Antifungals Flashcards
Superficial mycoses
limited to outermost layer of skin and hari
Cutaneous mycoses
extended deeper into epidermis, and also include invasive hair and nail diseases; restricted to keratinized layers of skin, hair, nails; “dermatophytes” - athlete’s foot, ringworm, etc.
Subcutaneous mycoses
involve dermis, subcutaneous tissues, muscle and fascia; chronic and can be initiated by trauma to skin allowing fungi to enter; difficult to treat and may require surgery
Cause of subcutaneous mycoses
trauma to skin allowing fungi to enter
Systemic mycoses due to primary pathogens
start in lungs and spread to many organ systems; inherently virulent
Systemic mycoses due to opportunistic pathogens
immune deficiencies who would otherwise not be infected (AIDS, abx); ex. Candidiasis, Aspergillosis, Cryptococcosis
Opportunistic pathogens
Candidiasis, Aspergillosis, Cryptococcosis
What is the main target of antifungals? what drugs are the exceptions?
Cell wall/membrane; Griseofulvin and flucytosine
What is amphotericin B
polyene antifungal abx produced by strep nodosus
MOA of amphotericin B
interaction with sterol of fungal membrane, ergosterol, that causes depolarization and results in loss of intracellular components – pore formation (CIDAL)
Spectrum of ampho B
broad; fungicidal
DOC for systemic infections
Ampho B
Ampho B kinetics
IV
poor CNS penetration
Excreted slowly by kidney (nephrotoxic)
Detected in urine several weeks after therapy
Toxicities of amphotericin B
bind to human membrane sterols leading to toxicities:
Infusion related toxicity (immediate): chills, fever, muscle spasms, vomiting, h/a,; lessened by slowing infusion rate/decreasing dose
Reaction over time (cumulative): NEPHROTOXIC; Azotemia * (elevated BUN and creatinine); renal damage is dose dep. and can lead to irreversible kidney damage
acute hepatic failure, jaundice, anorexia, nausea, weight loss, hypokalemia
Hypersensitivity
Give w/ caution with aminoglycosides (nephrotoxic)
6weeks-4 months of treatment
Ergosterol mimics
Cholesterol in humans- leads to toxic side effects of ampho B
Duration of Ampho B
use as short a time as you can, then switch to something less; usually 6 weeks-4 months
Flucytosine use
great for CNS infections
Flucytosine (5-FC) MOA
antagonism of fungal DNA and RNA; flucytosine is converted to 5-fluorouracil which interferes w/ fungal DNA/RNA synthesis
Converts 5-FC to 5-FU
cytosine deaminase
Cytosine deaminase
bacterial have it; humans do not.
Side effect of flucytosine
GI intolerance; only bacterial have cytosine deaminase; won’t convert prodrug to active drug
DOC for cryptococcus
flucytosine (CNS) + amphotericin B
Seen in HIV patients
TB
Cryptococcus
Spectrum of flucytosine
lower than ampho B, cryptococcus*, some strains of candida, aspergillus, sporotrichum
Gets into CNS
flucytosine
Fluconazole
Voriconazole (some)
Kinetics of flucytosine
absorbed orally
enters CSF and aqueous humor
renal elimination (renal impairment can lead to toxicity)
Toxicity of flucytosine
depression of bone marrow (anemia, leukopenia, thrombocytopenia)
GI distrubances
Elevate ALT or AST (reversible upon discontinuation of the drug) (liver function)
Azoles
Ketoconazole Fluconazole* Voriconazole Itraconazole Isavuconazonium Posaconazole
(Kate finds veronica in interesting places)
Azole MOA
inhibit synthesis of ergosterol- leads to depletion of ergosterol in cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth (fungistatic)
Cidal
Ampho B
Flucytosine
Static
Azoles (immune competant individuals)
Ketoconazole spectrum
broad antifungal (like ampho B)
Ketoconazole kinetics
oral
widely distributed in body, largely bound to plasma albumin, low CNS penetration
extensively metabolized prior to elimination (hepatic)
Ketoconazole typically only used as
shampoo or topicals
Ketocanazole
GI upset, pruritus
POTENT INHIBITOR OF P450
Gynecomastia and impotence (inhibition of adrenal and testicular function)
Prolonged QT
elevation of serum enzymes
Dizziness, somnolence, H/a, arthralgia, myalgia, fever/chills, N/v
Contraindications of ketoconazole
acute/chronic hepatic disease
Oral ketoconazole
only used when no other antifungal tx can be used
Fluconazole
oral/IV
penetrates body fluids, CSF
DOC for fungal meningitis
Fluconazole
Use of fluconazole
fungal meningitis
suppressive and/or prophylactic therapy in HIV patients (+ bactrim)
Toxicity of fluconazole
less toxic than ampho B/flucytosine, better tolerated than keto
less drug interactions, but potent inhibitor of CYP2C9
H/A*, GI
Voriconazole kinetics
IV/oral
Modest CSF penetration
hepatic elimination
DOC for aspergillus
Vorizonazole + ampho B
Voriconazole use
Aspergillus
Esophageal candidiasis
Voriconazole toxicity
Drug interactions (metabolized by p540 and inhibits P450- drug interaction w/ itself; metabolized by 2C19, inhibits 2C19 the least); 2C19 genetic polymorphism (extensive/poor metabolizer: changes drug concentration)
Visual impairment: reversible; acuity, photophobia, changes in color/ligh; take off drug
Itraconazole spectrum
similar to ketoconazole and fluconaole but greater activity against Aspergillus (but voriconazole is DOC for Asp- itraconazole has drug interactions)
Itraconazole kinetics
Oral, IM;
oral bioavailability: capsules higher than oral solution; two dosage forms should not be used interchangeably!!!
