Antifungals: systemic

When it comes to treating fungal infections, what are 6 things to be considered?

• there's a prolonged course of treatment

• Cost will add up over time

• Monitoring for adverse effects

• Potential for drug interactions

• Possibly life-long therapy

• Lots of pharmacokinetic work to be done

*What are four common properties of azoles that?

1) Hepatotoxicity: monitoring liver damage vs. liver function

2) Teratogenic

3) Some fungi/molds have inherent resistance

4) Resistance to one azole does not imply resistance to other azoles

Which of our Azoles are systemic antifungal medications?

• Ketoconazole

• Fluconazole

• Itraconazole

• Voriconazole

Which of our Azoles are topical antifungal medications?

• Miconazole

*What is the general mechanism of action of our Azoles?

inhibit C-14(alpha) demethylase that leads to funky ergosterol, which makes for unstable cell wall of fungi and more susceptible to cell death.

What is ketoconazole's intended use?

•Topical mycotic infections

•Malassezia dermatitis

• Not first choice for systemic fungal infections

Ketoconazole is used to treat ___________ mycotic infections.

topical

*Is ketoconazole our first choice for treating systemic fungal infections?

NO

What are three pharmacokinetic considerations for Ketoconazole?

•Absorption is enhanced with gastric acidity --> give with food

•Highly protein bound

•Distributes to skin well

*What are the three main adverse effects of ketoconazole?

• GI upset

• Hepatotoxicity

• Inhibits synthesis of steroid hormones: Cortisol, Testosterone

*Ketoconazole has NUMEROUS drug interactions, what are the two main ones to consider for now?

• Inhibits cytochrome P450

• Inhibits P-glycoprotein

*Why would you NOT want to use a cytochrome P450 substrate or p-glycoprotein substrate drug (like cyclosporine) at the same time at Ketoconazole?

because Ketoconazole will inhibit the metabolism of said drugs

and increase the blood concentration of the cytochrome P450 substrate drug (like cyclosporin)

*Why would you want to use a cytochrome P450 substrate or p-glycoprotein substrate drugs (like cyclosporin) at the same time at Ketoconazole?

to keep cost down for cyclosporin - so that it will be longer lasting, can get away with giving less cyclosporin - especially in larger dogs

If you administer a p-glycoprotein substrate drug, like ivermectin, along with ketoconazole - what is going to be the result and why?

Ivermectin will be present at higher blood concentrations - because ketoconazole is a p-gp inhibitor.

It is not safe to prescribe extra-label doses of ivermectin to an animal receiving which of the following drugs? and why?

Nitenpyram

Fipronil

Selamectin

Spinosad

Moxidectin

Spinosad - because it is a p-glycoprotein inhibitor and will lead to increase blood concentration of ivermectin in blood (even in non-mutant p-glyc. dogs)

Would fluconazole be a good choice for treating a systemic fungal infection caused by Aspergillus?

NO

What is the intended use of Fluconazole?

• Systemic fungal infections

• Aspergillus is inherently resistant

What are four pharmacokinetic considerations to keep in mind with Fluconazole?

• Best oral bioavailability

• Not highly protein bound

• Penetrates CNS

• Water soluble: • Excreted --> active form in urine, Renal dosing considerations

What route of administration allows for the greatest bioavailability of Fluconazole?

orally

What are three potential adverse effects of Fluconazole?

• GI upset

• Hepatotoxicity

• Bone marrow dyscrasias

Why would you monitor a patient on fluconazole by performing routine CBC/Chem?

to monitor for signs of hepatotoxicity and bone marrow dyscrasias

*What are the drug interactions to consider for fluconazole?

Inhibits cytochrome P450 (so might not want to use with cytochrome P450 drug with fluconazole)

What is the intended use of Itraconazole?

• Systemic fungal infections

• Not first line for CNS infections

Itraconazole is used to treat ___________ fungal infections.

systemic

What are five pharmacokinetic considerations for Itraconazole?

• Oral capsules --> give with food

• Oral solution --> give on empty stomach

• Do not use compounded itraconazole! (if Dr. P were to ask an exam question on these considerations - it would be on this)

• Extensive hepatic metabolism

• Concentrates well in skin

Should Itrazonazole be compounded?

NO

What are three potential adverse effects of Itraconazole?

• GI upset

• Hepatotoxicity

• Vasculitis

What drug interactions should be considered with Itraconazole?

• Inhibits cytochrome P450

What is the intended use for Voriconazole?

• Systemic Aspergillus

• Systemic mold infections

• Not active against Sporothrix spp.

