Antifungals Flashcards
Five main antifungal drug classes/drugs:
1) Polyenes
2) Azoles
3) Pneumocandins (& echinocandins)
(4) Pyrimidines)
5) Drugs used to treat dermatophytosis
polyenes: an important drug in this category, and some characteristics
1) Polyenes
* E.g., amphotericin B
* Broad spectrum, fungicidal
* High systemic toxicity
azoles: an important drug in this category, and some characteristics
- E.g., itraconazole
- Broad spectrum, fungistatic
- Very low toxicity
pneumocandins: an important drug in this category, and some characteristics
- Newest AF drugs, low toxicity, replacing polyenes for systemic therapy
- E.g., caspofungin
important drug used to treat dermatophytosis
Terbinafine
difference between bacterial and fungal cell and consequence
Unlike bacteria, fungi are eukaryotic
>harder to attack without affecting host
main targets of antifungal drugs, generally
Plasma membrane
>Most systemic drugs (polyenes, azoles)
Cell wall
>(pneumocandins)
Protein synthesis, Nucleic acid synthesis
>(Flucytosine)
specific component of fungal plasma membrane that is the target of many antifungals
Plasma membrane contains ergosterol instead of cholesterol
> target of many antifungals
plyenes mechanism of action and toxicity
Polyenes bind ergosterol in fungal membrane
> inserted into membrane
> several molecules come together to form a pore
> pores cause fungal cell to lyse (fungicidal)
Unfortunately, it also binds cholesterol to some extent in mammalian cells somewhat > toxic to host
what is Amphotericin B?
A polyene macrolide antifungal
pharmacokinetics of Amphotericin B; absorption, distribution
Conventional amphotericin B is usually formulated with bile salts to improve solubility, however can cause adverse effects
Poor oral absorption; usually given IV
Distributes to extracellular fluid; poorly into CNS
pharmacokinetics of Amphotericin B; elimination
Most metabolized in liver
> bile; smaller amount excreted in urine
Long half-life: ~ 26 h in dogs; drug continues to be excreted for weeks after discontinuation of therapy
spectrum of Amphotericin B
Broad (greater than the azoles)
* Many serious systemic mycotic infections
clinical use of amphotericin B
Systemically, main use is in dogs & cats with life-threatening systemic mycoses, esp. in immunocompromised patients due to the fungicidal nature of the drug
Ampho B is often administered once followed by longer follow-up therapy with azole
Systemic use is sporadic in equine medicine, rare/absent in food animals
route of administration of amphotericin in most species
Topical administration in most species
Amphotericin B adverse effects and how to minimize
The most toxic antimicrobial drug in clinical use
Main adverse effect is dose-dependent nephrotoxicity seen primarily with bile salt formulations
IV admin should be slow (4-6 h)
Lipid-complex formulations are much safer
The first relatively safe class of antifungal drugs; now the most commonly used for systemic antifungal therapy
Azoles
Azoles spectrum and bioavailability
Broad spectrum; fungistatic
Good oral bioavailability
which types of azoles are worse for systemic use and more toxic? which are better? which are good for topical?
For systemic use, older imidazoles (e.g., ketoconazole) are usually less effective and are more toxic than newer triazoles (e.g., itraconazole)
For topical use, imidazoles & triazoles are
often interchangeable (good efficacy, low toxicity)
Azoles mechanism of action
Triazoles inhibit fungal P450 enzymes involved in ergosterol formation
>generally fungistatic effect
Azoles inhibit mammalian hepatic P450 enzymes
> inhibits metabolism of many concurrently administered drugs
difference in safety profile between imidazoles and triazoles
Imidazoles: endocrine adverse effects are common with systemic therapy
Triazoles: generally very safe
types of azoles?
imidazoles and triazoles
what is ketoconazole? what is it used for?
Systemic imidazole
* The first azole to be marketed
* No longer used as an antifungal (eclipsed by the triazoles)
because it inhibits mammalian sterol synthesis
- Sometimes used in the management of hyperadrenocorticism because of its ability to inhibit cortisol synthesis (a use unrelated to its antifungal properties)
what is ketoconazole? what is it used for?
Systemic imidazole
* The first azole to be marketed
* No longer used as an antifungal (eclipsed by the triazoles)
because it inhibits mammalian sterol synthesis
- Sometimes used in the management of hyperadrenocorticism because of its ability to inhibit cortisol synthesis (a use unrelated to its antifungal properties)
Some topical imidazoles? why are they not used systemically?
Miconazole
Clotrimazole
Enilconazole
(Drugs too toxic for systemic use)
what type of drug is itraconazole? what is its spectrum, absorption, safety?
Fairly broad spectrum triazole
>used in cats, dogs
Good oral absorption
No adverse effects on mammalian steroid synthesis
Contraindicated in pregnancy > teratogenic effects
what are echinocandins? what is the main example? what is the mechanism?
A new class of antifungal drugs
Caspofungin is the main example
* Mechanism: Inhibits fungal cell wall synthesis
what are the uses of echinocandins?
- Fungistatic activity against Aspergillus spp., fungicidal activity against most Candida spp.
- In humans, all agents are well tolerated, with similar
adverse effect profiles and few drug-drug interactions - No animal data; experimental; expensive
spectrum is narrower than polyenes
what is the mechanism of terbafine?
inhibits ergosterol synthesis in virtually all dermatophytes (and several other types of fungi)
* Toxic metabolites accumulate > fungicidal
uses of terbinafine
fungicidal
* Originally more effective than itraconazole or griseofulvin for dermatophytosis, but resistance is a moving target and it depends on the strain
* Works synergistically with azoles
- Novartis
* Cats: Administered topically & orally; clipping may be important Dogs: Topical treatment alone is acceptable for localized infections but generalized infections respond better to topical + oral
* In severe cases, combination of oral & topical treatment of clipped animals gives fastest resolution (whether using terbinafine or azoles or a combination of drugs)
* Distributes to skin, nails, fat (& milk)
* Available over-the-counter
time of treatment for terbafine
Enters newly forming keratin > therapy typically requires 1-3 months for mycological cure
(much longer for nails)
main adverse effects of terbinafine
- Low incidence of adverse effects in dogs & cats
> well tolerated even for prolonged therapy (60 days) - May see GI upset; nausea & vomiting may indicate hepatic injury; rare but severe skin problems
- Inhibits some hepatic P450 enzymes > consider in animals receiving other drugs metabolized in the liver
Tolnaftate is useful against?
Effective against dermatophytes
how can we treat candida albicans?
- Mucocutaneous infections in many species
- Usually secondary to prolonged antibacterial treatment or immunosuppression
Treatment:
-Manage predisposing factors
-Depending on location, severity:
>Topical azole or polyene if lesions accessible
>Systemic azole or polyene +/- other
how can we treat Aspergillus fumigatus?
- Mucous membranes in dogs
- Air sacs in poultry
- Guttural pouch in horses
- Mastitis & abortion in cattle
Treatment:
-Usually preventable via management
-Depending on location, severity:
>Topical azole or polyene if lesions accessible
>Polyene or azole +/- other
how can we treat Blastomyces dermatitidis?
- Disseminated disease often starting in lungs, esp. in dogs
Treatment:
-May require combined amphotericin B + azole
-Often requires prolonged treatment if established
-Often combine with anti- inflammatory therapy for tx of fungal pneumonia, otherwise dead fungal cells trigger pulmonary inflammatory reaction that can be fatal