Least drug interactions
fluconazole
2C9 inhibitors
fluconazole
voriconazole
Isavuconazonium
azole; little toxicity - nephrotoxicity, QT, CYP3A4 inhibitor
Posaconazole
drug interactions; asperigillus/candida
Echinocandin drugs
Caspofungin
Micafungin
Anidulafungin
Echinocandin MAO
inhibits the synthesis of major fungal cell wall component, beta-1,3-D-glucan, which is not present in mammalian cells
PCN if antifungals
Echinocandins
Caspofungin properties
IV, slow infusion
Cidal “PCN of antifungals”
lack of nephrotoxicity and few drug interactions = attractive tx
Caspofungin use
invasive Aspergillosis in refractory patients (azole or ampho B resistant; esophageal candidiasis
Caspofungin toxicity
elevated liver enzymes (AST, ALT), histamine release, H/A, chills, GI side, effects occur
Micafungin and Anidulafungin
similar to caspofungin, altered pharmacokinetic properties
Local/Topical tx
Griseofulvin
Terbinafine
Nystatin
Dermatophytosis
Fungal infection that infects diff parts of the body; caused by group of fungi known as dermatophytes; invade and feed on keratin, outer layer of skin, hair, nails
Onychomycosis
dermatophytic onychomycosis “ringworm of the nail”
Caused of onychomycosis
dermatophytes, candida, and nondermatophytic molds
Griseofulvin MOA
bind to microtubules of certain fungi and destroys the mitotic spindle structure; fungiSTATIC
DOC onychomycosis
Griseofulvin
Griseofulvin use
onychomycosis; dermatophytosis infections of skin, hair, nails
Griseofulvin kinetics
STATIC
ORAL ONLY - no topical; poor solubility/asorption
Binds to keratin; prevents infection in new skin structures
excreted uncahnged in feces
Tx time for griseofulvin
6mo-1 year to allow for replacement of infected keratin
Griseofulvin toxicity
H/A*, GI, disulfiram-like effect *, CNS
Hematological distrubances, skin rash, photosensitivity, angioedema, albuminuria, hepatotoxicity, leukopenia
Contraindications of griseofulvin
Acute intermittent porphyria (increase attacks and heme production)
hepatocellular failure
Pregnancy and men 6 months prior to fathering child!!!!!!
Terbinafine
oral/topical
CIDAL
Terbinafine use
onychomycosis (not DOC), less active against candida
Terbinafine MOA
interferes w/ sterol biosynthesis; inhibits squalene monooxygenase; build-up of swualene is toxic to fungi
Nystatin
polyene antibiotic (like ampho B)
oral; topical
not absorbed appreciably from Gi, skin or mucous membrane
Nystatin use
candidal infections (oral for GI candida infections, topically for other candida infections)
Nystatin toxicity
N/V, diarrhea (oral)
Polyene antiobiotics
Amphotericin B
Nystatin
Efinaconazole
newest TOPICAL antifungal
DOC for candida
Nystatin
Efinaconazole use
onychomycosis caused by Trichophytan rubrum and Trichophyton mentagrophytes
DOC for Trich. rubrum and Trich
Efinaconazole topical solution daily for 48 weeks (probs not on test)
Efinaconazole MOA
forms bonds and causes pores to form and leakage (like ampho B)
