Antifungals Flashcards
what makes it challenging to target and destroy fungus?
they are eukaryotic organisms
which 2 mycoses make up the majority of systemic fungal infections?
aspergillus
candida
what are the 2 most common sites of fungal infection?
lungs
CNS
what 4 conditions/uses cause an increased risk of fungal infection?
broad spectrum antibiotics
chemotherapy
immunosuppressive therapy
chronic corticosteroids
what 2 disease states increase the risk of fungal infection?
AIDS/HIV
diabetes mellitus
why is there an increase in side effects of anti-fungal drugs?
they have homologous metabolic pathways for protein synthesis and cell division as humans
_____ is the sterol in human cells, while ____ is a unique sterol to the fungal cell membrane. Both are structurally similar.
cholesterol
ergosterol
why are antibiotics ineffective in fungal infections?
fungi have cell walls made of B-glucans and chitin, which are more rigid that bacterial cell walls
how does resistance occur in ergosterol binding drugs?
low concentrations of ergosterol
polyene that is an ergosterol binding drug; lipophilic part binds to ergosterol and hydrophilic part allows formation of pores, losing electrolytes and leads to cell death
amphotericin B
broadest spectrum against most pathogenic fungi
amphotericin B
using amphotericin B with which drug increases it’s uptake?
flucytosine
what are the 2 uses of amphotericin B?
initial (induction) therapy for invasive fungal infections
cryptococcal meningitis in HIV patients
how must amphotericin be given and why?
infusion
large molecule
what are the 4 infusion ADR of amphotericin B?
“Amphotericin makes you feel ampho-terrible with fever, chills, muscle spasms, and hypotension”
what should be done before starting amphotericin B? what can be given to minimize effects? (3)
1mg test dose to assess risk
antihistamine
antipyretics
corticosteroids
what is a dose-limiting ADR of amphotericin B? what should be total daily dose be?
nephrotoxicity
1.5 mg/kg
what dose is nephrotoxicity d/t amphotericin B no longer reversible?
3.6-4 gm
what kind of formulations of amphotericin B may cause less S/E d/t a decrease in binding to cholesterol in the renal cell membrane?
lipid-based formulations
which amphotericin B formulation has mild infusion-related S/E?
liposomal amphotericin B (L-AmB)
which 2 amphotericin B formulation have moderate infusion-related S/E?
ABLC (lipid complex)
ABCD (colloidal dispersion)
which amphotericin B formulation has high infusion-related S/E?
AmB-d deoxycholate (salt form)
what can nephrotoxicity d/t amphotericin lead to in a patient?
anemia (decreased production of erythropoietin)
for the treatment of cryptococcal meningitis in HIV patients, what can be added to amphotericin B? (2)
flucytosine
fluconazole
topical polyene antifungal that is much more systemically toxic than amphotericin B?
nystatin
2 uses for nystatin?
superficial infections of candida albicans
oral candidiasis (2nd line)
2 administration routes of nystatin for oral candidiasis?
suspension; swish and hold
troches (throat lozenge)
DNA synthesis inhibitor
flucytosine
what is flucytosine converted to in fungal cells and how?
5-FU
cytosine permease
deaminase
how does resistance occur in flucytosine?
defect in enzyme that converts 5-FC to 5-FU
administration of flucytosine (5-FC)?
oral
5 ADR of flucytosine?
“Naughty Vampires (flucytosine) Demand Hearty Blood Meals”
Nausea
Vomiting
Diarrhea
Hepatotoxicity
Bone Marrow suppression (dose-dependent)
what med is used with amphotericin B for synergistic effect?
flucytosine
-azoles
ergosterol synthesis inhibitors
how does resistance occur in azoles?
altered binding d/t mutation in gene coding for fungal P450 enzyme
name the 3 ergosterol synthesis inhibitor imidazoles?
“Mic went on Keto to cloTrim down”
ketoconazole
clotrimazole
miconazole
name the 5 ergosterol synthesis inhibitor triazoles?
