Antifungals Flashcards
Classification of mycoses: (2)
- systemic (potentially life threatening)
2. Superficial
Current effective antifungal agents target
- membranes (ergosterol)
- nucleic acids (limited)
- cell wall (1 drug class)
Drugs used for systemic fungal infections
- Amphotericin B
- flucytosine
- Imidazoles and bis-triazoles:
- fluconazole
- itraconazole
- voriconazole
- Caspofungin
Amphotericin B
- effective (broad spectrum agent) for most serious systemic mycoses
- especially those that are immediately threatening
- Gold standard for anti-fungal effectiveness by which other drugs are judged
uses of amphotericine B
-due to side effects, only used for proven or highly suspected systemic infections
mechanism of action amphotericin B
-very lipophillic; binds ergosterol in fungal membranes producing rapid membrane instability/leakage
explain the dosing of amphotericin B and the importance of it
Total cumulative dose is very important because if you go over 3-4 g of amphotericin B then you can get irreversible kidney damage
side effects for Amphotericin B
- fever, nausea, vomiting, headache, chills
- hypotension, hypokalemia, tachypnea
- 90% will show nonpermant nephrotoxicity
- permanent renal damage can occur (total dose)
- reversible hypocromic, normocytic anemia
Flucytosine (5-FC)
- Serious infections: Candida, cryptococcus
- used in conjunction (synergistic) with amphotericin B
MOA of Flucytosine (5-FC)
-fungi contain a cytosine deaminase not found in humans which converts 5-FC to 5-FU- metabolites of 5-FU then block nucleic acid synthesis
side effects of Flucytosine
- nausea, vomiting diarrhea, enterocolitis
- Leukopenia, thrombocytopenia
- use extreme caution in those with renal insufficiency or bone marrow depression
- reversible elevated hepatic enymes
Imidazole and triazole antifungals for serious fungal infections
- fluconazole
- voriconazole
- itraconazole
MOA of the imidazoles and triazoles (fluconazole itraconazole and voriconazole)
- inhibits 14-a-sterol demethylase, a fungal cytochrome P450 that converts lanosterol to ergosterol
- net effect is inhibit ergosterol synthesis. Not a rapid onset of action because no effect on existing ergosterol
Clinical uses of Fluconazole
- Cryptococcus
- Candida: many sites including CNS and urinary
- some C. albicans
- some C glabrata
- but NOT C krusei
Clinical uses itraconazole
- Blastomyces
- Histoplasma
- Candida in esophagus and oropharynx (NOT CNS and urinary)
- more albicans and glabrata
Clinical uses of voriconazole
- Aspergillus
- Candida (NOT urinary)
- many species including glabrata and krusei
which of the -azoles (fluconazole, itraconazole, voriconazole) penetrate the CNS
Fluconazole is the only -azole that penetrates the CNS
which of the -azoles (fluconazole, itraconazole, voriconazole) is an active drg in the urine
Fluconazole if the only -azole that is active in the urine
side effects common to fluconazole, itraconazole, voriconazole
- nausea, vomiting, rash, diarrhea, headache
- mild hepatotoxicity: discontinue with onset of liver dysfunction
- inhibits metabolism of several other drugs: potent inhibitor os cytochrome P450s (CYP3A and 2C families) which metabolize about 70% of all drugs
itraconazole contraindications
- do not give itraconazole with other drugs that are metabolized with CYP3A4
- potential for serious cardiovascular events including death when some of these drugs are given with itraconazole
which of the -azoles (Fluconazole, itraconazole, voriconazole) has the LOWEST incidence of hepatotoxicity
-Fluconazole
side effects uniqe to voriconazole
- visual disturbances (30%)
- Photosensitive compoennt to rash
antifungals that target cell wall
Caspofungin
Caspofungin
- treatment of invasive Aspergillus
- Candidda, esophageal and systemic
- broad species coverage including glabrata and krusei
MOA Caspofungin
- inhibits fungal cell wall synthesis by noncompetitively blocking synthesis of B (1,3) D glucan
- no cross resistance with imidazoles and triazoles
side effects of Caspofungin
- fever, nausea/vomiting, flushing
- phlebitis at injection site
Drugs for treatment of superficial mycoses
- nystatin
- Imidazoles and bis-triazoles
- Fluconazole
- miconazole
- clotrimazole
- itraconazole
- Ophthalmic Infections
- natamycin
Fluconazole-superficial
- mucous membrane Candida infections
- oral dose
- vaginal
- urinary tract
- oropharynx
Miconazole-suerficial
-topical for vaginal Candida
Clotrimazole-superficial
- Candida
- Topical use
- oral troches or vaginal creams
side effects Clotrimazole
abnormal liver function
Itraconazole superficial infection
- Candida
- oropharyngeal ad esophageal
- oral dose, not topical
Nystatin
- mechanism similar to amphotericin B
- topical use for Candida
- side effects: GI distress
Amphotericine B superficial infection
- topical
- cutaneous or mucosal Candida: not for dermatophytes
Treatment of ophthalmic fungal infections
-natamycin
natamycin
- Use
- Mechanism
- toxicity
- ophthalmic infections (topical)
- specially useful for Fusarium, Cephalosporium
- mechanism similar to amphotericin B
- toxicity: conjunctival chemosis and hyperemia
Topical Treatments for dermatophytes
- miconazole, clotrimazole
- tolnaftate
- terbinafine
- ciclopirox
topical treatment for fungal nail infections
- Ciclopirox
- Terbinafine
Ciclopirox
- FDA approved topical Rx for mild to moderate fungal nail infections
- 48 weeks
Terbinafine
- 12 week therapy for nail infections
- blocks synthesis of ergosterol
Terbinafine side effects
diarrhea, dyspepsia, abdominal pain
inhibits CYP2D6
Griseofulvin
- use
- MOA
- for recalcitrant dermatophytic infections of skin, hair, nails
- treatment for tinea capitis
-interferes with microtubule function/mitotic spindle/mitosis
Griseofulvin side effects
- contraindicated in those with porphyria ad advanced liver disease
- increased metabolism of several drugs
- use with caution in those with penicillin allergies (bc produced in Penicillum mold)
Itraconazole-dermatophyte
use and side effects
-oral 3 month therapy for fungal toenail infections
- se:
- nausea vomiting, rash diarrhea, headache, edema
- inhibits metabolism of many drugs
- discontinue if signs of liver dysfunction appear
