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Describe diagnosis of fungal disease.
- culture should be paired with histopathology or cytology- sometimes these are enough when compatible clinical signs
- immunodiagnostic methods- antigen detection (more rapid than culture, good if you know what you're looking for, only validated in dogs), antibody detection (poor sensitivity and specificity, not good)
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Prokaryotes versus eukaryotes.
- Prokaryotes: bacteria; no nuclear membrane, simple plasma membrane, peptidoglycan cell wall
- Eukaryotes: fungi; nuclear membrane, sterol plasma membrane, chitin (polysaccharide) cell wall
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What are MOAs of the different classes of antifungals? (3)
- Cytoplasmic membrane (ergosterol): Polyenes, azoles, allylamines
- DNA synthesis: flucytocine
- Protein synthesis: flucytocine
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What are pre-requisites for systemic antifungal therapy?
- must have a definitive diagnosis, able to afford expense, watch for side effects/ monitoring
- [because anti-fungals are more toxic than antimicrobials]
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Fungi primarily use _______ in their cell membrane.
ergosterol
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What is the MOA of -azoles?
inhibit fungal cytochrome P450
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What are clinical uses of -azoles?
- systemic mycoses (Blastomycoses, Histoplasmosis, Coccidioides)
- dermatophytes
- Sporothrix
- Cryptococcus
- candida
- +/- Aspergillus (Itraconazole systemic, Clotrimazole topical)
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-Azoles are NOT useful against...
zygomycetes (Mucor) [except itraconazole may be effective]
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Describe the pharmacodynamic properties of Ketoconazole, Itraconazole, Fluconazole, and Voriconazole.
- Ketoconazole: low Vd, no BBB
- Itraconazole: tissue conc> plasma, no BBB
- Fluconazole: tissue conc>> plasma conc, DOES CROSS BBB
- Voriconazole: tissue conc>>>plasma conc, DOES PENETRATE BBB
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Describe the metabolism and drug interactions of Ketoconazole.
- strong mammalian P450 inhibitor (combined with cyclosporin to lower the dose of this expensive drug by slowing its metabolism)
- teratogenic
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What is the most broad spectrum -azole?
itraconazole
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Describe the metabolism and uses of itraconazole.
- more specific for fungal P450 and fewer side effects than ketoconazole (but more $$)
- more potent than keto against dermatophytes, Aspergillus, Zygomycetes, dimorphic fungi, Candida
- used in birds
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Describe clinical applications of fluconazole. (4)
- CNS fungal infections (b/c crosses the BBB)
- Cryptococcus nasal disease in cats
- Candidiasis (UTIs, peritonitis)
- anecdotal reports of efficacy against Blasto in dogs
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What is the spectrum of polyenes?
broad-spectrum (all fungi)
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Polyenes are ________.
fungicidal
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What is the MOA of polyenes?
- direct binding of ergosterol (also binds cholesterol in animal cells--> high toxicity)
- Ampho B only- macrophage activator to enhance immune response
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What is the go to drug for treating Blasto in dogs?
Fluconazole
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What are the drugs in the class polyenes? How is each administered? (2)
- Amphotercin B- IV
- Nystatin- topical
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What are clinical applications of Amphotercin B?
**Last resort drug** (b/c causes hepatotoxicity, nephrotoxicity)
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How can you decrease toxicity of Ampho B? How does it work?
- lipid complex preparations- Abelcet (lipid encapsulated products)
- lipid-ampho B complexes stick to HDL cholesterol--> less free (toxic) amphoB in serum--> decreased uptake by renal epithelium (less nephrotoxic)--> increased uptake by reticulinendothelial system--> increased affinity for ergosterol
- USUALLY TOO EXPENSIVE
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What is the MOA of Terbinafine (allylamine)?
inhibits ergosterol synthesis
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What is the clinical application of terbinafine?
- not widely used
- sometimes used to treat ring worm in cats
- anecdotal evidence that it can be used to treat pythiosis in combination with itraconazole
- heptotoxic
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What is the clinical use of griseofulvin? How is it administered?
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What is the MOA of griseofulvin?
- inhibits mitosis and microtubule assembly
- concentrates in forming keratin
- fungicidal to cells that are actively dividing, quiescent fungal cells will survive (ie. bathe your patients as well as treating!)
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What are side effects of griseofulvin? (3)
- hepatotoxic (P450 INDUCER)
- idiosyncratic anemia
- teratogenic
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