Antifungals Flashcards
What are the benefits of fungi
source of many medications
penicillin and other beta-lactams
Food-edible mushroom
Insect control-process of competitive exclusion to actively compete for nutrients
Biotech-yeast species used to produce peptide drugs
What are the levels of fungal treatment
prophylaxis
Empiric
Targeted
what is prophylaxis treatment of fungal infections
preventive treatment of a specific pathogen in an at risk pt
what is empiric treatment for fungal infections
treatment as soon as possible or probable fungal infection
based on presence of symptoms consistent with a fungal infection, but no positive culture data
what is targeted treatment of fungal infections
definitive positive culture data exists allowing for targeted treatment
Who is at risk for getting fungal infections
Immunosuppressed patients
What are big challenges of fungal infections
hard to diagnose potential toxicity need for targeted therapy development of resistance to available agents limited formulations aggressiveness of pathogen
What drugs make up the Azoles
fluconazole
Itraconazole
Voriconazole
Posaconazole
what drugs make up the polyenes
Nystatin
Amphotericins
what is the definition of a fungistatic drug
inhibit growth then the immune system can then complete eradication of pathogenic fungi
What is the definition of fungicidal drugs
kill fungal pathogens. dependent on mechanism of drug and ability to reach adequate concentration at the site of action
preferred treatment in immunocompromised patients
Amphotericin what class does it belong to? when was it first made? how is it administered? how long is its half-life? what is the dose adjustment in renal or hepatic impairment?
polyene macrolide antifungal 1950's only IV form can make oral rinse 15days no dose adjustment for renal or hepatic impairment
what is the mechanism of action for amphotericin?
binds to and disrupts ergosterol in fungal cell membrane.
Disrupts membranes integrity leading to creation of pores in cell membrane
alteres membrane permeability
This leads to leakage of intracellular components out of the cell and fungal cell death ensues
What organism are resistant to Amphotericin
Candida lusitainae
Pseudallescheria boydii
Candida krusei (somtimes)
what are some adverse effects of amphotericin that are infusion related
fever, chills, rigors, hypotension
what should you premedicate patients with before getting amphotericin
acetaminophen
diphenhydramine
merepridine
hydrocortisone
What should you do to test a patients risk/tolerance of ampotericin
administer 1mg test dose to asses risk. need to monitor for 15-30min
what are adverse effects of amphotericin due to chronic use
Renal toxicity increased Scr increased nitrogen comp. like BUN renal tubular acidosis K&Mg wasting hepatic toxicity increased LFT
what is the purpose of creating lipid formulations of amphotericin?
created to improve tolerability
helps deliver amphotericin to affected tissue
reduce toxicity, but don’t eliminate it
high expense limits use
what are the clinical uses of amphotericin
reserved for life threatening or refractory conditions
Given IV over 2-6 hours
what is the mechanism of action for flucytosine
taken up by fungal cells and converted to 5-Fu and then 5-FdUMP and 5-FdUTP
these molecules inhibit fungal DNA and RNA synthesis
has synergistic action with amphotericin
what are the adverse effects of flucytosine
myelosupression (bonemarrow)
hepatotoxicity
what re the clinical uses of flucytosine
mostly used to treat crytococcal meningitis
almost always used with other antifungal
rapid development of resistance
what makes up the imidazoles (3)
ketoconazole
miconazole
clotrimazole
what makes up the triazoles
4
itraconazole
fluconazole
voriconazole
posaconazole
what is the MOA for the azoles
inhibit fungal cytochrome p-450 dependent enzyme lanosterol 14 alpha demethylase
reduces formation of ergosterol
considered fungistatic
what are the adverse effects of the azoles
Gi upset
increased LFTs
what are potential drug interactions for the azoles
inhibit the human CYP450 enzyme
Major target is CYP450 3A4
which has less enzyme selectivity imidazole or the triazoles
the imidazoles which is why they have more of an effect on the CYP450 enzymes. So they have more drug interactions
What how selective is ketoconazole for the CYP450 enzymes
how is its potentcy compared to new azoles?
what type of infection is it used for?
less selective for the fungal CYP450 enzymes
not as potent as the newer azoles
used in topical fungal infection
what species for Itraconazole cover?
candida and apergillus but have been replaced by voriconazole due to better bioavalibility and penetration of CNS
What is Itraconazole used to treat
onychomycosis
can also be used in histoplasmosis and blastomycosis
What are is fluconazole used for
for tx and prophylaxis of coccidiodal and cryptococcal meningitis.
Effective in treatment of canddida
used in pts as prophylaxis in neutropenic patients
what species does fluconazole have no effectiveness against?
aspergillus
with resistance seen in C. krusei and C. glabrata
Voriconazole what is it available in? how is its bioavialbility? what are the adverse effects? what do you need to does adjust for?
oral tabs, solution, IV form.
excellent bioavail
hepatic tox, rash, visual changes
just need hepatic impairment adjustment
How is voriconazoles coverage?
broad range of activity
candida, aspergillus, fusarium, scedosporium
used in prophylaxis and invasive fungal infections
what organism does posaconazole cover
candida, aspergillus, other molds
what is posaconazole approved for?
prophylaxis of fungal infections in immunosuppressed pts
can also be used for salvage therapy in systemic fungal infections
What dosage forms is posaconazole available in
oral solution, IV, and tablets
What increased the bioavailability of posaconazole?
when taken after a full meal or with an acidic carbonate beverage
What class of fungi do echinocandins treat
candida and apergillus
what dose form are echinocandins available in?
IV only
what is the MOA of echinocandins
inhibit beta-1,3-glucan synthase
inhibits creation of component of fungal cell walls
disrupts fungal cell integrity and leads to cell death
Echinocandins are fungistatic against which of the two fungi
aspergillus
echinocandins are fungicidal against which fungi
candida
what are the adverse effects of echinocandins
typically well tolerated
GI effects
flushing reaction if unfused too fast
increased LFT
what is echinocandins used for
limited to IV
often used in refractory cases or in patients with renal or hepatic impairment
what drugs are part of the echinocandins class
caspofungin
micafungin
anidulafungin
what is caspofungin used to treat
disseminated candidiasis, salvage treatment of apergillosis or empiric treatment of possible fungal infection
what is micafungin used to treat
esophageal candidiasis, candidemia and prophylaxis of candida infections in SCT patients
what is andifulafungin used to treat
esophageal candidiasis and invasive candidiasis
what is griseofulvin used to treat
how is it absorbed
what is its MOA
what is the risk associated with it
used to treat fungal skin and nail infection
very poor oral absorption is increased with a high fat meal
Works by binding to keratin in skin and prevents spreading of fungal infection
take weeks to be effective
risk of liver toxicity
what is terbinafine used to treat what is its MOA how is it dosed what is its dose form what are the risks with this medication
treats dematophytoses and onychomycosis interferes with ergosterol synthesis by inhibiting squalene epoxidase dosed over several months topical cream or tablets hepatic tox. with oral tablets
what is tolnaftate used to treat
used in topical creams and sprays
treats athletes foot and other superficial infections
works by interfering ergosterol synthesis
risk of skin irritation
what is nystatin used to treat
what is its dose form
active candidiasis
well tolerated topically
powders, cream, vaginal suppositories, oral suspension
how do you select antifungal treatment
identify patient with or at risk for fungal infection
consider level of treatment (prophylaxis vs empiric vs targeted treatment)
consider fungi involved and severity
select therapy from available agents based on route, spectrum of activity, availability cost and tolerability
