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Antifungal Drugs

Dr. Meera Ababneh, PharmD, PhD.

Treatment Obstacles
Structural characteristics of fungi Slow growth of fungi Infection frequently in poorly vascularized areas Often in immunocompromised patients

Antifungal Overview

Fungal Infections

Superficial/cutaneous
Dermatophytosis (tinea, ringworm) Candidiasis (yeast)

Systemic
Aspergillosis Blastomycosis Coccidiomycosis Histoplasmosis Paracoccydioidomycosis Sporotrichosis

Treatment of Dermatomycosis

Ringworm, athletes foot, jock itch treatment choice may depend on organism, location, level of inflammation, immune status, etc

Systemic Therapy

Oral medications may be necessary for:


extensive infections tinea capitis immuno-compromised folliculitis Onychomycosis Recurrent/chronic infections

Antifungal Drugs

ALLYLAMINE Terbinafine ECHINOCANDINS Caspofungin, Micafungin, anidulafungin AZOLES Ketoconazole, Itraconazole, Fluconazole, Voriconazole, Posaconazole PYRIMIDINE ANALOG Flucytosine POLYENE MACROLIDE

Amphotericin B

Terbinafine

Allylamine, keratophilic and fungicidal Pharmacokinetics:


Administration oral or topical Highly protein bound but widely distributed

high concentrations persist in the stratum corneum hair and nails

Disposition -primarily hepatic metabolism

Terbinafine

Contraindications (for oral admin);


Reduce dose w/ impaired hepatic clearance Preg cat B, but not during lactation

Interactions (for oral admin):


Inhibits CYP 2D6 numerous interactions Other Interactions

Increases clearance of cyclosporine Rifampin doubles terbinafines clearance rate Cimetidine decreases terbinafine clearance

Terbinafine

Adverse effects - headache/dizziness and GI effects most common


Hepatic injury - rare, but should monitor LFT Mild to serious skin reactions (rare) Transient lymphopenia and neutropenia (rare) Neuropsychiatric effects in pediatrics (rare)

Indications

superficial dermatophytic infections(topical) onychomycosis (oral)

Itraconazole

Moderate spectrum triazole Administration:

Oral - decreased pH favors absorption


Take capsule w/ food, solution w/o Avoid gastric acid inhibitors

Distribution -good except CNS Disposition - hepatic metabolism; long t1/2

Itraconazole

Contraindications/Interactions:
Patients w/ heart failure Liver disease Preg cat C Potent inhibitor of CYP 3A4 also inhibits P-gp numerous interactions Avoid drugs which increase QT interval

Itraconazole

Adverse effects: Generally well tolerated


GI distress Headache/dizziness Cardiovascular effects Increased hepatic transaminase activity in 510%; serious hepatic damage (rare) Peripheral neuropathy, visual disturbances, hearing loss, tinnitus (rare)

Fluconazole

Triazole, broad spectrum PK: Administration:

Oral - not pH or food dependent; bioavailability 90% Intravenous


Very good, including CNS; 50-90% of blood levels

Distribution

Disposition - Primarily renal; long t1/2 -30 h

Fluconazole

Indications:
Candidiasis (except krusei) Cryptococcosis: Fluconazole is the best azole agent for fungal meningitis because of high CSF levels

Fluconazole

Contraindications / Interactions:

Preg cat C (teratogenic in animals) Inhibits CYP450 enzymes decreased clearance of some drugs Rifampin increase fluconazole clearance Avoid drugs which prolong QT interval
GI effects & headache most common Increased hepatic transaminases QT prolongation and torsades de pointes (rare)

Adverse effects: generally well tolerated


Griseofulvin

Binds to microtubules, disrupts mitosis Long term therapy required


2 4 wks for skin infection 4-6 wks for hair/scalp 4 8 wks foot infections 3 4 months for fingernails 6+ months for toenails

Oral administration
Microparticles Enhance with fatty food

Griseofulvin

Adverse effects ---> secondary course of treatment


Headache: 15% incidence Hypersensitivity reactions Teratogenic and carcinogenic in animals

Itraconazole or Terbinafine preferred

Topical Treatment of Dermatophytosis

Antifungal creams containing:

Clotrimazole Miconazole Ketoconazole Terbinafine

Undecylenic acid and salts (Desenex: Zn salt) Tolnaftate(Tinactin) -T. pedis, T. cruris Selenium sulfide suspension (Selsun) -for seborrhaic dermatitis of scalp Benzoic and salicylic acids (Antinea) Potassium iodide -also used for cutaneous sporotrichosis

Superficial Candidiasis

Clotrimazole

Topical product Variety of preparations - cream, lotion, solution, oral lozenge (use appropriate prep!) MOA: typical of azoles PK: Poor penetration beyond the skin, 5-10% following intravaginal use