Is Voriconazole active against Sporothrix spp.?

nerp

_______________ is effective against systemic Aspergillus infections, whereas _____________ is not.

Voriconazole

Fluconazole

What are three pharmacokinetic considerations of Voriconazole?

• Good oral bioavailability

• Absorption is reduced with food

• Penetrates the CNS well (might consider this drug for fungal infections that have spread to CNS)

*What makes Voriconazole a good potential choice to treating fungal infections that have spread to the CNS?

this drug penetrates the CNS well

*What are five adverse effects to consider with Voriconazole?

• Gastrointestinal upset

• Visual issues - staring

• CNS signs

• Hepatotoxicity

• Do not give to cats

*Can Voriconazole be given to cats?

NO

What are drug interactions to consider with Voriconazole?

• Many possible

• Full extent still unknown

What is the intended use of Miconazole?

• Topical preparations

Miconazole is toxic when given ____________

systemically

What route of administration is available for Miconazole?

topical!

What are two clinical examples/forms of Miconazole?

- Medicated shampoos

- Potentiated effect (shampoo/wipe combined with Chlorhexidol(sp?))

All of the -azoles have relatively good bioavailability orally and is given orally, except which one?

Miconazole

Ketoconazole distributes to _______ well

Fluconazole penetrates the _______ well

Itraconazole concentrates in _______ well

Voriconazole penetrates the _______ well.

__________ is only used topically!

skin

CNS

skin

CNS

Miconazole

*What is the mechanism of action of Amphotericin B?

binds ergosterol (component of fungal cell membrane) and creates pore in fungal cell membrane - fungal cell dies a leaky death

*What is the intended use of Aphotericin B?

• Bad, life-threatening systemic fungal infections

What are pharmacokinetic considerations for Amphotericin B?

• Minimal PO absorption: must be IV

• Cumulative nephrotoxicity limits dosing

• Newer lipid-incorporated products: AmB remains bound to phospholipids, Limits binding to mammalian cholesterol

Amphotericin B is not absorbed well orally and must be given via what route of administration?

IV

Amphotericin B will lead to nephrotoxicity - so how is this mitigated/monitored?

check urine for casts - sign of nephrotoxicity - so when we see casts - we stop giving the drug

What are three adverse affects of Aphotericin B?

• Cumulative nephrotoxicity (matter of when, not if)

• Gradual dose escalation

• Monitor urine sediment for casts

What are the drug interactions of Amphotericin B?

• Incompatible with LRS (lactated ringer solution)

• Other nephrotoxic drugs!

Amphotericin B is incompatible with ___________ _________ solution.

lactated ringers

Amphotericin B should not be used with other _____________ drugs!

nephrotoxic

*What is the mechanism of action of Allyamines, like Terbinafine?

It inhibits the squalene epoxidase enzyme so that squalene accumulates in fungal cell and its membrane integrity is altered

What is the intended use of Terbinafine?

• Dermatophyte infections

• Multimodal therapy: systemic fungal infections

What are the pharmacokinetic considerations of Terbinafine (Allylamines)?

• Good PO bioavailability

• Lipophilic

• Distributes well to skin

Terbinafine distributes well to _______.

skin

What are three adverse effects of Terbinafine?

• Gastrointestinal upset

• Hepatotoxicity

• Facial pruritus in cats

What are drug interactions (or lack there) of Terbinafine?

• Does not affect cytochrome P450

*What is the mechanism of action of Nystatin?

binds ergosterol (component of fungal cell membrane) and creates pore in fungal cell membrane - fungal cell dies a leaky death

*Nystatin is limited to a ____________ treatment (route of administration)

topical

*What is the use of Nystatin?

• Limited to topical treatment

• Candidiasis in birds

Nystatin is used to treat Candidiasis in ________.

birds

What are some pharmacokinetic considerations of Nystatin?

• Not absorbed by intact epithelium

• Systemic toxicity possible

What is a potential adverse effect of Nystatin?

• More toxic than amphotericin B when absorbed

Are there any drug interactions to consider with Nystatin?

• Not reported for oral nystatin

What species is Nystatin typically used in as an oral admnistration?

chickens/poultry

*Azoles will inhibit _____________ synthesis in the fungal cell.

erogosterol

*In what cases should Amphotericin B be reserved for?

• Bad, life-threatening fungal infections

*Allyamines (terbinafine) inhibit ___________ epoxidase.

squalene

*What is the only formulation of Nystatin?

topical

*Which of our anti-fungals are primarily used for systemic fungal infections?

Ketoconazole

Itraconazole

Fluconazole

Voriconazole

Amphotericin B

Terbinafine

*Which of our anti-fungals are primarily used for topical fungal infections?

Miconazole

Nystatin