“I want to Tri to be a FI VIP”
fluconazole
itraconazole
voriconazole
isavuconazole
posaconazole
why are triazoles better than imidazoles?
have better selective inhibition of fungal P450 enzyme
which azole has the highest risk for D-D interaction?
ketoconazole
which 2 drugs have the least risk for D-D interaction d/t having the least inhibition of CYP3A4?
fluconazole
posaconazole
2 ADR of ketoconazole?
“Keto is for girls - gynecomastia and mestrual irregularities”
use of imidazoles?
cutaneous mycoses (fungus)
use of triazoles?
systemic mycoses (fungus)
spectrum of fluconazole?
elimination?
CYP inhibition?
2 ADR?
C. albicans
renal
CYP2C9
alopecia
hepatotoxicity
spectrum of itraconazole?
elimination?
CYP inhibition?
3 ADR?
C. albicans
aspergilli
liver
CYP3A4
diarrhea
CHF
hepatotoxicity
which environment is needed for itraconazole to be absorbed?
low pH (acidic)
spectrum of voriconazole?
elimination?
CYP inhibition? (2)
3 ADR?
broad
liver
CYP3A4. CYP2C19
rash
visual disturbance
hepatotoxicity
spectrum of posaconazole?
elimination?
CYP inhibition?
ADR?
broad
fecal
CYP3A4
less hepatotoxicity
what spectrum of activity should we aim to use?
narrow spectrum
spectrum of isavuconazole?
elimination?
CYP inhibition?
ADR?
C. albicans
aspergilli
cryptococcus
liver
CYP3A4
less D-D and ADR
what is the 1st line treatment for oral candidiasis? (3)
clotrimazole troche
miconazole
+/- nystatin (last option)
treatment for resistant oral candidiasis?
oral fluconazole
-funin / -fungerp
echinocandins; fungal cell wall inhibitors
inhibit B-glucans and are highly selective since humans don’t have it
echinocandins; fungal cell wall inhibitors (-fungin)
2 uses for echinocandins; fungal cell wall inhibitors?
most candida
azole- and polyene-resistant species
how does resistance occur in echinocandins; fungal cell wall inhibitors?
altered B-glycan synthase (too much efflux pump)
6 ADR of echinocandins; fungal cell wall inhibitors?
“F HERE”
Fever
Headache
Erythema
Rash
Embryotoxic
why do echinocandins have a low bioavailability? route of administration?
large molecule
IV only
drugs that induce which enzyme will lead to a need of increased caspofungin dose?
P450 enzyme
what 2 immunosuppressants are increased when used with caspofungin?
tacrolimus
cyclosporin
the only echinocandin used orally and approved for vulvovaginal candidiasis?
ibrexafungerp
what 2 immunosuppressant should be avoided when taking caspofungin?
tacrolimus
cyclosporin
what are the 2 uses for clotrimazole and miconazole?
vaginal candidas
oral candidas
topical miconazole inhibits metabolism of which drug?
warfarin
-fine
allyamines
accumulate in keratinized layer of skin and nails; inhibit fungal enzyme which usually creates lanosterol of fungus, leading to depletion of ergosterol (inhibiting first stop of ergosterol synthesis)
allyamines (-fine)
2 uses for allyamines?
onychomycosis of toenails/fingernails
athlete’s foot (tinea pedis)
2 ADRs of terbinafine?
GI
CYP2D6 inhibitor
accumulates in keratinized layer of skin, hair, and nails; inhibits fungal cell mitosis
griseofulvin
accumulates in keratinized layer of skin, hair, and nails; inhibits first step of ergosterol synthesis like terbinafine
tolnaftate
uses for griseofulvin and tolnaftate?
dermatophytes/tinea
superficial fungal infections of skin, scalp, and hair
6 ADRs of griseofulvin?
GI upset
dizziness
confusion
hepatotoxicity
leukopenia
photosensitivity
how should griseofulvin be taken to increase absorption?
with fatty food
what can be used as an adjunct therapy for tinea capitis?
ketoconazole shampoo
