Antifungals

Define mycoses

Fungi that are parasitic microorganisms that live off living or dead organic matter

What are superficial mycoses?

Fungal infections of the stratum corneum or hair shaft with no living tissue invaded and no illicit inflammatory response from the host

What are cutaneous mycoses?

Fungal infections of the living layer of the skin/hair/nails that creates an inflammatory response to the microbe and its metabolites

What are subcutaneous mycoses?

Chronic, localized infections in the dermis and subcutaneous tissue after trauma introduces the fungus

What is an example of a unicellular fungi?

Yeast like candida

What is an example of a multicellular fungi?

Dermatophytes such as mold

What is dimorphic fungi?

A fungal infection that can change from mold (multicellular) to yeast (unicellular)

What is a dermatophytoses?

Fungal infection of the skin, hair, and nails

What are the three primary targets for antifungal therapies?

Cell wall synthesis, steroid synthesis, nucleic acid/protein synthesis

Echinocandin MOA

Non competitive inhibitor of beta-(1,3)-glucan synthase

What do echinocandins treat?

Candida, Aspergillus

What are some important PK considerations for echinocandins?

Only IV infusion, can’t penetrate CNS or eyes

What are some adverse reactions for echinocandins?

Embryotoxic, teratogenic, hepatotoxicity

What drug-drug interactions occur with echinocandins?

Cyclosporine, rifampin, anti-HIV drugs

What are the uses of caspofungin?

Candidiasis, salvage therapy for aspergillosis

What are adverse effects of caspofungin?

Increased liver enzymes, phlebitis

What are uses of micafungin?

Treatment and prophylaxis for candida infection

Micafungin adverse effects

Hyperbilirubinemia, phlebitis, rash, abdominal discomfort, hypersensitivity reactions

Anidulafungin uses

Resistant candida and aspergillus

Anidulafungin adverse effects

DVT, liver toxicity, hypokalemia

Polyene MOA

Higher affinity for ergosterol compared to other membrane sterols, which forms a channel and increases membrane permeability, leading to cell death

Polyene toxicity

Nephrotoxicity

Polyene MOR

Mutations in ergosterol biosynthesis pathway that lead to synthesis of sterols other than ergosterol

Polyene PK considerations

Poor oral absorption, can’t be given orally for systemic infection

Amphotericin B uses

Histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcal meningitis, disseminated candidiasis

Amphotericin B adverse effects

Anemia, ion loss, inflammatory cytokines leading to flu like symptoms during infusions, nephrotoxicity

What is the benefit of using lipid formulations of Amphotericin B?

Less likely to induce nephrotoxicity

Amphotericin B PK considerations

Only IV infusion, loooong half like (1-2 days in plasma, 15 days for elimination)

Nystatin formulations

IV, topicalN

Allylamine MOA

Selective inhibitor of fungal squalene epoxidase

Terbinafine uses

Yeast, onychomycosis, dermatophytoses

Terbinafine PK considerations

Lipophilic compound that concentrates in sebum and has a long elimination half life

What is the mainstay of therapy for systemic life threatening fungal infections?

Azole antifungals

Azole MOA

Inhibit fungal enzyme 14-alpha demethylase

What drugs can decrease oral absorption of azoels?

Drugs that increase gastric pH, metal ion containing drugs due to chelation

Azole MOR

Mutations in 14-alpha demethylase, overexpression of membrane efflux pumps

Ketoconazole adverse effects

GIT disturbances, toxic hepatits

Itraconazole use

Chronic pulmonary aspergillosis, onychomycosis, mucosal candida, blastomycosis, histoplasmosis

Where is itraconazole metabolized and excreted?

Metabolized in the liver, excreted by the kidneys

Itraconazole adverse effects

Rash, diarrhea, nausea, worsening of CHF, hepatotoxicity, nephrotoxicity

What is fluconazole used to treat?*

Vaginal candidiasis, fungal meningitis, systemic cryptococcal infections

Describe the bioavailability of fluconazole*

Very high and independent of pH

What is an adverse effect of voriconazole?

Peripheral edema

Voriconazole use

First line for invasive aspergillosis, mold infections

Does voriconazole cross the BBB?

Yes

Voriconazole contraindications

CYP3A4 substrates due to QT prolongation

Flucytosine MOA

Interfere with nucleic acid and protein synthesis

Why is flucytosine used as adjunct therapy with Amphotericin B?

Helps increase CNS penetration for amphotericin B

Flucytosine adverse effect

Myelosuppression due to conversion to 5-FU

Griseofulvin MOA

Selectively inhibits fungal cell mitosis by inhibiting mitotic spindle formation

Griseofulvin adverse effect

Liver toxicity