PMOC: Antifungal Agents

Mycology

Study of Fungi

Types of Fungal Infections | Systemic

• Deep-seated mycoses

• Inhaled into the lungs

Types of Fungal Infections | Opportunistic

• Immunocompromised patients

• Occurs when the use of antibacterial antibiotics, Immunosuppressive agents, Cytotoxins , Irradiation , Steroids

Types of Fungal Infections | Subcutaneous

Develops beneath the skin’s surface

Types of Fungal Infections | Cutaneous/ Superficial

Dermatophytoses (Most Common)

Dermatophytoses | Tinea manuum

Hand

Dermatophytoses | Tinea pedis

Foot (Athlete’s Foot)

Dermatophytoses | Tinea corporis

Trunk, Arms, Legs

Dermatophytoses | Tinea capitis

Scalp

Dermatophytoses | Tinea sycosis/barbae

Beard

Dermatophytoses | Tinea cruris

Groin (Jock’s Itch)

Dermatophytoses | Tinea unguium

Nails (Onychomycosis)

Common Targets of Antifungals

• Cell Wall (Chitin and B-Glucan)

• Cell Membrane (Ergosterol)

• DNA Synthesis

• Mitosis

  • Intermediary Metabolism

Topical Agents for Dermatophytoses | Fatty Acids

Sebum → Acidic, fatty substance on the skin that acts as a natural antifungal agent

Topical Agents for Dermatophytoses | Fatty Acids

Propionic Acid

• Present in perspiration (0.01%)

• Salt forms are used because they are nonvolatile and odorless

Topical Agents for Dermatophytoses | Fatty Acids

Zinc Propionate

Fungicide in adhesive tapes

Topical Agents for Dermatophytoses | Fatty Acids

Undecyclenic Acid

• a.k.a. 10-undecenoic acid

• Obtained from the destructive distillation of castor oil

• Traditionally for athlete’s foot

• Cure rates are low

• A severe irritant

Topical Agents for Dermatophytoses | Fatty Acids

Salicylic Acid and Resorcinol

Antiseptic and Keratolytic

Topical Agents for Dermatophytoses | Fatty Acids

Benzoic Acid

Whitfield’s Ointment, USP

• 6% TO 12% Benzoic Acid

• 3% to 6% Salicylic Acid

Topical Agents for Dermatophytoses | Phenols and Their Derivatives

Interfere with cell membrane integrity and function

Topical Agents for Dermatophytoses | Phenols and Their Derivatives

Examples

• Haloprogin

• Clioquinol

• Ciclopirox Olamine

Nucleoside Antifungals | Flucytosine

• MOA: Inhibits DNA Synthesis

• Active: 5-Fluorouracil

• Narrow-spectrum, Oral antifungal agent

• Synergistic with Amphotericin B

• Use: Serious systemic infections caused by Candida and Cryoptococcus spp.

Antifungal Antibiotics | Polyenes

• Structure:

  • Conjugated double bonds

  • Hydroxyl group

  • Mycosamine (glycosidically linked deoxyaminohexose)

• MOA: Penetration of the fungal cell membrane (false membrane components)

• Also effective for Leishmania spp.

• Low Concentration: Fungistatic

• High Concentrations: Fungicidal

Antifungal Antibiotics | Polyenes

Amphotericin B

• Source: Streptomyces nodosus

• Structure: 38-membered heptaene ring (5 double bonds)

• Use: Treatment of severe, potentially life-threatening fungal infections (parenteral)

• A/E: Nephrotoxicity

  • Shake-and-Bake Syndrome

• DOC: Systemic mycoses

Antifungal Antibiotics | Polyenes

Nystatin

• Source: Streptomyces noursei

• Structure: 38-membered hexaene ring (6 double bonds)

• Aglycone: Nystatinolide

• Use: Local and gastrointestinal monilial infections

  • Cream, ointment, or Powder → Cutaneous and mucocutaneous candidiasis

  • Vaginal tablets → Vaginal candidiasis

• DOC: Local Candidiasis

Antifungal Antibiotics | Polyenes

Natamycin

• Source: Streptomyces natalensis

• Structure: 26-membered pentaene ring (5 double bonds)

• 5% Ophthalmic Suspension: Fungal conjunctivitis, blepharitis, and ketatitis

• DOC: Fungal Conjunctivitis

Antifungal Antibiotics | Griseofulvin

• Source: Penicillium griseofulvin

• Isolated originally as a “curling factor” in plants

• MOA: Mitotic spindle poison

• Use: Refractory ringworm infections

  • Refractory → ‘di na tinatablahan ng first DOC

• Has a poor oral bioavailability

  • Micronized form

  • Taking the drug with fatty meal

Allylamines and Related Compounds

• MOA: Inhibition of squalene epoxidase

• Fungicidal: Dermatophytes

• Fungistatic: Candida spp.

Allylamines and Related Compounds | Naftifine Hydrochloride

• The prototype allylamine

• 1% Cream and Gel: Ringworm, Athlete’s Foot, and Jock Itch

Allylamines and Related Compounds | Terbinafine Hydrochloride

• More potent than Naftifine

• 1% Cream: Tinea pedis, Tinea corporis, and Tinea cruris

• Oral: Onychomycosis

Allylamines and Related Compounds | Tolnaftate

• Not an allylamine

• Active against superficial tinea infections

Azole Antifungal Agents

• The largest class of antifungals

• MOA: Inhibition of lanosterol 14a-demthylase

• Active against dermatophytoses and life-threatening, deep systemic fungal infections

Azole Antifungal Agents | Imidazole

Clotrimazole

For tinea infections and vulvovaginal candidiasis

• Brand Name: Canesten

Azole Antifungal Agents | Imidazole

Tioconazole

For vulvovaginal candidiasis

• Brand Name: Trosyd

Azole Antifungal Agents | Imidazole

Miconazole

For tinea infections, cutaneous candidiasis, oral candidiasis, vaginal candidiasis

• Brand Name: Daktarin

Azole Antifungal Agents | Imidazole

Ketoconazole

• 2% Cream and Shampoo: Cutaneous candidiasis and tinea infections

• Acidic pH: Optimal dissolution and absorption

• D/I (Applicable Only for Systemic)

  • Antacids, H2 Blocker, Anticholinergic, and Amphotericin B

  • Enzyme Inhibitor

• A/E: Anti-androgenic effects

Azole Antifungal Agents | Triazoles

Terconazole

• For vulvovaginal moniliasis

• Available in creams and suppositories

Azole Antifungal Agents | Triazoles

Itraconazole

• Orally active

• Primarily used for systemic fungal infections

• Acidic pH: Optimal dissolution and absorption

• D/I:

  • Antacids and H2 Blockers

  • Enzyme Inhibitor

• Increased bioavailability with foods

Azole Antifungal Agents | Triazoles

Fluconazole

• Suitable for both oral and intravenous administration

• Excellent oral bioavailability and long elimination half-life

• Can penetrate the CSF (Cerebrospinal Fluid) → Can be use for the brain infections

• Agent of choice for cryptococcal meningitis

• Prophylaxis against cryptococcosis in AIDS patients

Azole Antifungal Agents | Triazoles

Voriconazole

Has potent activity against a broad variety of fungi

Echinocandins

• MOA: Inhibition of (1,3)-B-glucan synthase

• Active against Candida and Apergillus spp

Echinocandins Examples

• Caspofungin

• Micafungin

• Anidulafungin

Aureobasidins

• Source: Aureobasidium pullulan

• MOA: Inhibition of Inositol phosphorylceramide synthase

  • Enzyme for Cell wall