetase blocking dTMP synthesis
- F-FU to FUMP
- FUMP to FUDP to 5-FUTP
- 5-FUTP inhibits protein synthesis
Flucytosine+Amphotericin B = synergistic
**indicated for SERIOUS infections caused by CANDIDA and/or CRYPTOCOCCUS
AE - bone marrow toxicity due to accumulation of 5-fluorouracil formation (aka anticancer drug) formed as metabolite
What are the different groups of Azoles?
Imidazoles - Ketoconazole, Miconazole, Clotrimazole
Triazoles - Itraconazole, Fluconazole, Voriconazole, Posaconazole [more specific]
MOA and AE of azoles?
Fungal cytochrome P450 enzyme 14-a-sterol demethylase catalyzes the conversion of Lanosterol to ergosterol. – Azoles inhibit this enzyme therefore reducing ergosterol synthesis, disrupting the membrane and increasing permeability.
AE - relatively nontoxic with minor reaction of GI upset
Ketoconazole?
- Inhibits mammalian cytochrome P450 enzyme
- decreased plasma testosterone levels leading to gynecomastia, decreased libido, loss of potency in men, menstrual irregularities in women
- high doses inhibit adrenal steroid synthesis and decrease plasma cortisol concentrations
- STRONG INHIBITOR of CYP3A4 (low selectivity so affects human cells as well)
- poor penetration of CSF that is best absorbed at low gastric pH
Uses: superficial mycoses, Systemic drug for superficial mycosis Dermatophytosis
[hepatic elimination]
Fluconazole?
- good CSF penetration with high oral bioavailability (IV or oral admin)
- MODERATE INHIBITOR of CYP3A4
- STRONG INHIBITOR of CYP2C9
DOC
- Esophageal, oropharyngeal, vulvovaginal or urinary candidiasis
- Candidemia
- Coccidioidomycosis
- consolidation and maintenance therapy for cyrptococcal meningitis post induction with amphotericin B
- Alt to amphotericin B for non-severe Cryptococcal meningitis
- Initial and secondary prophylaxis against cryptococal meningitis
- Systemic drug for superficial mycosis
*ineffective against aspergillus and other filamentous fungi (only works on yeasts)
[RENAL ELIMINATION]
Itraconazole?
- Metabolized by CYP3A4
- STRONG INHIBITOR of CYP3A4
- poor bioavailability, poor CSF penetration, needs acidic gastric pH to be absorbed
Uses:
- preferred azole for mycoses due to dimorphic fungi blastomyces, sporothrix and histo
- effective against aspergillus (but has been replaced by voriconazole)
- Used for superficial infections - dermatophytoses and onychomycosis (mycosis of the nails)
[hepatic elimination]
Voriconazole?
DOC - INVASIVE ASPERGILLOSIS (as well as everything else Itraconazole covers)
Metabolized by and inhibits CYP2C19, CYP2C9, CYP3A4 [hepatic elimination]
AE - transient visual disturbances
Posaconazole?
Zygomycetes (ex. Mucor) activity
Inhibits CYP3A4
Echinocandins (Caspofungin - prototype)?
Activity against CANDIDA and ASPERGILLUS but NOT cryptococus neoformans
IV administration, structure is cyclic peptide linked to long chain fatty acid
MOA - inhibits synthesis of B(1,3)-D-glucans in the fungal cell wall disrupting its structure leading to cell death
Griseofulvin?
Systemic drug for superficial mycosis used to treat ONLY dermatophytosis. Absorption is improved when administered with fatty foods.
MOA - disrupts mitotic spindle and inhibits mitosis
Uses - severe dermatophytosis of skin, hair and nails, [has recently been replaced by itraconazole and terbinafine]
Induces P450 enzymes
Terbinafine?
Systemic drug for superficial mycosis - Allylamine
Oral formulation
Inhibition of squalene eposidase preventing ergosterol synthesis (step prior to azole activity). Not only does it prevent cell wall synthesis, but also allows for accumulation of toxic levels of squalene in the fungal cell.
Uses - similar to giseofulvin how it accumulates in keratin but is more effective in onychomycosis. Also used topically for tinea cruris and tinea corporis
AE - GI upset, rash, headache, taste disturbance
**DOES NOT AFFECT P450 SYSTEM
Systemic drug for superficial mycosis?
- Nystatin
- Amphotericin B
- Clotrimazole - most commonly used topical azole
- Miconazole - most commonly used topical azole
- Ketoconazole
- Terbinafine - for tenia crurus and tenia corporis
Nystatin?
Cousin of amphotericin B - related structure with same mechanism of action
It is too toxic for IV administration, so is administered via cutaneous, vaginal or oral admin. ONLY USED for CANDIDIASIS. Not absorbed by GI tract, skin or vagina, little significant toxicity due to weak absorption in to systemic circulation.
