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Antifungal Drugs
antifungals
40
Veterinary Medicine
Professional
07/08/2020

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Cards

Term
Itraconazole
Definition
A broad-spectrum synthetic triazole that is highly lipophillic and insoluable in water
Term
Hydroxypropyl B-cyclodextrin
Definition
Added to the liquid formulation of brand name Itraconazole to provide solubility. Thus food is not required/recommended to be given with the liquid formulation.
Term
The use of ketoconazole concurrent with cyclosporin allows what % dose reduction?
Definition

75%

Via cytochrome P-450 inhibition

Term

What is the MOA of Nystatin?
Definition
Binding to sterols in the fungal cell membrane, leading to changes in permeability and fungal death due to osmotic destruction

Paterson. Journal of Small Animal Practice (2016) 57, 668–678
Term
MOA and example of Allylamines?
Definition
Disrupt ergosterol biosynthesis and prevent fungal cell wall formation. Terbinafine

Paterson. Journal of Small Animal Practice (2016) 57, 668–678
Term
What is the mechanism of action for ketoconazole (azole - imidazole)?
Definition

Inhibits the P450 enzyme 14a demethylase a

which leads to inhibition of the the conversion of lenosterol to ergosterol. This inhibits ergosterol synthesis in the cell membrane.

Inhibits triglyceride and phospholipid biosynthesis, inhibits cell wall chitin synthesis

fungi static, Can take 10 to 14 days to reach full affect

At high concentrations may be fungicidal and also will inhibit 11 hydroxylase blocking the conversion of deoxycorticosterone to corticosterone and also has anti-inflammatory effects

Term
What organisms is Ketoconazole used to treat?
Definition
Dermatophytes, systemic fungal infections, histoplasmosis, Blastomycosis, Coccidioides and Malassezia
Term
What are the potential side effects and contraindications for ketoconazole? What monitoring should be employed?
Definition

V/D, hepatotoxicity, rare thrombocytopenia, lightening of the hair coat, reduced synthesis of cortisol and testosterone, impotence/anestrus, Cataracs

Do not use with significant liver disease, pregnancy or in cats. Do not give with rifampicin, mitotane, theophylline and will alter the metabolism of cyclosporine and barbiturates

Absorbed better with a meal when there is acid in the stomach. Avoid giving with antacids

Term
What is the mechanism of action for itraconazole (azole - triazole)?
Definition

Inhibits the P4 50 enzyme 14 a demethylase which prevents the conversion of lanosterol to ergosterol which therefore inhibits ergosterol synthesis and incorporation into the cell membrane of fungi

Potent/more active than ketoconazole - The potency of each azole depends on it affinity for binding the P450 moiety, relative toxicity depends on it’s selectivity of action on mammalian versus fungal enzymes

Term
What organisms is itraconazole used to treat?
Definition

Dermatophytes, systemic fungal infections including histoplasmosis Blastomycosis and Coccidioides, Malassezia

First choice for treatment of cats with dermatophyte infection

Term
What are the potential side effects and contraindications for itraconazole?
Definition

V/D, hepatotoxicity, drug reactions possible

generally better tolerated than ketoconazole As it does not inhibit mammalian P450 as strongly

In one study up to 7.5% of dogs developed vasculitis on a higher end of the dose range (10mg/kg)

Do not give with antacids or proton pump inhibitors, do not use compounded products

Will not lower cortisol levels

Term
What is the mechanism of action for fluconazole (azole - triazole)?
Definition

Inhibits the P4 50 enzyme 14 a demethylase which prevents the conversion of lanosterol to ergosterol which therefore inhibits ergosterol synthesis and incorporation into the cell membrane of fungi

Improved CNS an ocular penetration; May not be as effective for dermatophyte infections

Term
What organisms can fluconazole be used to treat?
Definition

Systemic fungal infections including histoplasmosis Blastomycosis and Coccidioides, Malassezia

Because it has improved penetration into the CNS it is used for treating cryptococcus in cats

Term
What are potential side effects and contraindications for fluconazole?
Definition

V/D, hepatotoxicity

Do you not using pregnant animals

As with other azole drugs monitor liver enzymes

Term
What is enilconazole and how is it used (azole - triazole)?
Definition

Inhibits ergosterol synthesis in the same manner as other azole drugs.

topical formulation only! Used to treat dermatophyte infections (rinse, spray or environmental treatment)…Do not let cats lick it off themselves

Can be used in the nasal passages for treatment of aspergillosis

Term
What is voriconazole and how is it used (azole - triazole)?
Definition

Inhibits ergosterol synthesis in the same manner as other azole drugs.

More active and potent than fluconazole with better action against aspergillosis and fusarium

can cause neurotoxicity in cats, vomiting and hepatotoxicity; Monitor liver enzymes and CNS


Avoid in pregnancy or with liver disease

Term
How is clotrimazole most often used (azole - triazole)?
Definition
This medication has good efficacy against dermatophytes and Malassezia when used topically
Term
What is the mechanism of action for flucytosine?
Definition
Taken up into fungal cells and then delaminated to an active form by an enzyme called cytosine deaminase (mammalian cells have very little to none of this enzyme, giving this drug some specificity). In its active form the drug inhibits thymidylate synthetase, an essential enzyme for DNA synthesis and the active drug is also incorporated into RNA, disrupting it.
Term
What are the potential side effects and contra indications of flucytosine?
Definition

Often combined with amphotericin B and used to treat cryptococcus in cats

Anemia, thrombocytopenia, do not use in dogs = causes skin eruptions

Monitor CBC

Term
What is the mode of action of amphotericin B (polyene Antifungal)?
Definition
Binds to ergosterol in the fungal cell wall, causes leakiness (membrane depolarization and increased permeability) and cell death
Term
What is amphotericin B used to treat? What are It’s side effects and contra indications?
Definition

