Anti-Fungal Drugs

Classification
Antibiotics
Polyenes=Amphotericin B, Nystatin
Echinocandins=Caspofungin,Micafungin,Anidulafungin
Heterocyclic benzofuran=Griseofulvin
Antimetabolite
Flucytocine
Allylamines
Terbinafine
 Azoles
Imidazoles
• topicals=Clotrimazole,Miconazole
• systemic=Ketoconazole
Triazoles(systemic)=Fluconazole,Itraconazole,Voriconazole
Sterols
• Steroids with alcohol groups
present
• Cholesterol: animal cell
membranes
• Ergosterol: fungal cell
membranes
Mechanisms of action
Amphotericin B
• Binds ergosterol=Forms pores in membrane
• Electrolyte leakage = cell death
• Used for systemic fungal infections
Candidemia
Mucormycosis
Cryptococcus
Systemic histoplasmosis, blastomyces, coccidiomycosis
• Usually given intravenously
• Intrathecal administration meningitis
• Several unique and important side effects
Mechanisms not completely understood
Many related to binding of cholesterol
• Fever, chills
May be related to prostaglandin release
Minimize with NSAIDs
• Phlebitis
Pain, inflammation of vein used for infusion
Avoided by using a central line
Sometimes hydrocortisone given with infusion
• Hypotension, arrhythmias
• Nephrotoxicity
Causes renal vasoconstriction and toxic to tubules
Hydration reduces this complication
Liposomal Amphotericin B=Reduced incidence of nephrotoxicity
anemia due to decreased EPO production by kidney
Hypomagnesemia, hypokalemia
Distal (Type I) RTA
Nephrogenic diabetes insipidus=Hypernatremia
Nystatin
• Binds ergosterol (same mechanism Ampho B)
• Binds ergosterol=Forms pores in membrane
• Electrolyte leakage = cell death
• Used for systemic fungal infections
Candidemia
Mucormycosis
Cryptococcus
Systemic histoplasmosis, blastomyces, coccidiomycosis
• Highly toxic when given IV
• Not used systemically
Flucytosine
• Blocks fungal DNA/RNA synthesis
• Converted to 5-fluorouracil by cytosine deaminase
• Cytosine deaminase only present in fungi
• Causes impaired DNA/RNA synthesis
dUMP dTMP(thymidylate synthase)
• High incidence resistance when used alone
• Used in combination with Amphotericin B
• Main use is cryptococcal meningitis
• Major side effect is bone marrow suppression
• Some spontaneous conversion to 5-FU
• Leukopenia, thrombocytopenia
Azoles
Fluconazole, itraconazole, voriconazole, clotrimazole, miconazole,
ketoconazole
• Block ergosterol synthesis
• Inhibit P450 enzyme in fungi
• Enzyme converts lanosterol to ergosterol
• Side effects related to this mechanism:
• Inhibits liver P450 system
• Elevated levels of P450 meds (warfarin, theophylline)
• Hepatotoxicity
• Reported with all azoles
• LFTs monitored in patients on these drugs (oral)
Ketoconazole
• Life-threatening hepatotoxicity reported
• Rarely used any longer for this reason
• Suppresses cortisol synthesis (can be used in Cushing’s)
• Suppresses testosterone synthesis (causes gynecomastia)
Itraconazole
• Drug of choice for fungal pneumonias
• Also Sporothrix
Fluconazole
• Excellent activity against Cryptococcus
• Vulvovaginitis (Candida)
Clotrimazole
• Diaper rash
Voriconazole
• Severe, systemic fungal infections (Aspergillus)
• These agents are used as antifungal creams and pessaries for 7 to 14
days for Moniliasis. Examples:
Nystatin pessary,bd x10 days
Miconazole cream 2% x7days
Clotrimazole 100mg vaginal tablet x 7days or 1% cream for 7 to 10 days
Ketoconale 400 mg daily x 5days
• Fluconazole 150 mg single dose has also been found to be very
effective
• Husband should be treated with Nystatin ointment locally for few
days following each act of coitus
Echinocandins
Caspofungin, micafungin
• Inhibit cell wall synthesis
• Block synthesis of β-glucans (polysaccharides)
• β-glucans account for 30-60% cell wall
• Used for severe, systemic infections
Aspergillus
Candidemia
• Few side effects
GI upset
Infusion-related histamine release (flushing)
Terbinafine
• Blocks squalene epoxidase
• Key enzyme for ergosterol synthesis
• Given orally to treat dermatophyte infections
• Especially onychomycosis
• Side effects:
Headache (13% patients)
Hepatotoxicity (monitor LFTs)
Rarely blurry vision
Griseofulvin
• Blocks mitosis by interfering with microtubules
• Deposits in tissues with keratin
• Binds to keratin = resistance to fungal invasion
• Oral therapy for skin/nail infections
Side effects:
• Induces P450 (warfarin, theophylline levels will fall)
• Teratogenic: not safe in pregnancy
• Carcinogenic
• Other adverse effects:
• Liver toxicity
• Photosensitivity
• Porphyria attacks