Anti-fungals Flashcards
yeast
solid forms of fungi that reproduce by budding
have moist, shiny appearance in colonies
moulds
branching hyphae, multicellular
can reproduce by translocation of existing hyphae to new area or through spore formation and spread
dimorphic fungi
mould at room temp
yeasts at body temp
endemic fungi: coccidiodes immitis in southwestern US and central california–> valley fever
problems of treating fungal infxn
1) infxn looks similar to bacterial infxn
2) most centers don’t conduct antifungal susceptibility testing
3) condition of immune system of host–> control risk factors is important
polyenes
amphotericin B deoxycholate, lipid formulation of AmB and nystatin (topical)
work by binding to ergosterol in cell membrane–> disrupting its function
nephrotoxicity and infusion related reactions
lipid forms of AmB
AmB colloidal dispersion (ABCD)
AmB lipid complex (ABLC)
liposomal AmB (LAmB)
less used after introduction of echinocandins and broad-spectrum azoles
spectrum of polyenes
Good: most candida spp, aspergillus, C neoformans, dimorphic fungi and many moulds
moderate: zygomycetes
poor: candida lusitaniae, aspergillus terreus
toxicity of polyenes
nephrotoxicity via direct damage to distal tubules–> Mg and K wasting and indirect damage via vasoconstriction of afferent arteriole
infusion-related reactions: fever, chill, rigors and less common rash and increased transaminases
AmB nephrotoxicity can be attenuated by
sodium loading: give boluses of normal saline before and after AmB treatment–> inexpensive
Can give acetaminophen, diphenhydramine and hydrocortisone to decrease incidence and severity of infusion-related reactions
Meperidine can be given to prevent rigors but it has a neurotoxic metabolite that can affect pt with renal dysfunction because it’s eliminated renally
ABCD has worst infusion-related reaction, LAmB has the least reaction. All have less nephrotoxicity than AmB deoxycholate, but LAmB is the least nephrotoxic
Nystatin is used topically due to poor tolerance when given systemically
AmB formulations best for
cryptococcal meningitis, dimorphic fungi and some mould infections
reasonable to give if fungal infxn is suspected but source is unknown–> febrile neutropenia
double check dose and which formulation ur using
anti-metabolites
flucytosine (5-FC)
interferes with DNA synthesis
used in combination with AmB formulations for cryptococcal disease
hight toxicity–> rarely used for other infxn
Good: also for most candida spp
moderate: monotherapy against C. neoformans and candida spp
poor: mould, candida krusei
AE of 5-FC
also called fluorouracil for fungi
BM suppresion especially in high doses or prolonged courses
GI complaints more common but less severe
5-FC drug monitoring
check peak concentration about 2 hrs after dose is given. Also measure hematology values
due to resistence–> don’t use as monotherapy
Azoles
inhibit fungal cytochrome P450–> decrease ergosterol production–> also issues with drug interactions
ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, multiple tropical formulations
fluconazole
highly bioavailable
both oral and IV formulations
highly active against many candida spp
Good: C. albicans, C. tropicalis, C. parapsilosis, C. lusitaniae, C. neoformans, coccidiodes immitis
moderate: candida glabrata (can be susceptible dose-dependent or resistant)
poor: moulds, many dimorphic fungi, candida krusei
AE of fluconazole
can cause hepatotoxicity or rash
lower propensity for drug interactions, but still occurs
QT prolongation is possible
eliminated renally, so make sure to adjust dose to renal function. High doses may be required to treat candida glabrata
vulvovaginal candidiasis requires only one dose of 150 mg
fluconazole and ICU pts
can be used as prophylaxis. if pt has yeast in blood, try echinocandins instead
remember to check pts’s isolate to make sure that candida spp are susceptible
itraconazole
broader spectrum than fluconazole
Good: in addition to fungi covered by fluconazole, aspergillus spp, many dimorphic fungi
moderate: candida glabrata, candida krusei (can be susceptible dose-dependent, resistant)
poor: zygomycetes, many other moulds
remains drug of choice for some dimorphic fungi like histoplasmosis. Largely replaced by voriconazole in treating aspergillus and other mold infections
Also used to treat Onychomycosis
AE of itraconazole
in addition to hepatotoxicity, negative inotrope–> don’t give to HF pts
oral solution associated with diarrhea
