Antifungals

Introduction to Antifungals

In this video, the speaker discusses antifungal drugs and their mechanisms of action.

Mechanisms of Action

• Griseofulvin inhibits microtubules by preventing cell division.

• Flucytosine inhibits DNA replication and transcription by being converted into a metabolite called 5-fluorouracil (5-FU).

• Echinocandins inhibit the synthesis of beta-glucan in fungal cell walls.

Clinical Applications

• Antifungal drugs are used to treat fungal infections such as candidiasis, aspergillosis, and cryptococcosis.

• The choice of antifungal drug depends on the type of fungus causing the infection and the patient's medical history.

Side Effects and Resistance

• Common side effects of antifungal drugs include nausea, vomiting, diarrhea, and liver damage.

• Fungi can develop resistance to antifungal drugs through mutations or acquisition of resistance genes.

Fungal Cell Wall and Resistance to Osmotic Forces

In this section, the speaker discusses the importance of beta 1-3 glucans in fungal cell walls and their role in providing resistance to osmotic forces.

Beta 1-3 Glucans

• Beta 1-3 glucans are important components of fungal cell walls that provide resistance to osmotic forces.

• Inhibiting beta 1-3 glucan synthase with drugs like echinocandins can decrease resistance to osmotic forces, leading to decreased cell wall activity and potential cell death by lysis processes.

Mechanisms of Antifungal Drugs (Part 2)

In this section, the speaker discusses additional mechanisms of antifungal drugs, including terbenaphine and its inhibition of ergosterol synthesis.

Terbenaphine

• Terbenaphine inhibits squalene epoxidase, reducing the production of ergosterol necessary for stabilizing the fungal cell membrane.

• Another drug called azoles stimulates CYP450 14 alpha d-methylase, which is responsible for converting lanosterol into ergosterol.

Mechanism of Action of Antifungal Drugs

In this section, the speaker explains the mechanism of action of antifungal drugs.

Azoles

• Azoles are a type of antifungal drug that inhibits the synthesis of ergosterol, an important component of fungal cell membranes.

• There are two types of azoles: triazoles and imidazoles.

• Triazoles are very potent and include drugs such as voriconazole, itraconazole, isavuconazole, posaconazole, and fluconazole.

• Imidazoles are less potent and include drugs such as miconazole, clotrimazole, and ketoconazole.

Polyenes

• Polyenes are another type of antifungal drug that form pores in the fungal cell membrane by binding to ergosterol.

• This causes electrolyte imbalances and subsequent cell death.

• The two polyene drugs discussed in this section are amphotericin B and nystatin.

Clinical Usages of Antifungal Drugs

In this section, the speaker discusses the clinical usages of antifungal drugs.

Azoles

• Azole drugs can be used to treat a variety of fungal infections including candidiasis (yeast infection), aspergillosis (lung infection), cryptococcal meningitis (brain infection), histoplasmosis (lung infection), blastomycosis (lung infection), coccidioidomycosis (lung infection).

• Fluconazole is commonly used for prophylaxis in immunocompromised patients.

Polyenes

• Amphotericin B is used to treat systemic fungal infections such as cryptococcal meningitis and invasive aspergillosis.

• Nystatin is used topically to treat skin and mucosal infections caused by Candida species.

Echinocandins

• Echinocandins are a newer class of antifungal drugs that inhibit the synthesis of beta-glucan, an important component of fungal cell walls.

• They are used to treat invasive candidiasis and aspergillosis.

• Examples include caspofungin, micafungin, and anidulafungin.

Antifungal Treatment for Candidiasis

In this section, the speaker discusses the different antifungal treatments for candidiasis depending on the location of the infection.

Oropharyngeal Candidiasis

• Nestatin is the preferred agent for oral thrush or candidiasis near the pharynx or tonsils.

• Clotrimazole can also be used in a lozenge form.

Esophageal Candidiasis

• Oral fluconazole or itraconazole are recommended for esophageal lesions.

Vulvovaginal Candidiasis

• Topical azoles such as miconazole or clotrimazole are first-line agents.

• Fluconazole can be used if topical treatment is ineffective.

• Flucytosine can be added if fluconazole is not effective.

Intertriginous Candida Infections

• Nystatin is the preferred topical agent for intertriginous infections in moist areas such as axillary and anal genital areas.

Systemic Candidiasis

• Immunocompromised patients with systemic candidiasis require more systemic treatment.

• Fluconazole and amphotericin B are commonly used treatments.

