Antifungals Flashcards
All antifungals target the __________________, except ______________.
Cell membrane or cell wall; Griseofulvin and Flucytosine
DOC for all systemic fungal infections
Amphotericin B (Fungizone)
MOA of Amphotericin B
Polyene antifungal abx that binds to ergosterol (sterol of the fungal membrane) to form pores in the membrane
FUNGICIDAL because of the pores
Broadest spectrum antifungal
Amphotericin B
Downsides to amphotericin B
IV - must be given in hospital
Poor CNS penetration
Excreted slowly by kidney —> VERY nephrotoxic (but that shouldn’t stop you from giving it because systemic fungal infections are life threatening)
What is the theory behind amphotericin B toxicity
The target of amphotericin B (ergosterol) is structurally quite similar to human cholesterol
Infusion related amphotericin B toxicities
Chills (give them a blanket, damnit)
Fever, muscle spasms, vomiting headache
May occur with each injection
Can be lessened by slowing infusion rate or decreasing daily dose
Cumulative toxicities of Amphotericin B
POWERFULLY nephrotoxic agent (azotemia)
Don’t give together with other nephrotoxic meds (ie aminoglycosides)
Renal damage is dose dependent (can be irreversible)
6 weeks to 4 months of treatment
Azotemia
Azo= nitrogen
The BUN and serum creatinine levels are elevated
Indicative of kidney failure
MOA for Flucytosine
Metabolic antagonism of fungal DNA and RNA.
Flucytosine is converted to 5-fluorouracil which can then inhibit DNA or RNA synthesis
Has a tendency to disrupt normal flora
Antifungals good for CNS penetration
Flucytosine (for systemic infections)
Fluconazole
DOC for Cryptococcus infections
Flucytosine (because it can penetrate the CSF) plus amphotericin B
Spectrum for Flucytosine
Lower than Ampho B Cryptococcus neoformans*** Some Candida Aspergillosis fumigate Sporotrichum schenckii
Flucytosine toxicity
Depression of bone marrow (anemia, leukopenia, thrombocytopenia)
May elevate ALT/AST - effect is reversible upon discontinuation
GI disturbances (because it disrupts normal flora)
MOA for the Azoles
Inhibit the synthesis of ergosterol - leads to the depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth (fungistatic)
Ketoconazole
Broad antifungal spectrum
Not that great for systemic infections (used pretty much in shampoo now, not really used orally anymore)
Low CNS penetration
Toxicity with Ketoconazole
POTENT INHIBITOR of P450s —> drug interactions
Gynecomastia and impotence due to inhibition of adrenal and testicular function
Prolonged QT
Contraindicated with acute or chronic hepatic disease
Only considered when you can’t use anything else
Fluconazole (Diflucan)
Oral and IV
Good CNS penetration - good for fungal meningitis
Good for suppressive and/or prophylactic therapy in HIV+ patients
Less toxic than Ampho B or flucytosine and better tolerated than ketoconazole
Less drug interactions than other azoles (but inhibits CYP2C9)
Headache in 10-15%
DOC for Aspergillus
Voriconazole + amphotericin B
Voriconazole
IV and Oral
Modest CSF penetration
DOC for aspergillus with Ampho B
Drug interactions for Voriconazole
Metabolized by P450s (2C19>2C9>3A4) Inhibits P450s (2Cp>3A4>2C19) - inhibits itself but not completely
May see some differences in the populations based on genetics
Other voriconazole toxicities
Visual impairment (can be reversible) - changes in visual field and acuity, photophobia, and changes in color/light perception
Not well studied - just take them off it
Itraconazole
Active against many of the same fungi as ketoconazole and fluconazole but has great aspergillus activity (backup DOC behind voriconazole)
Oral, IM
Potent inhibitor of CYP3A4
Oral bioavailability of itraconazole
Capsules F=40-55% if on empty stomach, 90-100% with meal
Oral solution is 55% when fed and 72% on empty stomach
KEY - two dosage forms should not be used interchangably
Isavuconazonium (Cresemba)
Azole in terms of MOA (inhibits ergosterol synthesis)
QT and nephrotoxicity
Posaconazole (Noxafil)
Azole, it’s an new option, but not a lot of data
Lots of drug interactions
Backup for aspergillus and candida
MOA for echinocandins
Inhibits synthesis of ß(1,3)-D-glucagon (fungal cell wall component not seen in mammals)
Fungicidal
Caspofungin
Penicillin of the antifungals
Lack of nephrotoxicity and few drug interactions = good treatment option
Good for invasive aspergillosis in refractory patients
The other two echinocandins (Micafungin and Anidulafungin) are very similar but a little less effective
Alternate DOC for Aspergillis if Voriconazole + Ampho B doesn’t work
Caspofungin
DOC for onychomycosis
Oral Griseofulvin
May also give a topical, but need the griseofulvin to bind to keratin and take away the infection food source
Dermatophytosis
Fungal infection that affects different parts of the body, caused by a group of fungi known as dermatophytes.
Fungi invade and feed on keratin
Onychomycosis
Ringworm of the nail, can be caused by dermatophytes, candida or nondermatophyte molds
MOA for griseofulvin
Binds to the microtubles of certain fungi and destroys the mitosis spindle structure - fungistatic
Binding to the keratin takes away the food source for the dermatophytes - they can’t infect new cells
Griseofulvin toxicity
Headache
Some disulfiram-like effects
Contraindicated:
Acute intermittent porphyria
Hepatocellular failure
Pregnancy and men 6 months prior to fathering a child (some teratogenicity)
Terbinafine
Inhibits ergosterol synthesis like azoles, but causes cell death (azoles do not)
Oral or topical, 2nd drug for onychomycosis
DOC for candidal infections
Oral nystatin
MOA for nystatin
Polyene like Ampho B —> pores in cell membrane
Used primarily for candidal infections (orally) or topically for other infections