stronger inhibitor of cytochrome P450, QT prolongation
itraconazole formulations
capsules–> lower bioavailability than solution and are less preferred for systemic fungal infections
capsules should always be taken with full meals, whereas solutions should be taken on empty stomach
absorption can be lowered by agents reducing gastric acid; have pts take it with soda
absorption is very erratic and unpredictable, so monitor trough concentration during long term treatments
No more IV formulations
voriconazole
better absorbed than itraconazole and available in both highly bioavailable PO and IV
superior to AmB deoxycholate for invasive aspergillosis and has become drug of choice for that
Good: C. albicans, C. lusitaniae, C. parapsilosis, C. tropicalis, C. Krusei, C. neoformans, Aspergillus spp, many other moulds
moderate: C. glabrata (can be susceptible dose-dependent, or resistant), C. albicans that are fluconazole-resistant, fusarium spp
poor: zygomycetes
AE of voriconazole
hepatotoxicity, rash, drug interactions, visual effects such as seeing wavy lines or flashing (very common and dose-related), visual hallucination can also occur but less common
check concentration trough on long-term therapy
important voriconazole facts
active against many fluconazole-resistent strains of candida albicans, but is less active against them than fluconazole susceptible strains. echinocandins is a better choice, but consider a susceptibility testing if need to use voriconazole for an oral options
potent inhibitor and substrate of cytochrome P450, don’t use with rifampin. Cyclosporin (calcineurin inhibitor) requires dose adjustment. many pts who require voriconazole are immunosuppressed
IV form contains cyclodextrin vehicle that accumulates in renal dysfunction–> nephrotoxic–> don’t give to pts with creatinine clearance< 50 mL/min. PO avoids this issue
it’s eliminated hepatically–> not useful in treating candiduria
posaconazole
currently indicated only for prophylaxis of fungal infections in neutropenic pts and treatment of oropharyngeal candidiasis
Good: C albicans, C lusitaniae, C parapsilosis, C tropicalis, C krusei, aspergillus spp, zygomycetes, many other moulds, dimorphic fungi
Moderate: fusarium spp, candida glabrata (clinical data are lacking for many of them)
AE for posaconazole
hepatotoxicity, nasuea, rash, drug interactions via cytochrome P450
only available PO and must given with food. high fat food improves absorption (IV for in development)
echinocandins
caspofungin, micafungin, anidulafungin
inhibit the synthesis of beta-1,3-glucan which is a component of fungal cell wall
Lack of oral administration, but fewer drug interactions than azoles, safer than polyenes, greater activity against fluconazole-resistent yeasts
Good: C albicans, C glabrata, C lusitaniae, C parapsilosis, C tropicalis, C krusei, aspergillus spp
moderate: C parapsilosis, some dimorphic fungi
poor: zygomycetes, most non-aspergillus moulds, C neoformans
AE of echinocandins
mild histamine-mediated infusion-related reaction, but can be avoided by slowing infusion rate. Hepatotoxicity but not common
differences and facts of echinocandins
caspofungin and micafungin are eliminated hepatically by non-cytochrome P450 metabolism. anidulafungin degrades in plasma and avoids hepatic metabolism (however it still has hepatotoxic effects)
neither cidal or static effects against aspergillus spp., they cause aberrant, non-functional hyphae to be formed by the actively growing mould
less active against C parapsilosis, consider giving fluconazole instead
don’t use cyclosporine with caspofungin and sirolimus with micafungin
echinocandins are good for
invasive candidiasis in pts who are unstable. Also in treatment of invasive aspergillosis but not enough supporting data like voriconazole and polyenes.
all of them used for esophageal candidiasis and for prophylaxis for fungal infections in neutropenic pts
Not cheap!
ketoconazole
poor oral absorption
used topically in treatment of Dandruf
Terbinafine (Allyamine antifungal)
inhibits squalene epoxidase preventing synthesis of ergosterol
available PO and topically
used for dermatophytes and mainly onychomycosis (concentrates in nails, fat and skin)
metabolized in liver and excreted renally, long half life
AE: hepatotoxicity, neutropenia, steven-johnson syndrome
griseofulvin
inhibits fungal mitosis via interaction with microtubules
PO, prolonged half-life, active against dermatophytes, mainly headache as AE
fungal drug sites
