Anti-fungals Flashcards
2 basic forms of fungi
Yeast and mold
Shape of yeast
Single, small, oval cells
Shape of molds
Filamentous strands (hyphae)
Examples of yeasts
Candida spp., cryptococcus spp.
Examples of molds
Aspergillus spp.
Define dimorphic fungi
Species exists as either yeast or mold depending on external environment
What is thermal dimorphism?
Switch from mold form at ambient temperature to yeast form at body temperature
- Genetically controlled
RF for invasive fungal infections (6)
- Hematologic malignancies
- BM transplant
- Solid organ transplant
- Pt on corticosteroids or immunosuppressant meds
- Burn pts
- AIDs pts
Common primary care fungi
C. albicans & non-albicans candida
Examples of non-albicans candida spp.
- C. krusei
- C. glabrata
- C. guilliermondii
- C. lusitaniae
- C. tropicalis
- C. pseudotropicalis
- C. parasilosis
Resistance: C. krusei
Inherently resistent to fluconazole
Resistance: C. glabrata
Relatively resistent to fluconazole
Resistance: C. guilliermondii and C. lusitaniae
Inherently resistent to amphotericin B
Anti-cell wall agent
Echinocandins
Examples of echinocandins
- Caspofungin
- Micafungin
- Anidulafungin
Echinocandins MOA
Inhibit synthesis of B(1,3)-D-glucan (an essential component of cell wall of susceptible fungi)
Why is there low potential for toxicity with echinocandins humans?
Mammalian cells do not require B(1,3)-D-glucan
Echinocandin role in UTI therapy
Generally CANNOT use
- Not excreted in urine
Clinical indications for echinocandins
- Invasive candida infections (including most non-albicans candida)
- Aspergillus
How common is resistance against echinocandins?
Relatively rare
Anti-cell membrane agents
- Polyenes
- Azoles
- Allylamines
Examples of polyenes
- Amphotericin B products
- Nystatin
Amphotericin B products
- Conventional amphotericin B
- Amphotericin B lipid complex
- Liposomal amphotericin B
Which amphotericin B product is best tolerated?
Liposomal amphotericin B (but it’s $$$)
Indications for topical nystatin
- OP candidiasis
- Intertrigo
Polyenes MOA
Binds to ergoesterol -> alter cell membrane permeability -> leakage of cell components -> cell death
Sx that occur during infusions of polyenes
Fever, chills, rigors
Why do pt. experience sx during infusion of polyenes?
Directly stimulate monocytes/macrophages to release proinflammatory cytokines
Drug interactions polyenes
Other nephrotoxic drugs
Clinical indications of polyenes
- Aspergillosis
- Zygomycosis
- Histoplasmosis
- Blastomycosis
- Coccidioidomycosis
- Cryptococcus
- Sporothrichosis
Polyene ADRs (common)
- F/C/rigors
- HA, N/V, decreased BP, tachypnea
- Usually occur 1-3hrs into infusion & last 1 hr.
Treatment of common/infusion associated ADRs
Pretreat w/ APAP, diphenhydramine, meperidine +/- hydrocortisone
Polyene ADRs (dose-limiting)
- Nephrotoxicity
- Electrolyte abnormalities
Treatment of dose-limiting polyene ADRs
- Pre & post-infusion hydration (500mL NS)
- Avoid concomitant nephrotoxins
- Continuous infusion may mitigate
- Monitor SCr, K, Mg (may decrease)
Examples of azoles
- Ketoconazole
- Clotrimazole
- Econazole
- Miconazole
- Terconazole
- Tioconazole
- Fluconazole
- Itraconazole
- Voriconazole
- Posaconazole
- Isavuconazole
Topical “oral” azoles
- Clotrimazole
- Miconazole
Topical “skin” azoles
- Ketoconazole
- Clotrimazole
- Econazole
- Miconazole
Topical “vaginal” azoles
- Clotrimazole
- Miconazole
- Terconazole
- Tioconazole
OLD systemic azoles
- Ketoconazole
- Fluconazole
- Itraconazole
NEW systemic azoles
- Voriconazole
- Posaconazole
- Isavuconazoium
Bolded azoles from lecture
- Clotrimazole (oral, skin, vaginal)
- Miconazole (vaginal)
- Fluconazole (OLD systemic azole; available PO & IV)
Fluconazole MOA
Inhibit fungal CYP450 enzyme which converts lanosterol -> ergosterol (cell membrane); leads to cell lysis
Fluconazole MOR
- Mutations in 14a-demethylase (enzyme that converts lanosterol to ergosterol)
- Efflux pumps
Fluconazole is a strong INHIBITOR of CYP___, ____, and ____
2C9, 2C19, and 3A4
Fluconazole pharmacology
- Renally excreted (80% unchanged)
- > 90% bioavailability
- 30 hr half life
Clinical indications of fluconazole
- Candida infections (thrush, vaginitis, cutaneous, “invasive”)
In what population do we avoid the use of fluconazole?
Women TRYING to become pregnant & pregnant women
What should we use instead of fluconazole for pregnant women with vaginal candidiasis?
Clotrimazole (or other “vaginal” azoles)
Implications of fluconazole use in pregnancy
- Birth defects
- 1-2 doses linked to miscarriage in 1st and 2nd trimester
Birth defects associated with use fluconazole in pregnancy
- Short, broad head
- Abnl looking face
- Abnl development of the skullcap
- Oral cleft (lip or palate)
- Bowing of the thigh bones
- Thin ribs and long bones
- Muscle weakness and joint deformities
- CHD
Example of allylamines
Terbinafine
Terbinafine MOA
Inhibits squalene epoxidase -> inhibits ergosterol synthesis -> deficient cell membrane -> cell death
Terbinafine is a strong INHIBITOR or CYP___
2D6
What happens when terbinafine is taken orally?
Deposits in skin/nails resulting in relatively low bloodstream concentration
Clinical indications of terbinafine
- Cutaneous dermatophyte infections (topical)
- Onychomycosis (PO)
How long do we treat onychomycosis of the fingernails? Toe nails? And WHY?
Finger nails = 6 wks
Toe nails = 12 wks
*it takes months for nail to grow out
Terbinafine ADRs
- Dysgeusia (may persist after drug cessation)
- Hepatotoxicity
What do we do to monitor pt. on terbinafine?
Baseline LFT + “periodically” while on the drug
Category B antifungals
- Amphotericin
- Clotrimazole (skin, vaginal)
- Allylamines
Category C antifungals
- Echinocandins
- Most azoles
Category D antifungals
Fluconazole
