Lecture 25 4/29/24 Flashcards
What are the general characteristics of antifungal treatment?
involves use of immunosuppressants
-treatment is typically longer than antibacterial treatment, especially in immunocompromised patients
-drugs can be fungistatic or fungicidal
-immune system must help inhibit infection
-“trial and error” approach not useful
What are the general characteristics of fungal cells?
-eukaryotic
-cell wall contains mannoproteins, glucans, and chitin
-ergosterol is required for cell membrane
How do azoles work against fungi?
-inhibit 14alpha-demethylase, which normally converts lanosterol to ergosterol
-depletion of ergosterol and accumulation of 14alpha-methylsterols disrupts the cell membrane
What is the spectrum of action for azoles?
widely used to treat a variety of mycoses
Which azoles fall into the imidazoles class?
-ketoconazole
-clotrimazole
-enilconazole
What are the characteristics of imidazoles?
-poor oral bioavailability
-used for superficial topical infections
Which azoles fall into the triazoles class?
-itraconazole
-fluconazole
-voriconazole
-posaconazole
What are the characteristics of triazoles?
-more slowly metabolized
-decreased impact on mammalian sterol synthesis
What leads to the side effects and drug interactions associated with azoles?
-cross-inhibition of mammalian P450 enzymes
-inhibition of drug transport by efflux transporter
What are the characteristics of ketoconazole?
-used in Malassezia dermatitis and feline nasal/cutaneous cryptococcosis
-has poor CNS penetration
-can cause vomiting, diarrhea, lethargy, anorexia
-given with food
-may mildly elevate liver enzymes; must monitor values
What are the characteristics of itraconazole?
-most widely used azole
-used for treatment of various fungi
-oral suspension or capsules
-not to be used compounded; may not be effective
-give capsules with meal
-does not penetrate protected sites
-accumulates in skin and claws
-possible hepatotoxicity and cutaneous ulceration
What are the characteristics of fluconazole?
-narrowest spectrum of activity for azoles
-activity limited to Candida, Cryptococcus, Malassezia, some others
-tablets only; no compounded drugs
-can be given with or without food
-accumulates in body fluids
-used for CNS or UTI
-side effects uncommon; can affect GI and liver
What are the characteristics of voriconazole?
-drug of choice for CNS and ocular infections
-active against Cryptococcus, A. fumigatus, and Candida
-treats systemic yeast and mold infections
-great oral bioavailability
-good concentration in CSF, aqueous humor, and synovial fluid
-can cause hyporexia, diarrhea, inc. liver enzymes, CNS signs, and coat/skin problems
-avoid use in cats
What are the characteristics of posaconazole?
-similar to itraconazole, but with better activity against Histoplasma, Blastomyces, and Coccidioides
-absorption improves when given with food
-typically given as delayed-release tablet
-GI side effects possible but not common
-safe and tolerated long-term
-no liver enzyme increases
What are the characteristics of amphotericin B?
-polyene macrolide
-broad spectrum
-irreversibly binds to sterols in fungal membrane to form pores/channels and lead to ion leakage
-generally fungistatic; fungicidal at high doses
-immunomodulatory/activates macrophages
-poor water solubility; not well absorbed from GI tract
What are the characteristics of amphotericin B - deoxycholate?
-administered with dextrose
-binds to plasma proteins and cholesterol in membranes
-poor penetration of vitreous humor and CSF
-usually given IV, can be given SQ
What are the major adverse effects of amphotericin B - deoxycholate?
-nephrotoxicity
-emetogenic
-phlebitis at IV site
What are the characteristics of the lipid formulations of amphotericin B?
-less damage to kidneys
-decreased rate of transfer to mammalian cell membranes
-increased clearance from blood
-treatment efficacy correlates with dose
-selective uptake by macrophages
-good for Histoplasma and Leishmania spp.
What are the characteristics of the amphotericin B lipid complex?
-most common form in vet med
-can cause nephrotoxicity and infusion-related reactions
What are the characteristics of liposomal amphotericin B?
-AMB and lipid mixture
-nephrotox. and infusion-related reactions are less common
-inc. conc. in the eyes
What are the characteristics of 5-flucytosine?
-fluorinated pyrimidine
-deaminated by fungi, which interferes with DNA replication and protein synthesis
-not deaminated by mammalian cells; limits mammalian cell injury
-used in cats for Cryptococcosis
-toxic to dogs
-used in combo. with other drugs
-good penetration of CSF and aqueous humor
-side effects include myelosuppression, GI signs, kidney injury
What are the characteristics of terbinafine?
-synthetic allylamine that inhibits fungal squalene epoxidase
-accumulation of toxic squalene leads to fungal lysis
-used against dermatophytes and Malassezia spp. in dogs
-synergism with other antifungals may inc. efficacy
-better absorbed when given w/ food
-penetrates hair, skin, nails
-can cause GI signs, inc. hepatic enzymes, and eye problems in dogs
-can cause facial pruritis in cats
-can be used topically
What are the characteristics of echinocandins/caspofungin?
-inhibit glucan formation in cell wall
-ineffective against Cryptococcus spp.
-used to treat Coccidioides spp.
-possible synergism with other antifungals
-caspofungin-induced remission in dogs
What are the characteristics of doing combination antifungal drug treatment?
-no data in dogs and cats
-azoles are often combined with other antifungals
-AMB often used first, with patient later switched to azoles
-combinations increase risk of side effects; side effects accumulate
What are the characteristics of griseofulvin?
-binds to fungal tubulin and impairs microtubule function; leads to mitotic arrest
-only used against dermatophytes
-adverse effects include GI signs, pruritis, fever, anemia, myelosuppression
-induces P450 enzymes
-teratogenic
-not for use in FIV cats