Active against most fungi including Blastomycosis and Histoplasma and coccidiomycosis as well as some protozoa including leishmania

Can cause nephrotoxicity, fever, tremors and phlebitis

Use with extreme caution in animals with renal disease or dehydration

Term
What is griseofulvin?
Definition
I antifungal antibiotic that is the fermentation product of penicillium griseofulvum.
Term
What is the mechanism of action for griseofulvin?
Definition

Incorporates/binds to keratin precursors, then inhibits mitosis of fungal cells which die. Also inhibits nucleic acid synthesis and interferes with micotic spindle microtubules

Enhances the function of P4 50 enzymes, that’s enhancing clearance of other drugs

Term
What types of infection is griseofulvin used to treat? What are its special considerations, potential side effects and contra indications?
Definition

Effective in treating dermatophyte infections, poor efficacy for other fungal organisms

has anti-inflammatory and immune modulatory properties (Suppresses delayed type hypersensitivity and skin irritant reactions)

do not use in cats with FIV! Avoid with pregnancy and hepatic dysfunction

bone marrow toxicity, depression, neurotoxicity vomiting and diarrhea. Teratogenic.

Give with a fatty meal

Term
What is the mechanism of action for terbinafine (allylamine)?
Definition

Targets squalene epoxidase, inhibits ergosterol synthesis

Term

What is terbinafine used to treat? What is it safety profile?

Definition

Affective against dermatophytes and yeast

Persists in the SC for long periods of time

No contraindications and minimal side effects include vomiting, nausea, anorexia

Term
How are potassium iodide and sodium iodide used in the treatment of fungal infections?
Definition

Sodium iodide is preferred

Mechanism of action is unknown

Classically used to treat sporotrichosis in dogs but can also be a adjunct of treatment for zygomycosis, fungal granulomas and fungal infections in large animals

Term
What are the clinical signs of iodine toxicity?
Definition

Excessive lacrimation, swelling of eyelids, nonproductive cough, increased respiratory secretions, scruffy coat and alopecia

Iodine containing drugs should not be used in pregnant animals as they can cause abortion

Term
What is the mechanism of action for caspofungin?
Definition

Inhibits 1,3 b d glucan synthetase, this blocking fungal cell wall synthesis, inhibits hyphal growth

Fungicidal for most fungi

Term
What organisms can caspofungin treat? What should be monitored during treatment?
Definition

Dermatophytes, sporothrix, aspergillus and candida. Possibly pythium

Monitor liver enzymes

Term
What is the mode of action of Griseofulvin?
Definition
  • Inhibits cell wall synthesis, nucleic acid synthesis, and mitosis; disrupts mitotic spindle formation
  • micronized 25-60mg/kg PO q 12 hours (ultramicronized 2.5-15mg/kg q 12 hours)
  • Give with a fatty meal 
  • monitor CBC for bone marrow suppression
  • do NOT use if FIV or FELV +
Term
What is the mode of action of Ketoconazole?
Definition
  • Ketoconazole is an imidazole
  • It inhibits p450 enzymes, blocks 14α-demethylase preventing ergosterol synthesis and other actions
  • 5-10mg/kg PO q 24 hours
  • Give with food, not recommended for cats 
  • monitor for hepatotoxicity (rare)
  • be aware of drug interactions
Term
How long should systemic antifungal therapy be continued for all dermatophyte-infected animals?
Definition
  • Continue treatment until three negative cultures have been obtained (weekly intervals)
Term
What is the mode of action of Itraconazole?
Definition
  • Itraconazole is an triazole
  • It inhibits p450 enzymes, blocks 14α-demethylase and other actions
  • 5-10 mg/kg PO q 24 hours, may use every other week
  • Give with food, do not use if hepatic disease, up to 7.5% of dogs develop vasculitis (10mg/kg) 
  • Monitor liver enzymes
Term
What is the mode of action of fluconazole?
Definition
  • Fluconazole is a bis-triazole
  • It inhibits p450 enzymes, blocks 14α-demethylase
  • 10mg/kg PO q 24 hours
  • penetrates into CNS and eyes; monitor liver enzymes
Term
What is the mode of action for terbinafine?
Definition
  • Terbinafine is an allyalamine
  • It inhibits ergosterol biosynthesis and squalene epoxidase
  • 20-30 mg/kg PO q 24 hours
  • Monitor liver enzymes
Term
What is the mode of action of Lufeneron?
Definition
  • Inhibits chitin synthesis
  • 80-100mg/kg PO q 30 days
  • insufficient proof of efficacy to recommend use in treatment of dermatophytosis
Term
Amphotericin B MOA
Definition
  • Polyene antifungal 
  • Fungistatic
  • Binds to ergosterol---> membrane depolarization and increased membrane permeability
  • Given IV, nephrotoxic
  • Formulations:
    • Fungizone (colloid with bile salt deoxycholate)
    • Amphocil-complexed with cholesterol sulfate
    • AmBisome-encapsulated with liposomes
    • Abelcet- complexed with lipids
  • Monitor renal function
Term
Coccidiomycosis diagnosis
Definition
  • history of travel to endemic area
  • cytology: organisms seldom found
  • spherule (20-200um) and endospore (2-5um)
  • biopsy
  • culture is not recommended
  • serology not consistently reliable
  • Antigen detection
Term
Cryptococcosis: Cryptococcus neoformans & C.gattii- name virulence factors and risk factors
Definition
  • Virulence factors
    • Polysaccharide capsule
    • Melanin
    • Mannitol
    • Lactose
    • Phenol oxidase
  • Route of exposure
    • Inhalation
    • Direct skin penetration
  • Risk factors
    • Corticosteroids/Immunosuppression
    • Retroviral infection
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