Fungal Infections Overview

This section provides an overview of fungal infections, including candidiasis, aspergillosis, cryptococcosis, endemic fungi and mucormycosis. It also discusses the preferred first-line agents for treating these infections.

Candidiasis

• Echinocandins are the preferred first-line agent for systemic or invasive candidiasis.

• Fluconazole and amphotericin B can be considered as add-ons to echinocandins.

• Fluconazole is generally used as a second-line agent while amphotericin B is reserved for severe refractory cases.

Aspergillosis

• Aspergillosis primarily involves the respiratory system and can cause a lot of damage to the lungs.

• Voriconazole is the preferred first-line agent for invasive aspergillosis.

• Isoviconazole and echinocandins are also effective against invasive aspergillosis.

• Amphotericin B is reserved for severe refractory cases.

Cryptococcosis

• Cryptococcus primarily involves the lungs but can spread to the meninges causing meningitis.

• The induction therapy for cryptococcus consists of amphotericin B and flucytosine for two weeks followed by maintenance therapy with fluconazole.

Endemic Fungi

• These fungal infections are dependent on geographical areas and include blastomycosis, histoplasmosis, and coccidiomycosis.

Mucormycosis

• Mucormycosis is a rare but severe fungal infection that can affect various parts of the body.

• Treatment involves surgical debridement and antifungal therapy with amphotericin B.

Dermatophyte Infections

• These are superficial fungal infections that affect the skin, hair, and nails.

• Treatment involves topical or oral antifungal agents depending on the severity of the infection.

Systemic Fungal Infections

This section covers the different types of systemic fungal infections, their symptoms, and treatment options.

Types of Systemic Fungal Infections

• Different types of systemic fungal infections can cause pneumonia, meningeal involvement, skin and bone lesions.

• Preferred agents for treating blasto, histo, and coccidio are itraconazole or fluconazole. Amphotericin B is used for severe refractory cases.

• Mucormycosis is a type of mold that can cause sinusitis and pneumonia in patients with diabetes. Treatment includes iso vuconazole as the first line agent or amphotericin B if there is a contraindication to azoles.

Treatment Options

• Antifungals such as iso vuconazole or amphotericin B are used to treat mucormycosis. Debridement may also be necessary.

• Topical agents such as ketoconazole and meconazole are preferred for treating tina versa color. Ketoconazole is the preferred agent.

• Dermatophyte infections require different treatments depending on where the infection is located.

Treating Systemic Fungal Infections

This section covers the treatment options for systemic fungal infections.

Preferred Agents

• Itraconazole is believed to be superior to fluconazole for treating blasto, histo, and coccidio.

• Amphotericin B is used for severe refractory cases of blasto, histo, and coccidio.

Alternative Agents

• Fluconazole is a decent alternative to itraconazole for treating blasto, histo, and coccidio.

• Amphotericin B can be used if there is a contraindication to azoles for treating mucormycosis.

Dermatophyte Infections

This section covers the treatment options for dermatophyte infections.

Treatment Options

• Topical agents such as ketoconazole and meconazole are preferred for treating tina versa color. Ketoconazole is the preferred agent.

• Dermatophyte infections require different treatments depending on where the infection is located.

Fungal Infections and Antifungals

This section discusses the different types of fungal infections and their treatments, as well as the adverse effects of antifungal medications.

Types of Fungal Infections and Treatments

• Tinea corporis occurs near the growing region, tinea pedis occurs near the feet region, and tinea ungium involves toenails.

• Topical azoles like miconazole and clotrimazole are preferred for treatment. Oral itraconazole is another option, followed by griseofulvin. Terbenaphine is best suited for oncomycosis.

Adverse Effects of Antifungal Medications

Amphotericin B

• Nephrotoxicity requires monitoring of renal function.

• Can cause inflammation and irritation of blood vessels during infusion, leading to phlebitis.

• Suppresses bone marrow, causing anemia from decreased red blood cell formation.

• Lowers potassium and magnesium levels, increasing risk of arrhythmias like torsades de points due to increased QT interval.

Terbenaphine

• Can cause liver damage.

Note that other antifungals can also cause liver damage similar to terbenaphine.

Antifungal Drug Toxicity

This section discusses the potential adverse effects of antifungal drugs and how to monitor for them.

Terbinafine and Echinocandins

• Terbinafine and echinocandins can cause hepatotoxicity, so liver function tests should be monitored while on these drugs.

• Echinocandins are also associated with histamine release during infusion, which can cause flushing.

• Echinocandins may activate mast cells in the skin, leading to vasodilation and flushing.