Clotrimazole

Contraindications:

Vaginal - Preg Cat B; not <12 yrs; may interfere w/contraceptive devices & spermicides Lozenges - Preg Cat C; not <3 yrs Topical - Preg Cat B; ok for pediatrics Avoid ocular contact
Cyp3A4 inhibitor --> increased levels of tacrolimus w/ oral lozenges

Interactions:

Adverse effects: burning, itching, stinging, polyuria (intravaginal exposure)

Nystatin

Polyene macrolide Pharmacokinetics -not absorbed from the GI tract Adverse effects -too toxic for systemic use Indications
Mouth (oral Candidiasis [thrush]) Skin and mucous membranes - Intravaginal (2 week course) Lower GI tract (oral administration)

Broad Spectrum Antifungal Drugs for Superficial Candiasis

Cutaneous
Topical azole treatment (clotrimazole [Gyne Lotrimin], miconazole [Monistat]) Systemic azole treatment for extensive infections, immunocompromised, folliculitis

Vaginal Candidiasis:
Topical Azoles (butoconazole, clotrimazole, miconazole, tioconazole, terconazole) Systemic treatment fluconazole, itraconazole

Broad Spectrum Antifungal Drugs for Superficial Candiasis

Oral Candidiasis:
clotrimazole lozenges [Mycelex troche] nystatin mild oral fluconazole for moderate to severe

Compounds for Deep/Systemic Disease

Voriconazole

Triazole w/ spectrum slightly better than itraconazole PK:


Administration -oral (96% bioavailability) and IV (beta cyclodextran vehicle) Distribution - generally good, --> CSF Disposition primarily metabolized dose dependent t 1/2

Indications

invasive aspergillosis

Voriconazole

adverse effects
reversible visual disturbances (30%) increased hepatic transaminase activity photosensitivity

Interactions -many interactions involving altered metabolism (Cyp3A4 inhibitor)

Posaconazole

Triazole, potent broad spectrum antifungal PK:


Administration - oral - greatly increased by high fat meal disposition -fecal elimination of unchanged drug and metabolites Prevention of Candida and Aspergillus in severely immunocompromised patients Non responsive aspergillosis and candidosis

Indications

Posaconazole

Contraindications / Interactions

Proton pump inhibitors, H2 receptor blockers and antacids (impair absorption) Inhibits CYP3A4 Drugs which prolong QT interval
GI effects, fatigue & headache most common increased hepatic transaminase activity QT prolongation and torsades de pointes (rare)

Adverse effects - generally well tolerated


Echinocandins

Inhibit synthesis of 1-3-beta-D-glucan in cell wall

No mammalian equivalents

Pharmacokinetics
Administration -IV Disposition -redistribution and slow hepatic metabolism, fecal elimination

Echinocandins

Contraindications / Interactions

Drug interactions - relatively few identified


metabolism increased by rifampin, dexamethasone, others levels increased by cyclosporin Caspofungins decrease tacrolimus levels

Decrease dose w/hepatic impairment, but not renal


Occasional effects due to histamine release (rash, itching, urticaria, flushing, hypotension) fever Nausea and vomiting

Adverse effects -generally well tolerated


Indications

Capsofungin

Aspergillosis-invasive Severe Candida infections(hospitalized patients)


esophageal candidiasis Candidemia and other complicated candida infections (intra abdominal abscess, peritonitis)

Anidulafungin

Micafungin

esophageal candidiasis prophylaxis against Candida infections in patients undergoing hematopoietic stem cell transplantation

Amphotericin B: Deoxycholate
(Fungizone) or liposomal (Amphotec, Albecet, AmBisome) preparations

Pharmacokinetics

Administration
IV - most common, deoxycholate suspension or liposomal preparations Local application

Distribution:
Wide except for CSF >90% protein bound Binds to cell membrane and tissue lipids

Reason for liposomal preps - alternate binding site to host tissue

Amphotericin B

Pharmacokinetics
Disposition:
Biphasic:

Initial (distribution) T 1/2 = 24 Hrs Elimination: T 1/2 = 15 Days Metabolism and urinary excretion

Excreted in urine several weeks after administration stops

Amphotericin B

Therapeutic uses:
Major treatment for most rapidly progressing or severe systemic mycoses despite toxicity Used as induction therapy Used for non-responsive infections Well characterized in pregnant patients

Amphotericin B

Adverse effects:

Infusion related - pretreat w/ NSAID, antihistamine or cortisone and meperidine


Fever and Chills Vomiting Headache Hypotension

Renal toxicity: deoxycholate form


80% of patients azotemic Preload w/ sodium to px/minimize

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