Lec41 Antifungals Flashcards
What are the 3 main targets for antifungal therapy?
cell membrane: fungi use argosterol instead of cholesterol
DNA synthesis: restricted to serious infections because more side effects
cell wall: fungi have cell wall, we do not
What are two types of cell wall inhibitors?
inhibitors of glucan synthesis = echinocandins
inhibitors of chitin synthesis = nikkomycin
what is mech of action of cell membrane inhibitors? example?
they inhibit ergosterol synthesis
- azoles
What type of antifungal causes direct cell membrane damage?
polyenes
What are the two types of polyene antibiotics?
- amphotericin B
- nystatin [topical]
What are the classifications of systemic azole antibiotices?
imidazoles: ketoconazole
triazoles: itraconazole, fluconazole,
2nd gen triazoles: voriconazole, posaconazole
What are benefits of azoles for systemic use?
- broad therapeutic window, wide spectrum of activity, low toxicity
What is mech of action of azoles?
- bind lanosterol 14a-demethylase a P450 enzyme responsible for production of ergosterol
- thus blocks ergosterol production
What are potential side effects of azoles?
- azoles act by blocking a fungus cyt p450 enzyme, may see cross reactivity with human cyt p450
- – drug interactions
- – impairment of steroidneogenesis [keto, itra]
- nausea, vomiting, rash –> more likely with high doses and AIDS
- may cause hepatotoxicity
What are advantages and disadvantages of fluconazole?
advantages: low side effects, both IV/PO formations, high bioavailability
- favorable pharmacokinetics
disadvantages: fungistatic, resistance is increasing, narrow spectrum, possible p450 drug interactions
What is fluconazole good for treating?
- primarily used for Candida albicans, cryptococcus neoformans
- also active against dermatophytes [trichophyton], dimorphic fungi
- see primary resistance in many non-albicans candida
- -> C. krusei always resistant
- -> C glabrata often resistant
- -> tropicalis rarely resistant
- no activity against aspergillus or most mould fungi
What are fluconazoles drug interactions
- iincreases phenytoin, cyclosporin, rifabutin, warfarin, zidovudine conc
- rifampin reduces fluconazole level to half
Can fluconazole penetrate CSF?
yes very well
What is bioavailability to fluconazole?
very high >90% means little difference between oral and IV forms
What can itraconazole treat?
- similar candida coverage as fluconazole [C albicans, C tropicalis, sometimes C. globrata, never C. krusei]
- also can treat aspergillus
How is fluconazole cleared?
mostly renal
How is itraconazole excreted?
- hepatic metabolism and via bile
Can itraconazole pentetrate the CSF?
nope! so not good for meningeal fungal infection
Is there an oral form of itraconazole?
yep but not very good absorption
what can voriconazole treat?
- very broad
- includes most candida, aspergillus, fusarium
- can’t treat zygomycoses
Is there an oral form of voriconazole?
Yep with >90% bioavailability
How is voriconazole cleared?
mostly hepatic
Can voriconazole penetrate CSF?
Yep! good for meningitis
What are adverse side effects of itraconazole?
- nausea and vomitting
- osmotic diarrhea
- taste disturbances
- maybe hepatic
What are adverse side effects of voriconazole?
- nausea and vomitting
- visual disturbances [reversible, decreased vision, altered color perception, worse with IV than oral]
- hallucination in 2-5%
- hepatic
- rash
Of fluconazole, itraconazole, and voriconazole whihc have most drug interactions?
- itraconazole has strong interactions
- voriconazole moderate - strong
- fluconazole weak
inhibit cyp 34A
What is fluconazole usually used to treat?
- invasive or mucocutaneous candidiasis
- maintenance therapy for cryptococcal meningitis
- coccidiodomycosis
What is itraconazole usually used to treat?
- azole of choice for invasive histoplasma, blastomycosis, sporothrix
- dermatophyte infections and onychomycosis
What is voriconazole usually used to treat?
- drug of choice for invasive aspergillosis
- cancer/neutropenia prophylaxis
What is posaconazole usually used to treat?
- prevent mold infections in patients with neutropenia/cancer [only have oral form
How is psaconazole administered? what is it used to treat?
- broad activity including against zygomycetes
- only oral form
- requires fatty meal for absorption
- use for prophylaxis prevention of invasive mold infections in pts at risk
What is terbinafine used to treat?
- its a systemic antifungal agent but used to treat superficial fungal infections
- mainly used for onychomycosis
What is mech of terbinafine? side effects?
- interferes with ergosterol synthesis
- no drug interactions
- can cause liver inflammation
How is terbinafine administered?
orally
What is nystatin? what do you treat? side effects?
- a topical polyene
- treat mucocutaneous candidiasis [oral thrush]
- little toxicity
What is clotrimazole? what do you treat? side effects?
- a topical azole antifungal
- treat mucocutaneous candidiasis, dermatophyte infections
- little toxicity
What is amphotericin B? mech of action?
