ANTIFUNGAL AGENTS

Dr. Vandana Tayal

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Factors Contributing to the Increased Prevalence of Fungal Infections

More aggressive treatments for cancer Increase in number and types of bone marrow and solid-organ transplant procedures Increasing numbers of AIDS patients and longer surviving AIDS patients Greater numbers of other immunocompromised patients More aggressive intensive care medicine in adults New and more widely used prosthetic devices

Widespread use of broad-spectrum antibiotics

Increasing intravenous drug abuse Catheter-borne infection
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Clinically important fungal pathogens

Opportunistic yeasts

Candida spp. Cryptococcus Other Yeasts Aspergillus spp. Fusarium spp. Zygomycetes

C. albicans,* non-albicans Candida spp.* C. neoformans Trichosporon species, Blastoschizomyces species *A. fumigatus, A. terreus, A. flavus, A. niger, and others F. solani, F. oxysporum, and others Rhizopus spp., Mucor, Absidia

Opportunistic moulds (hyalohyphomycetes)

Dematiaceous moulds (phaeohyphomycetes)

Pseudallescheria boydii Bipolaris Alternaria and other rare pathogens

Endemic dimorphic moulds

Histoplasma capsulatum Coccidioides immitis Blastomyces dermatitidis Penicillium marneffei

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* Most common organisms

Diseases due to fungal pathogens

Superficial Mycoses

Dermatophytes (Tinea)

skin, hair and nails

Systemic Mycoses

Coccidiodes immitis Coccidiomycosis. Histoplasma capsulatum intracellular mycosis of the RES. Blasomyces dermatitidis lungs and may disseminate to skin and other sites.
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Diseases due to fungal pathogens

Opportunistic Mycoses
Candida

albicans mouth (thrush), female genitalia (vulvovaginitis), skin and nails. Disseminated: thrombophlebitis, endocarditis, and involvement in other organs such as the lungs and kidneys. fourth leading cause of bloodstream infections. Cryptococcus neoformans meningitis in AIDS patients. Aspergillus lung, brain, sinuses, or other organs in some immunosuppressed patients. Mucormycosis sinuses, eyes, blood, brain.
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Antifungal Drugs

Polyene antibiotics: Amphotericin B, nystatin,

natamycin Antimetabolites: 5-Fluorocytosine

Azoles:
Imidazoles: Ketoconazole (systemic) Clotrimazole, miconazole (topical) Triazoles: Itraconazole, Fluconazole, voriconazole Allylamines: Terbinafine

Griseofulvin Echinocandins: Caspofungin Other Topical antifungal agents: Tolnaftate,

Undecylenic acid, ciclopirox olamine, benzoic acid
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Generalized fungal cell depicting the sites of action of antifungal agents

, Allylamines

Echinocandins
Inhibition of cell wall synthesis

Critical need for newer antifungal agents

Alarming rise in invasive fungal infections.

Resistance against the existing antifungal

agents (Azoles, Nucleoside analogues). Serious adverse effects.

Ergosterol synthesis pathway and points of inhibition by antifungal agents

Squalene Allylamines Squalene epoxide Lanosterol Azoles 14-Demethyllanosterol

Zymosterol
Fecosterol Ergosterol Polyenes
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Polyene antifungals

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Class & Compound Mechanism of Action

Spectrum of Activity

Polyene antibiotics
Amphotericin B. Interaction with ergosterol, Lipid formulation of formation of aqueous channels, amphotericin B. increased membrane permeability Nystatin. to univalent and divalent cations,
cell death. Candida spp., Aspergillus spp, other filamentous fungi,

Coccidioides immitis,
Histoplasma capsulatum, Blastomyces dermatidis.

ergosterol

ergosterol with pore

+ a polyene
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Amphotericin B
Fungicidal, discovered in 1956 Streptomyces nodosus Mechanism of Action The selective effect is achieved because the sterol in highest concentration is ergosterol and polyenes have a high affinity for ergosterol. The membranes become leaky. Ergosterol has two conjugated double bonds that is lacking in mammalian membrane steroids (mainly cholesterol).

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Pharmacokinetics

not absorbed orally. It is given as a colloidal dispersion by slow iv infusion. i.v, topical and intrathecal (never be given
intramuscular)

It is highly bound to cholesterol-lipoprotein, plasma t - 24 hrs and 1-2 weeks from tissues mostly metabolized in liver (60%) some is excreted by kidney does not readily pass the blood-brain barrier
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Clinical use of amphotericin

Gold standard for treatment of severe,

potentially life threatening fungal infections

Deep-seated fungal infections

Topically for oral, vaginal and cutaneous candidiasis and otomycosis Leishmaniasis
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Adverse Effects
Reactions on infusion - headache, fever, chills, anorexia, vomiting, muscle and joint pain. Pain at site of injection and thrombophlebitis Nephrotoxicity - chronic renal tox in up to 80% of patients - most common limiting toxicity of the drug. Hematologic - anemia due to BM depression Other less common reactions - neuropathy, hearing loss, allergic, etc. Drug interactions- Aminoglycosides, cyclosporine, vancomycin

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Advantages of liposomal preparations

1) Improved safety profile 2) Targeted Drug delivery (Liver and spleen main sites of systemic fungal infection)

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Nystatin

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Nystatin

Streptomyces noursei in 1951 Fungicidal, Broad spectrum of activity

Uses for local therapy only (not absorbed).