Azoles

• Azoles, particularly triazoles, are hepatotoxic and require monitoring of liver function tests.

• Azoles are CYP450 inhibitors, which can increase the concentration of other drugs in the bloodstream. This can lead to increased risk of bleeding if taking warfarin concurrently.

• Ketoconazole specifically can cause gynecomastia and increase the risk of arrhythmias due to low potassium levels.

Adrenal Insufficiency from Ketoconazole

This section discusses how ketoconazole can affect steroid synthesis pathways in humans, potentially leading to adrenal insufficiency.

• Ketoconazole inhibits steroid synthesis pathways in humans similarly to how it works in fungi.

• P.O. ketoconazole use can inhibit production of hormones such as cortisol and aldosterone, leading to adrenal insufficiency.

Antifungal Medications

In this section, the speaker discusses various antifungal medications and their adverse effects.

Visual Dysfunction and Azoles

• Voriconazole is the most particular agent that has been shown to cause visual dysfunction.

• Decrease the dose or remove the medication if a patient experiences visual dysfunction when taking voriconazole.

• Azoles are CYP450 inhibitors, but griseofulvin is a CYP450 inducer.

• Griseofulvin can reduce the concentration of other drugs circulating in the body, making them less effective.

Griciofulvin

• Griciofulvin is hepatotoxic and should be monitored with LFTs.

• It is teratogenic and carcinogenic, so it should not be given to pregnant patients.

Flucytosine

• Flucytosine is teratogenic and can suppress bone marrow production leading to pancytopenia.

• CBC monitoring is recommended for patients on flucytosine.

Case Studies

Mechanism of Action

• Terbenifene inhibits squalene oxidase reducing formation of linosterol in ergosterol thereby reducing stability of cell membrane.

Cytochrome P450 14 Alpha Dimethylase Enzyme Inhibitors

• The azoles inhibit cytochrome P450 14 alpha dimethylase enzyme including triazoles (voriconazole, itraconazole, isobuconnazole, posaconazole, fluconazole) and imidazoles.

Antifungal Drugs

In this section, the speaker discusses different antifungal drugs and their mechanisms of action.

Drugs that form pores

• Nestatin and amphotericin B are examples of drugs that form pores in the fungal cell membrane.

Drugs that inhibit beta 1,3 glucan synthase

• Beta 1,3 glucans are important for cell wall stability and resistance to osmotic forces. Inhibiting beta 1,3 glucan synthase reduces the formation of these structures and can cause cell death.

Griseofulvin

• Griseofulvin inhibits microtubules, preventing chromosomal separation during fungal division.

Flucytosine

• Flucytosine is converted into 5-fluorouracil by cytosine deaminase and binds with DNA to prevent replication and transcription.

Treatment options for candidiasis

• Oropharyngeal candidiasis: Nystatin or clotrimazole lozenges.

• Esophageal candidiasis: Oral fluconazole or itraconazole.

• Vulvovaginal candidiasis: Topical azoles (e.g., miconazole), PO fluconazole, or flucytosine if others fail.

• Intertriginous candidiasis: Topical nystatin.

• Systemic/invasive candidiasis: Echinocandins (first line), PO fluconazole, or amphotericin B.

Treatment options for aspergillosis

• Voriconazole is first line, followed by isavuconazole, echinocandins, and amphotericin B.

Treatment options for cryptococcal meningitis and pneumonia

• Induce with flucytosine and amphotericin B within the first two weeks, then maintain with fluconazole.

Endemic fungal infections

• Histoplasmosis in the Midwest US, blastomycosis in the Great Lakes region, and coccidioidomycosis in the Southwest US.

Treatment of Fungal Infections

This section covers the treatment options for various types of fungal infections.

Treatment for Mucor

• Isavuconazole is the preferred first-line treatment for mucor.

• Amphotericin B can be used if isavuconazole is contraindicated.

• Debridement of the infected area may also be necessary.

Treatment for Tinea Versicolor

• Topical ketoconazole or miconazole are the preferred treatments for tinea versicolor.

Treatment for Tinea Capitis, Tinea Corporis, Tinea Cruris, and Tinea Pedis

• Topical agents such as miconazole, chloramizal, and ketoconazole are used as first-line treatments.

• Oral itraconazole can be used if topical agents fail.

• Griseofulvin may also be considered in some cases.

Treatment for Onychomycosis (Tinea Unguium)

• Terbinafine is the preferred treatment option.

• Griseofulvin may also be effective.

Overall, these treatments should cover most cases of fungal infections. If you have any questions or concerns about your specific case, consult with a healthcare professional.