Antifungals Flashcards
Risk factors for invasive candidiasis
Prolonged ICU
Central vein catheters
Prolonged broad spectrum therapy
Parenteral nutrition–>fatty content
Recent surgery
Hemodialysis
DM
Aspergillus
Mold within the environment
Primarily causes disease in immunocompromised hosts (neutropenic)
Most common site is pulmonary
Diagnosis: positive cultures
Endemic
May cause disseminated disease via pulmonary infection
May cause disease in normal host: higher risk with suppressed cell-mediated immunity
Prevalence (Indiana)
- histoplasma
- blastomyces
Cryptococcus neoformans
Encapsulated yeast that affects the CNS and respiratory tract
Higher risk with HIV, transplant, high-dose steroids
Causes: cryptococcal meningitis
Amphotericin B
Natural product
Amphoteric–>acidic and basic groups
Structure: lipophilic bottom and hydrophilic top
Macrolide ring–>LOOK AT STRUCTURE
Fungicidal
Amphotericin B MOA
Binds to ergosterol in fungal cell membranes causing leakage of cations & proteins and withdraws ergo from membrane
Specific as humans contain cholesterol
Amphotericin B dosing
Deoxycholate: 0.5-1 mg/kg/day
Liposomal: 3-5 mg/kg/day over 2 hours
Lipid complex: 5 mg/kg/day infused at 2.5 mg/kg/hr
Amphotericin B PK
Poorly absorbed after oral administration–>IV only
Oral is only used for GI infections
Poor penetration into CSF
Not metabolized: degrade in situ
Amphotericin B side effects
Infusion-related reactions:
- pretreat with Tylenol or antihistamines
- solution: reduce rate of infusion or ambisome
Nephrotoxicity!!!
- causes increase in SCr and BUN
- pretreat with 0.5-1 L NS over 30 min before and 0.5-1 L NS after
Electrolyte abnormalities: hypokalemia, hypomagnesemia
Terbinafine (also Naftifine or Butenafine or Tolnaftate
Ergosterol pathway:
Squalene–>squalene epoxidase–>squalene epoxide–>lanosterol–>14-alpha demethylase–>intermediate–>delta-14-reductase–>intermediate–>delta-8-delta-7 isomerase–>ergosterol
Terbinafine MOA
Inhibits squalene epoxidase reducing formation of ergosterol and accumulation of squalene
Fungicidal: 2500-fold selectivity for fungal enzyme compared to humans
Azoles MOA
Inhibits the binding and activation of oxygen by CYP450 in 14-alpha demethylase to inhibit lanosterol to ergosterol
Azole metabolism
Metabolized by CYP450 in the liver into inactive metabolites
Ketoconazole
Structure: dioxolane ring and imidazole ring
Reduced metabolism via CYP3A4
Drug interaction: CYP3A4 inhibitor
Itraconazole
Structure: modified dioxolane ring and triazole ring
1st line: Histoplasmosis, blastomycosis
Itraconazole dose
200 mg PO TID, then 200 mg PO BID
Trough goal > 1.5 ug/mL
Itraconazole PK
Metabolized via CYP3A4
Active metabolite=hydroxyitraconazole
Clearance decreases with higher doses
Absorption is dependent on gastric acidity
Capsule=take with food or acidic cola
Solution= take on empty stomach
Itraconazole side effects
Hepatotoxicity
Congestive HF=Black Box Warning!!
QTc prolongation
CYP3A4 inhibitor
Contraindicated in pregnancy
Fluconazole
Structure: F in place of Cl on benzene and 2 triazole rings
Indication:
1st line for invasive candidiasis
C. albicans–> 800 mg loading then 400 mg
C. glabrata–> 1200-1600 mg loading then 800 mg
Dosing: daily based on TBW
Fluconazole PK
High oral bioavailability (90%)
Decent CSF penetration
60% uninflamed
80% inflamed
Excreted unchanged in the urine
- renal dose adjustment–> ONLY AZOLE
Fluconazole Side effects
QTc prolongation
LFT elevation
Fluconazole drug interaction
CYP2C9 inhibitor
Voriconazole
F in place of Cl on benzene and triazole ring and fluoropyrimidine with a methyl to improve binding
1st line: invasive aspergillosis
Loading: 6 mg/kg q12h
Maintenance: 4 mg/kg q12h or 200 mg q12h
Voriconazole PK
Metabolized by CYP2C19, CYP3A4, CYP2C9–>PGx
Clearance decreases with high doses–>saturation
High oral bioavailability (96%)
- take 1 hour before or after meals
Avoid IV if CrCl < 50 mL/min