Candida -corneal, conjunctival, cutaneous, gut Candidiasis inhaled corticosteroid induced oral candidiasis Combined with tetracycline to prevent monilial overgrowth Available in oral tablets, powder for suspension, vaginal tablets No significant adverse effects with topical use

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Natamycin

cultures of Streptomyces natalensis. Monilial and trichomonas vaginitis

supplied as a 5% ophthalmic suspension for the treatment of fungal conjunctivitis, blepharitis and keratitis.

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Flucytosine

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Flucytosine - A fluorinated pyrimidine

synthesized in 1957 as an antitumor agent. Narrow spectrum fungistatic Cryptococcus neoformans, chromoblastomyces and few Candida spp.

Given orally Penetrates into CNS

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5-flucytosine permease 5-flucytosine (outside) (inside)

Cytosine deaminase

5dFUMP (inhibits thymidylate synthase)

5-fluorouracil
Phosphoribosyl transferase 5-dFUMP
dTMP
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RNA
dUMP

Uses
used with amphotericin B (cryptococcal meningitis) and with itraconazole (chromoblastomyosis).

Resistance is common.

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Untoward effects

nausea, vomiting, marked diarrhoea bone marrow suppression leucopenia, anemia and thrombocytopenia alopecia mild reversible liver dysfunction

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AZOLE ANTIFUNGALS

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Structure of Azoles

Imidazoles

Triazoles

Clotrimazole, Econazole, Miconazole (topical)

Ketoconazole (systemic)

Itraconazole, Fluconazole, voriconazole

more potent, less toxic and provide effective oral therapy for many systemic fungal infections.

Mechanism of action of Azoles

Lanosterol demethylase

Spectrum of activity - Dermatophytes, candida spp., C.immitis. Cryptococcus sp., Staph aureus, strep faecalis, Bact Fragilis and leishmania (NOT Aspergillus sp, non candida albicans sp) 29

Ketoconazole (KCZ)

Oral, broad spectrum Most of the use of this drug for significant fungal infections has been replaced by fluconazole and itraconazole.

Pharmacokinetics

Absorption variable (better in acidic medium) Half life -1-6 hrs Poor concentration in CSF Metabolized by Cyt. P450 enzymes
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Therapeutic Use:
Dermatophytosis Oral, esophageal, mucocutaneous, vaginal candidiasis coccidiomycosis, histoplasmosis if not severely ill or immunocompromized. Dose 200mg OD or BD

Drug interactions CYP3A4 inhibitor- raises warfarin, phenytoin, sulfonylurea levels Polymorphic ventricular tachycardia with cisapride, astemizole, terfenadine

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Adverse Effects
Headache, rash, loss of appetite - Endocrine: menstrual abnormalities, gynaecomastia, azoospermia, decreased libido and potency - Hypertension and fluid retention - mild hepatotoxicity (10%), fatal Hepatitis (rare 1/10,000 )
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Contraindicated pregnant & nursing mothers

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Topical imidazoles
Clotrimazole Tinea infections Athletes foot Otomycosis Candidiasis- vaginal, oral, cutaneous Corynebacterial skin infections

Well tolerated- local irritation Econazole- inferior in vaginitis

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Fluconazole (FCZ).
Oral and IV. Broader spectrum of activity than KCZ Longer acting, safer and more efficacious Indications Candidiasis (oral, esophageal, cutaneous, vaginal) in immunocompromised Coccidoidal meningitis and histoplasmosis Cryptococcus infections inc Cryptococcal meningitis Dermatophytosis Fungal keratitis

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Adverse effects

N,V, abdominal pain, rash and headache. A few reports of severe hepatotoxicity and 1% show an increase in transaminases. ventricular tachycardia with cisapride No inhibition of steroid synthesis Not as potent an inhibitor of P450 as KCZ

Contraindicated in pregnant and lactating mothers

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Itraconazole (ICZ).

