Lecture 25 4/29/24

Question 1

What are the general characteristics of antifungal treatment?

Answer 1

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

Question 2

What are the general characteristics of fungal cells?

Answer 2

-eukaryotic
-cell wall contains mannoproteins, glucans, and chitin
-ergosterol is required for cell membrane

Question 3

How do azoles work against fungi?

Answer 3

-inhibit 14alpha-demethylase, which normally converts lanosterol to ergosterol
-depletion of ergosterol and accumulation of 14alpha-methylsterols disrupts the cell membrane

Question 4

What is the spectrum of action for azoles?

Answer 4

widely used to treat a variety of mycoses

Question 5

Which azoles fall into the imidazoles class?

Answer 5

-ketoconazole
-clotrimazole
-enilconazole

Question 6

What are the characteristics of imidazoles?

Answer 6

-poor oral bioavailability
-used for superficial topical infections

Question 7

Which azoles fall into the triazoles class?

Answer 7

-itraconazole
-fluconazole
-voriconazole
-posaconazole

Question 8

What are the characteristics of triazoles?

Answer 8

-more slowly metabolized
-decreased impact on mammalian sterol synthesis

Question 9

What leads to the side effects and drug interactions associated with azoles?

Answer 9

-cross-inhibition of mammalian P450 enzymes
-inhibition of drug transport by efflux transporter

Question 10

What are the characteristics of ketoconazole?

Answer 10

-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

Question 11

What are the characteristics of itraconazole?

Answer 11

-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

Question 12

What are the characteristics of fluconazole?

Answer 12

-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

Question 13

What are the characteristics of voriconazole?

Answer 13

-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

Question 14

What are the characteristics of posaconazole?

Answer 14

-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

Question 15

What are the characteristics of amphotericin B?

Answer 15

-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

Question 16

What are the characteristics of amphotericin B - deoxycholate?

Answer 16

-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

Question 17

What are the major adverse effects of amphotericin B - deoxycholate?

Answer 17

-nephrotoxicity
-emetogenic
-phlebitis at IV site

Question 18

What are the characteristics of the lipid formulations of amphotericin B?

Answer 18

-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.

Question 19

What are the characteristics of the amphotericin B lipid complex?

Answer 19

-most common form in vet med
-can cause nephrotoxicity and infusion-related reactions

Question 20

What are the characteristics of liposomal amphotericin B?

Answer 20

-AMB and lipid mixture
-nephrotox. and infusion-related reactions are less common
-inc. conc. in the eyes

Question 21

What are the characteristics of 5-flucytosine?

Answer 21

-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

Question 22

What are the characteristics of terbinafine?

Answer 22

-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

Question 23

What are the characteristics of echinocandins/caspofungin?

Answer 23

-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

Question 24

What are the characteristics of doing combination antifungal drug treatment?

Answer 24

-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

Question 25

What are the characteristics of griseofulvin?

Answer 25

-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