Antifungal

Two broad groups of fungi

yeasts and molds

superficial mycoses

nails, skin, hair, acute; non-life threatening

subcutaneous mycoses

puncture wounds; acute or chronic; non-life threatening

systemic mycoses

soft tissue infections; UTIs; pneumonia; meningitis; septicemia; chronic; can be life-threatening

dermatophytoses

superficial fungal infections of the skin, hair, and nails caused by molds that feed on keratin (enzyme keratinase)

Genera of fungi the commonly cause skin disease of people and animals

Epidermophyton, Trichophyton, Microsporum

Sporotrichosis

usually happens after handling contaminated plant material, fungus enters skin through small cuts or scrapes “Rose gardener’s disease”

Oropharyngeal candidiasis (Thrush)

most common fungal infection in humans, white lesions (plaques) on tongue or oropharyngeal muscosa

Vulvovaginal candidiasis

women develop more frequently when taking abx, oral contraceptives, or during menses and pregnancy

candidiasis need to be distinguish as cause from others such as bacterial vaginosis or trichomoniasis

Candidal diaper dermatitis

“diaper rash”

warm moist areas under diapers

can happen in adults between skin folds

In immunocompromised patients, Candida can cause:

esophagitis and disseminated infections

These are acquired by inhalation as a spore form, never transmitted from person to person. Asymptomatic, pneumonia

Histoplasma capsulatum (HISTOPLASMOSIS)

Blastomyces dermatitidis (BLASTOMYCOSIS)

Coccidioides immitis (COCCIDIOIDOMYCOSIS

Coccidioidomycosis

Valley fever

endemic on in regions of Western Hemisphere

dust storms, earthquakes, and digging causing outbreaks

Cryptococcus neoformans

inhaled into lungs usually asymptomatic

major manifestation is meningoencephalitis

Aspergillus fumigatis

Aspergillus flavis

aflatoxin

causes liver damage and liver cancer

colonize and contaminate grains before harvest or during storage

Target #1

bind to ergosterol and “open up” the fungal cell membrane

Target #2

inhibit key enzymes needed for the synthesis of ergosterol, thereby preventing the fungal cell membrane from being formed

Target #3

inhibit the formation of the fungal cell wall

Target #4

inhibit the synthesis of fungal RNA and subsequent fungal protein synthesis

Target #5

bind to fungal microtubules and prevent them from participating in cell division

Amphotericin B

grandfather of antifungal agents

covers almost all medically important fungi

must be given IV

causes many side effects

Amphotericin B Adverse Effects

shaking, fever, chills, headaches, nausea, vomiting, hypotenison, tachypnea, Weight loss, malaise, acute liver failure, anemia, thrombocytopenia and mild leukopenia

Usually start 1-3 hours after starting infusion lasts about 1 hour

_______ is the major dose-limiting toxicity of amphotericin B.

Nephrotoxicity

____ is active only against Candida species

Nystatin

Nystatin is available in

topical formulation (creams, ointments, and powders)

orally administered tablets and suspensions for intestinal candidiasis

What is the common Mechanism of Action (MOA) for Azoles?

They block 14α-demethylase, which stops the synthesis of ergosterol (weakening the fungal cell membrane)

What are the four main ways these antifungals differ from one another?

1. Spectrum of activity

2. Bioavailability (how well they're absorbed)

3. Adverse effects

4. Drug interactions

oral azoles

fluconazole, itraconazole, voriconazole, ketoconazole, posaconazole

_____ _________ that are too toxic for systemic use and for this reason, are primarily used for topical fungal infections

topical azoles

what topical azoles cover vulvovaginal candidiasis

miconazole, tioconazole, monistat, vagistat

what topical azoles cover oropharyngeal candidiasis?

miconazole, oravig buccal tablets

what topical azoles cover dermatphytoses?

clotrimazole, lotrimin, oxiconazole, oxistat; luliconazole, luzu; miconazole, sertaconazole, ertaczo

what topical azoles cover onychomycosis?

efinaconazole, jublia

adverse effects of fluconazole

GI distress, headache, rash, anaphylaxis, hepatic necrosis, OT interval prolongation

same for Itraconazole

DDI Precautions of Fluconazole

inhibitor of CYP3A4, shouldn’t be taken with statins, warfarin, and some benzodiazepines

labeled category D for pregnancy due to increased risk of birth defects during first trimester

Itraconazole is indicated for

Aspergillosis

Blastomycosis

Histoplasmosis

Coccidioidomycosis

Onychomycosis

Sporotrichosis (cuteneous)

Compare the bioavailability and food requirements for Itraconazole Capsules vs. Solution.

• Solution: More bioavailable (preferred); take without food

• Capsules: Variable absorption; must be taken with food.

Voriconazole is used for

invasive aspergillosis, esophageal candidiasis, disseminated Candida infections involving the skin, abdomen, bladder, and kidney

Adverse effects of Voriconazole

blurred vision, photophobia and altered perception of color or images, rash, and hallucinations

Why is Ketoconazole seldom used today, and what is its major limitation in systemic infections?

• Usage: Replaced by newer azoles with fewer side effects.

• Niche Uses: Histoplasmosis, Blastomycosis, or Coccidioidomycosis.

• Limitation: Meningitis (it cannot cross the blood-brain barrier).

What is the primary FDA-approved indication for Terbinafine?

Onychomycosis (toenail or fingernail infections) caused by dermatophytes

How does the MOA of Terbinafine differ from the Azole class?

• It inhibits ergosterol synthesis by blocking squalene epoxidase (Azoles block 14α-demethylase).

What lab must be assessed before and during Terbinafine treatment?

Liver function (due to the risk of hepatic injury and increased aminotransferases).

What unique, persistent adverse effect is associated with Terbinafine?

Taste disturbance (which may persist for weeks after stopping the drug).

Butenafine

topical cream for tinea infections

Naftifine

prescription product for treatment of tinea pedis, tinea corporis, and tinea cruris

What is the MOA of the Echinocandins (Caspofungin, Micafungin, Anidulafungin)?

inhibit beta-(1,3)-glucan synthase, which stops the synthesis of beta-(1,3)-glucan (a key fungal cell wall component).

Name three Echinocandins and their required route of administration.

Caspofungin, Micafungin, and Anidulafungin. All are for IV use only.

Which Echinocandin is specifically approved for Aspergillosis?

Caspofungin. (While all three treat various Candida infections, Micafungin and Anidulafungin are not used for Aspergillosis).

How are Echinocandins generally tolerated, and what are the most common side effects?

Generally well tolerated. Occasional side effects include headache, rash, fever, hypotension, and mild liver toxicity.

What serious reaction has been reported during the infusion of Echinocandins?

Anaphylaxis

When must the dosage of an Echinocandin be reduced?

In patients with moderate hepatic (liver) dysfunction.

True or False: Echinocandins are known for having many dangerous drug-drug interactions (DDIs).

False. They have very few DDIs