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)
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
What are MOAs of the different classes of antifungals? (3)
- Cytoplasmic membrane (ergosterol): Polyenes, azoles, allylamines
- DNA synthesis: flucytocine
- Protein synthesis: flucytocine
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]
Fungi primarily use _______ in their cell membrane.
What is the MOA of -azoles?
inhibit fungal cytochrome P450
What are clinical uses of -azoles?
- systemic mycoses (Blastomycoses, Histoplasmosis, Coccidioides)
- +/- Aspergillus (Itraconazole systemic, Clotrimazole topical)
-Azoles are NOT useful against...
zygomycetes (Mucor) [except itraconazole may be effective]
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
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)
What is the most broad spectrum -azole?
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
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
What is the spectrum of polyenes?
broad-spectrum (all fungi)
Polyenes are ________.
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
What is the go to drug for treating Blasto in dogs?
What are the drugs in the class polyenes? How is each administered? (2)
- Amphotercin B- IV
- Nystatin- topical
What are clinical applications of Amphotercin B?
**Last resort drug** (b/c causes hepatotoxicity, nephrotoxicity)
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
What is the MOA of Terbinafine (allylamine)?
inhibits ergosterol synthesis
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
What is the clinical use of griseofulvin? How is it administered?
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!)
What are side effects of griseofulvin? (3)
- hepatotoxic (P450 INDUCER)
- idiosyncratic anemia