- amphoteric polyene macrolide
- binds sterols in fungal cell membrane
- creates transmbembrane channel and electrolyte leakage [creates pores]
What is amphotericin B active against?
active against most fungi except aspergillus terreus, scedosporium
What are side effects of original amphotericin? what are the new preparation?
- classic formulation –> serious toxic side effects, renal damage
- lipid associated formulations make it less toxic [liposomal amphotericin B {L-AMB}, amphotericin B colloidal dispersion {ABCD}, amphotericin B lipid complex {ABLC}]
What are the drug names for the 3 different lipid formulatiosn of amphotericin B?
ambisome = L-AMB albecet = ABLC amphotec = ABCD
What are side effects of amphotericin B as administered?
- renal toxicity
- — increase renal vascular resistance –> low GFR, azotemia = accumulation of urea in blood stream
- — increase tubular permeability –> distal tube ischemia, wasting of K, Na, Mg
- get bigger renal effects in pts volume depleted or on concomitant nephrotoxic agents –> MAKE SURE PT HAS FLUIDS
What is amphotericin B used to treat?
- standard antifungal therapy –> drug of choice for:
- – cryptococcal meningitis
- – mucormycosis in combo with surgery
- – induction therapy for histoplasmosis
- – invasive fungal infections that don’t respond to other therapy
- cannot tret: aspergillus terreus, scedosporium, some candida lusitanae, maduralla, some paecilomyes
What is flucytosine [5FC]? administration?
- anti-metabolite against DNA/RNA symthesis
- marketed as Ancotil
- IV or oral administration
What are side effects of fluytosine [5FC]? When do you particularly need to monitor?
- vomitting, diarrhea
- altered liver function tests
- bone marrow toxicity
- need to monitor blood conc of drug when used in conjunction with amphotericin B
What do you treat with flucytosine?
- fungistatic and fungicidal acativity against yeasts, only fungistatic against aspergillus fumigatus
What is mech of action of echinocandins?
- inhibit fungal cell wall synthesis of glucan
- loss of cell wall glucan –> osmotic fragility
What can echinocandins be used to treat?
- fungicidal against: most candida species including non-albicans, pnseumocystis carinii
- acive but usually not fungicidal against: aspergillus
- no activity against cryptococcus neoformans
- no activity against other molds: fusarium, zygomycosis, trichosporon
What are 2 drugs of choice for aspergillus?
- floriconazole
- amphotericin
What are the 3 echinocandins?
- capsofungin
- micafungin
- anidulafungin
What are adverse effects of capsofungin?
- mostly mild and do not require treatment discontinuation
- usually infusion related: intravenous site irritation, mild to moderate infusion related fever/headache/flushing/erythema/rash
- asymptomatic increase serum transaminases
What are common causes of fungal endopthalmitis?
- candida albicans most common [slow progression, better prognosis]
- aspergillus [rapid progression, vision threatening]
What are predisposing factors to fungal endopthalmitis?
- invasive disease
- immunosuppression
- malignancy
- long term broad spectrum antibiotics
- neutropenia
- organ transplant
- dialysis
- AIDS
- liver disease
- indwelling cathers
- IV drug use
What are signs of fungal endopthalmitis?
- decreased vision
- photoboia
- pain
- red eye
- viritis [esp. in aspergillus]
- pseudo-hypopynon [layering exudate]
- retinal findings
What is treatment for fungal endopthalmitis?
- usually systemic amphotericin + intravitreal administration
- or: systemic fluconazole, systemic flucytosine, systemic and intravitreal voriconazole
Which fungi are dimorphic?
- histoplasma
- coccidioides
- blastomyces
- paracoccidioides
- penicillium
What are major treatments for candida?
- fluconazole
- amphotericin
- echinocandins
What are major treatments for cryptococcus neoformans?
- amphotericin [maybe with combined 5FC]
- fluconazole for prophylaxis
What are major treatments for histoplasma?
- amphotericin
- itraconazole
- voriconazole
What are major treatments for blastomyces dermatidis?
- amphotericin
- itraconazole
- fluconazole
What are major treatments for coccidioides?
- amphotericin
- then fluconazole in immunosuppressed
What are major treatments for paracoccidioides brasiliensis?
- itraconazole, amphotericin B, or TMP-SMX
What are major treatments for penicillium marneffei?
- amphotericin and 5FC
What is treatment for zygomytes?
- surgical debridement with amphotericin
- posaconazole for prophylaxis
What is treatment for aspergillus?
- voriconazole or amphotericin for invasive disease
What is treatment for pnseumocystis jiroveci?
- TMP-SMX
What is major treatment for topical dermatophytes
topical meds –>
What is major treatment for eumycetoma?
- surgical
- posaconazole on compassionate bases
What is major treatment for sporotrichiosis?
- itraconazole [sporonox]
