LECTURE 5 dr. Nico

• Micosis


  Fungal infection
• Systemic fungal infections


  • Aspergillosis
  • Coccidioidomycosis
  • Cryptococcosis
  • Histoplasmosis
  • Paracoccidiomycosis
  • Candidiasis
• Superficial fungal infections

  • Dermatophytosis (Trichophyton, Microsporum, Epidermophyton)
  • Tinea capitis, tinea cruris, tinea unguium (onychomycosis)
  • Non-Dermatophytosis (Pityriasis Versicolor, Piedra)
• Fungal and bacteria have different cell structures, especially the cell membrane which contains ergosterol in fungi and cholesterol in mammals

  
• Fungi are resistant to antibiotics and bacteria are resistant to antifungals
• There is a control mechanism between fungal and bacterial growth
• Mechanism of action of antifungal drugs

  • Target ergosterol to destroy cell membrane integrity
  • Inhibit ergosterol synthesis
  • Block production of β-(1,3)-glucan protein to damage cell wall
  • Inhibit DNA/RNA synthesis
  • Inhibit fungal cell mitosis
• Systemic antifungal drugs


  • Amphotericin B
  • Azole derivatives
  • Pyrimidines analog (Flucytosine)
  • Echinocandine (Kaspofungin)
  • Terbinafine

  
• Topical antifungal drugs


  • Griseofulvine
  • Azole derivatives
  • Tolnaftate
  • Nystatin

  
• Characteristics of systemic fungal infections

  • Increasing incidence
  • Slow onset
  • Difficult to diagnose and eradicate
  • Long duration of therapy
• Amphotericin B

  Polyene antifungal that binds to sterols in the fungal cell membrane, causing leakage of cell contents and cell death
• Spectrum of Amphotericin B

  • Histoplasma capsulatum
  • Cryptococcus neoformans
  • Coccidioides immitis
  • Candida
  • Aspergilus spp
  • Trichophyton
• Pharmacokinetics of Amphotericin B

  • Very poor oral bioavailability
  • Widely distributed including placenta, CSF, and vitreous humour
  • Metabolism unclear
  • Slowly excreted mainly by the kidneys
• Indications for Amphotericin B

  • Coccidiomycosis
  • Paracoccidioidomycosis
  • Aspergillosis
  • Chromoblastomycosis
  • Candidosis
• Amphotericin B preparations


  • Conventional amphotericin B deoxycholate (Fungizone)
  • Lipid formulations (ABLC, ABCD, Ambisome)
• Advantages of lipid amphotericin B formulations

  • Lower nephrotoxicity than conventional amphotericin B
  • Fewer fever and chills reactions than conventional amphotericin B
• Flucytosine


  Synthetic antifungal that inhibits fungal protein synthesis and DNA synthesis
• Antifungal spectrum of Flucytosine

  • Cryptoccocosis
  • Candidosis
  • Chloromomycosis
  • Aspergillosis

  
• Pharmacokinetics of Flucytosine


  • Completely and rapidly absorbed
  • Widely distributed including CSF
  • Mainly renally excreted, requiring dose adjustment in renal impairment
• Side effects of Flucytosine

  • Hematologic (neutropenia, thrombocytopenia, pancytopenia, bone marrow depression)
  • Liver (elevated SGPT/OT)
  • GI (nausea, vomiting, diarrhea, enterocolitis)
• Azole antifungals

  Inhibit the fungal enzyme 14α-demethylase, blocking ergosterol synthesis in the fungal cell membrane
• Examples of azole antifungals

  • Imidazoles (Ketoconazole, Miconazole, Clotrimazole)
  • Triazoles (Itraconazol, Fluconazol, Voriconazol)

  
• Ketoconazole

  Broad spectrum synthetic imidazole antifungal for systemic and topical use
• Pharmacokinetics of Ketoconazole

  • Variable absorption, impaired by food and increased stomach pH
  • Tissue limited distribution, does not penetrate the blood-brain barrier
  • Extensively metabolized in the liver, can inhibit metabolism of other drugs
• Indications for Ketoconazole

  • Histoplasmosis of the lungs, bones, and joints
• Side effects of Ketoconazole

  • Gastrointestinal disturbances (nausea, vomiting)
  • Liver function impairment
  • Endocrine effects (gynecomastia, decreased libido, impotence, menstrual problems)
• Ketoconazole is contraindicated with drugs that can cause ventricular arrhythmia (terfenadin, astemizole, cisapride)
• Itraconazole

  Triazole antifungal with faster and more complete absorption than ketoconazole, and a wider spectrum of activity
• Fluconazole

  Triazole antifungal available in IV and oral formulations, with wide distribution including the central nervous system

  
• Voriconazole

  Newer triazole antifungal effective against systemic aspergillosis and candidiasis resistant to other azoles

  
• Drugs that interact with Voriconazole

  • Rifampicin, Carbamazepine, Quinidine (cannot be taken concomitantly)
  • Rifabutin, sulfonylureas, benzodiazepines, statins, phenytoin (increase blood levels and toxicity)

  
• Caspofungin

  Newest class of antifungal drugs, the echinocandins, that inhibit fungal cell wall synthesis

  
• Drugs that interact with Caspofungin

  • Cyclosporine, tacrolimus (decreased serum concentrations)
  • Carbamazepine, dexamethasone, efavirenz, nelfinavir, phenytoin, rifampicin (reduced caspofungin serum concentration)

  
• Terbinafine

  Synthetic allylamine antifungal that inhibits ergosterol biosynthesis in the fungal cell wall
• Indications for Terbinafine

  • Dermatophytosis, especially onychomycosis
  • Tinea versicolor
  • Cutaneous candidiasis

  
• Adverse effects of Terbinafine

  • Gastrointestinal disturbances and headache
  • Rarely hepatotoxicity, severe neutropenia, Stevens-Johnson syndrome, toxic epidermal necrolysis

  
• Griseofulvin

  Antifungal isolated from Penicillium that inhibits fungal mitosis and nucleic acid synthesis
• Pharmacology of Griseofulvin

  • Well absorbed orally, especially with fatty meals
  • Metabolized in the liver
  • Excreted mainly in the urine
  • Has high affinity for keratinized skin areas
• Side effects of Griseofulvin

  • Headache
  • Gastrointestinal symptoms
  • Arthralgia
  • Peripheral neuritis
  • Urticaria
• Griseofulvin induces metabolism of warfarin and oral contraceptives, while barbiturates inhibit its metabolism