Oral and IV, also a suspension.. broader activity than KCZ or FCZ DOC for paracoccidiodomycosis and chromomycosis Aspergillosis histoplasmosis, blastomycosis, sporotrichosis oral and esophageal candidiasis. dermatophytic infections of the toenail and fingernail (Tinea unguium) less effective than FCZ
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Indications

Adverse Effects

nausea, Gastric intolerance Dizziness, pruritis, headache rash elevated transaminases; a few reports of severe hepatotoxicity. Ventricular arrythmias with terfenadine

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Voriconazole

Structure Activity Relationship

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Voriconazole (VCZ).
Introduced in 2002 oral, i.v Spectrum of activity - superior than fluconazole (4-16 fold) & itraconazole

Indication

Invasive aspergillosis Refractory candida infections Oropharyngeal candidiasis Refractory Fusarium & Scedosporium infection
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Pharmacokinetic
Route of administration Bioavailability (%) Half-life (hr) Primary route of elimination

Oral, i.v 90 6 Hepatic (Cyt P-2C19, 2C9, 3A4)

Adverse effects Drug interactions

Transient visual disturbances hepatic transaminases Skin rash 1-5% Many

Allylamines

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Terbinafine

Oral and topical more limited spectrum of activity than the azoles fungicidal effective against dermatophytes and candida.

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Ergosterol synthesis pathway and points of inhibition by antifungal agents

Squalene Allylamines Squalene epoxide Lanosterol Azoles 14-Demethyllanosterol

Zymosterol
Fecosterol Ergosterol Polyenes
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Pharmacokinetics
Indications Treatment of onychomycosis of the toenail or fingernail due to dermatophytes.

Candidiasis

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Adverse Effects

Gastric upset, rash, taste disturbance monitor CBC and hepatic function in patients receiving long term therapy now has a boxed warning on rare hepatotoxicity; maybe 1/50,000 treated; Erythema, itching, dryness, rashes with topical use no significant drug interactions
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Griseofulvin

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Griseofulvin
Antibiotic produced from Penicillium griseofulvum. Oral Fungistatic Mechanism of action Binds to microtubules/ disrupts mitosis multinucleated and stunted fungal hyphae Dermatophytes actively concentrate it incorporates into keratin precursor cells and ultimately into keratin which cannot then support fungal growth

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Indications
Infections of skin, hair, nails; Prolonged therapy until new tissue replaces old diseased tissue. Dose- 125-250 mg QID

Body skin Palm, soles Finger nails

3 weeks 4-6 weeks 4-6 months

Toe nails

8-12 months
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Pharmacokinetics

used orally, not topically metabolized in liver f/b renal excretion t ~ 24 hours

CYP 3A4 inducer induces warfarin metabolism and reduces Oral Contraceptive efficacy

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Adverse effects

Nausea, headache GI disturbances photosensitivity hypersensitivity possibly teratogenic

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Echinocandins

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Echinocandins
Novel MOA - Inhibit 1,3--D glucan synthase

leading to depletion of cell wall glucan and osmotic instability.

Caspofungin Micafungin Anidulafungin

Spectrum of activity Rapidly fungicidal against most Candida spp. & Aspergillus spp. Active against Histoplasma, Blastomyces and cyst form of Pneumocystis carinii Not active against Cryptococcus neoformans
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Pharmacokinetic Parameters
Caspofungin Bioavailability (%) Protein Binding (%) Half-life (hr) Primary route of elimination

Poor (<1%)
97 9-11 Hepatic
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Caspofungin
Indications Invasive aspergillosis. Candidemia and the following Candida infections: Intra-abdominal abscesses, esophageal, peritonitis and pleural space infections. As effective and less toxic than amphotericin B in treatment of fungal infections.

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Adverse effects

Fever Nausea, vomiting Headache Phlebitis Histamine release reaction Rash infrequent

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Limitations of traditional antifungal agents

CLASS
POLYENES Amphotericin B

LIMITATIONS
Exhibits significant toxicities. Frequent treatment failures. Chemically unstable. No oral formulation.
High cost (20-50 times). Only topical formulation. Emergence of Resistance. Fungistatic. Significant drug interaction potential. Toxicity on long term use.

Lipid based Amphotericin B Nystatin AZOLES Fluconazole Itraconazole Ketoconazole

NUCLEOSIDE ANALOGUES 5-Flucytosine

Emergence of Resistance. Narrow spectrum of activity. Toxicity. Narrow spectrum of activity. Fungistatic.

CELL MITOSIS INHIBITOR Griseofulvin

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Topical Antifungals

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Topical Antifungals

For stratum corneum, mucosa, cornea by dermatophytes & Candida.

Many azoles; nystatin (Candida only); Tolnaftate; naftifine; terbinafine; Undecylenic Acid , Whitfields ointment (Benzoic+Salicylic Acid)
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Tinea infections

FIGURE 1. Kerion, a severely inflammatory, boggy, indurated, tumor-like mass that may occur in tinea 66 capitis

Tinea barbae

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Tinea Corporis

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Tinea cruris

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Tinea pedis involving the toe webs.

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