AntiFungal Therapy - Zheng 5/12/16 Flashcards
fungal infections
- superficial
- subcutaneous
- systemic
superficial: skin, hair, nails
subcut: dermis, subcutaneous tissues and/or adj structures
systemic: disseminated infection of internal organs
- HIV pts
- autoimmune pts
- cancer pts
- organ transplant pts
- widespread use of antibiotics
antifungal drug classification
- location
- mech of action
location
- systemic (oral and IV)
- systemic (for mucocutaneous inf)
- topical drugs
mechanisms/targets
- nucleic acid synthesis inhibitor : flucytosine
- cell wall disruptors : echinocandins
- cell membrane disruptors (fungal cell membranes contain ergosterol instead of cholesterol)
- amphotericin B (amphipathic pore former)
- azoles (block ergo biosynth; gen toxic byproducts)
- nystatin (ergosterol binder; pore former)
- allylamines (block ergo biosynth; gen toxic byproducts)
drugs for systemic infections
amphotericin B
- structure
- mech of action
- target fungi
- resistance
- clinical use
macrolide with amphipathic ring structure
mechanism of action:
- nonpolar side binds tightly to ergosterol in membrane
- polar side forms pores for ion leakage
- mycosamine sugar is the key linker between amphotericin-ergosterol
**selective for ergosterol in fungal membrane (won’t hit human/bacterial cell membranes!)
targets
- yeast: Candida albicans, Cryptococcus neoformans
- endemic fungi: Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitus
- pathogenic molds: Aspergillus fumigatus, Mucor
resistance
- intrinsic resistance: Candida lusitaniae, Pseudallescheria boydii
- acquired resistance can occur in vitro via decreased/modified ergosterol or inability to penetrate cell wall BUT not clinically significant
clinical use
- drug of choice for life-threatening systemic inf BUT toxic side effects
- often initial tx, followed by chronic tx with triazoles
- topical eyedrops for mycotic corneal ulcer/keratitis
- local injectction for fungal arthritis
drugs for systemic infections
amphotericin B
- targets
- resistance
- clinical use
targets
- yeast: Candida albicans, Cryptococcus neoformans
- endemic fungi: Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitus
- pathogenic molds: Aspergillus fumigatus, Mucor
resistance
- intrinsic resistance: Candida lusitaniae, Pseudallescheria boydii
- acquired resistance can occur in vitro via decreased/modified ergosterol or inability to penetrate cell wall BUT not clinically significant
clinical use
- drug of choice for life-threatening systemic inf BUT toxic side effects
- often initial tx, followed by chronic tx with triazoles
- topical eyedrops for mycotic corneal ulcer/keratitis
- local injectction for fungal arthritis
drugs for systemic infections
amphotericin B
- admin
- PK
- toxicity
adminstration
- nearly insoluble in water
- not well absorbed orally → only given orally for GI inf
- given IV (suspension in deoxycholate)
- excretion: urine (halflife 15d)
- levels not affected much by hepato/renal issues
**liposomal prep : lets you get higher doses with lower nephrotox BUT more expensive
toxicities
- infusion related toxicity
- fever, chills, headache, vomiting, hypotension
- deal with it by…
- decreasing dose
- premed with antipyretics, antihists, meperidine, hydrocortisone
- slower tox
- renal damage
- variable anemia
- occasional hepatic damage
drug interactions with nephrotoxic drugs (aminoglycosides, cyclosporine)
drugs for systemic infections
flucytosine
- mechanism
- selectivity
- resistance
prodrug → eventually converted into nucleotide analogues that stall n.a. synth
mechanism of action
- taken up by fungal cytosine permease
- flucytosine → 5-fluorouracil [cytosine deaminase]
- 5FU → 5FUTP : inhibits RNA synth
- 5FU → 5FdUMP : inhibits DNA synth
selectivity
- cytosine permease only found in fungal cells - reason why this is a good antifungal but a lousy anticancer drug
- mammalian cells do not convert 5FC → 5FU well
resistance
- loss of 5FC → 5FU conversion
- loss of 5FU → 5FUMP conversion
- loss of cytosine permease
drugs for systemic infections
flucytosine
- admin
- clinical use
oral administration → rapid absorption from GI
- distributes well (incl CSF)
removed by kidney (halflife 3-6hr)
- kidney dysfx → toxicity!
synergistic with amphoB, itraconazole
clinical use
- limited spectrum action : Candida, Cryptococcus
- typically given in combo to avoid resistance (with azoles, amphoB)
drugs for systemic infections
flucytosine
- toxicity
- drug interaction
toxicity
- decrease fx of bone marrow (leukopenia, thrombocytopenia)
- rash, GI effects
why? conversion to 5FU by GI tract bacteria!
drug interactions with drugs that suppress bone marrow
drugs for systemic infections
azoles
- classification
imidazoles (2N in 5 member ring)
- ketoconazole
- clotrimazole
- miconazole
triazoles (3N in 5 member ring)
- itraconazole
- fluconazole
- voriconazole
drugs for systemic infections
azoles
- mech of action
- resistance
block P450 lanosterol demethylase (ERG11) → block ergosterol synthesis (3rd step)
- binds to active site
- diverts synth pathway to accumulation of toxic methylsterols → inhibit fungal enzymes localized on membrane
resistance
- pumps (similar to bacteria)
- alteration or overexpression of target : alters drug affinity
- ERG3 loss of fx : mitigation of toxicity
drugs for systemic infections
azoles
- selectivity
- target
- toxicity
- drug interactions
selectivity
binds less effectively to mammalian P450s → somewhat specific for fungal cells
- Candida spp, Cryptococcus neoformans, endemic mycoses, dermatophytes, Aspergillus, Pseudallescheria boydii (amphoB resistant strain!)
toxicity
- minor GI distress
- liver enzyme abnormality → rare drug-induced hepatotox
drug int
- affects P450 drug metabolism (cyclosporine, warfarin, dihydropyridine, buspirone)
imidazoles
ketoconazole
- first oral azole
- mostly replaced by triazoles, BUT is much cheaper
miconazole, clotrimazole
- only used topically
triazoles
itraconazole
most potent azole → used for severe inf
favored over ketoconazole due to…
- broader spectrum
- fewer side effects (more selective)
administration/distribution/availability/metabolism
- oral admin (abs is improved with food/gastric acid)
- widely distributed, incl CSF
- limited bioavailability → improved with cyclodextrin formulation
- lipid soluble
- metabolized by liver via CYP 3A4 (halflife 30-40h)
- primary metabolite (hydroxyitraconazole) also has antifungal props
toxicity: GI distress, teratogenic
drug interaction:
- H2 and PPIs that decrease gastric acid secretion
- drugs metabolized by P450s
triconazoles
fluconazole
oral admin
- well absorbed, not affected by gastric acidity
wide distribution (incl CSF)
long halflife (25-30h)
fewest effects on hepatic microsomal enzymes (less drug ints)
wide therapeutic index
triconazoles
voriconazole
posaconazole
newest triazoles
improved bioavailability
posaconazole : broadest spectrum
