Antifungal therapy Flashcards
What are the mechanisms of action of currently available antifungals. Give at least an example for each
Cell wall perturbation
- E.g., Echinocandin
Cell membrane perturbation
- E.g., Azoles, polyenes, terbinafine
DNA synthesis perturbation
- E.g., Flucytosine
What is the chemical family of Amphotericin B
Amphotericin B (AMB) is a polyene macrolide produced naturally by Streptomyces nodosus
What is the mechanism of action of Amphotericin B
It binds to ergosterol in the fungal cell membrane (the main sterol in mammalian cell membrane is cholesterol), causing the formation of pores, leading to leakage of potassium and cell death
What is the route of administration for Amphotericin B
AMB is very poorly absorbed orally, so it must be administered parenterally
What are the principal pharmakocinetic characteristics of AMB
AMB is widely distributed in the body, however it is highly protein bound
What is a striking paradox concerning AMB when regarding its pharmakocinetic and activity
It has apparently poor penetration into the CNS, CSF, bone, eye and non-inflamed body cavities
Despite this, it appears to be the most effective drug for disseminated and CNS cryptococcosis
- its effects are enhanced by the addition of 5-flucytosine, which has a good penetration into the CNS
What are Amphotericin B toxic effects
The drug’s toxic effects are due to the similarity between fungal ergosterol and mammalian cholesterol in cell membranes
The main deleterious effect is its nephrotoxicity
- possibly due to peri-glomerular vasoconstriction
- AMB may also be directly toxic to tubular epithelial cells
Regarding the potential nephrotoxicity of AMB, could it be possible to use it in animals with pre-existing renal disease
Quite often its use is imperative in combating serious systemic fungal infections
Administration of AMB may be justified in animal with renal dysfunction as long as the animal is closely monitored with frequent measurement of serum urea and creatinine levels (at least weekly)
- The nephrotoxic effects of AMB are often reversible if given sufficient time for azotemia to correct between doses
Which precautions should be taken when using AMB
It is essential that:
- animals are well hydrated during treatment with AMB
- other drugs with potential for nephrotoxicity are avoided
What are the standard doses for AMB
Start with 0.5 mg/kg twice weekly until azotemia develops
Then reduce the dose to 0.7-0.8 mg/kg once weekly (with further reductions as required)
What is the mechanism of action of azole derivatives
Azoles function by decreasing ergosterol formation in the fungal cell membrane by inhibiting one of the enzymes in the sterol biosynthesis pathway
This has the effect of increasing membrane permeability and allowing leakage of cellular contents
Damaged cells have also an impaired uptake of purine and pyrimidine precursors
Are azoles derivatives fungistatic or fungicidal
They are fungistatic and often need too be given for protracted periods in animals with systemic mycoses
Explain why ketofungol is currently under favoured to treat fungal infections
It has been replaced by the more effective and less toxic triazoles (fuconazoleand itraconazole)
Its absorption is enhanced by acid environment and small amounts of fatty foods
At doses required to treat systemic mycoses, ketoconazole is frequently hepatotoxic
Why triazoles (e.g., itraconazole) are less toxic than imidazoles (e.g., ketoconazole)
They more specifically bind fungal than mammalian enzyme in the sterol biosynthesis pathway
Compare and contrast Itraconazole and Fluconazole
Itraconazole has a broader spectrum (effective against yeasts and moulds, including dermatophytes) than fluconazole (for example it is effective against Aspergillus, whereas fluconazole is not)
Fluconazole is not as effective as itraconazole for treating dermatophyte infections because it is water soluble
However, itraconazole is highly protein bound and does not penetrate into the CNS or aqueous humor
How can you enhance itraconazole absorption
GI absorption of itraconazole is quite variable
It can be enhanced by feeding with food
What are the potential side effects of itraconazole
Hepatotoxicity is generally dose related
- Serum alanine transferase should be monitored monthly
Idiosyncratic anorexia and/or vomiting occur in some cats
Explain why fluconazole is an extremely useful anti-fungal agent
It is widely distributed in the body (including the brain, eye, and urinary tract)
It has an excellent safety profile
It has good fungistatic activity against most fungi except for Aspergillus
It is rapidly and nearly completely absorbed after oral administration
Approximately 70% of the drug is excreted via the urine in an active form, thus it is useful for fungal infections of the urinary tract (other than Aspergillus)
What is the dose for fluconazole in cats
50 mg, PO, q 12h
What is the mechanism of action of terbinafine
Terbinafine is a synthetic allylmine that inhibits the synthesis of ergosterol by blocking the activity of the enzyme squalene monooxygenase and causes the accumulation of squalene
What are the principal pharmakocinetic characteristics of terbinafine
It is metabolized in the liver, though not through the P-450 enzyme system
It tends to accumulate in fatty tissues for an extended period
What are the precautions of use in animals
It should be use with caution in animals with renal and liver insufficiency
- Dose adjustments should be made
It is concentrated in maternal milk, thus its use in nursing animals is generally not recommended
What are the potential side effcets of terbinafine
Inappetence
Vomiting
Diarrhea
Hepatotoxicity
What is the dose for terbinafine
30 mg/kg, PO, q24h
