antifungal lecture

8/2/2019 Antifungal Lecture

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ANTIFUNGAL AGENTS

Dr. Vandana Tayal


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Factors Contributing to the IncreasedPrevalence 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

Candidaspp. C. albicans,* non-albicans Candidaspp.* Cryptococcus C. neoformans Other Yeasts Trichosporon species, Blastoschizomyces species

Opportunistic moulds (hyalohyphomycetes) Aspergillusspp. *A. fumigatus,A. terreus, A. flavus, A. niger, and others Fusariumspp. F. solani, F. oxysporum, and others Zygomycetes Rhizopusspp., Mucor, Absidia

Dematiaceous moulds (phaeohyphomycetes) Pseudallescheria boydii Bipolaris Alternariaand other rare pathogens

Endemic dimorphic moulds Histoplasma capsulatum Coccidioides immitis Blastomyces dermatitidis Penicillium marneffei

* Most common organisms


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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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Opportunistic MycosesCandida albicansmouth (thrush), female genitalia

(vulvovaginitis), skin and nails.Disseminated: thrombophlebitis, endocarditis, and

involvement in other organs such asthe lungs and kidneys. fourth leadingcause of bloodstream infections.

Cryptococcus neoformansmeningitis in AIDS patients.Aspergillus lung, brain, sinuses, or other

organs in some immunosuppressedpatients.

Mucormycosis sinuses, eyes, blood, brain.

Diseases due to fungal pathogens


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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 sitesof action of antifungal agents

Echinocandins

Inhibition of cell wall synthesis

, Allylamines


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Critical need for newer antifungal agents

Alarming rise in invasive fungal infections.

Resistance against the existing antifungal

agents (Azoles, Nucleoside analogues).

Serious adverse effects.


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Ergosterol synthesis pathway and pointsof inhibition by antifungal agents

Squalene

AllylaminesSqualene epoxide

LanosterolAzoles

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 antibioticsAmphotericin B. Interaction with ergosterol, Candida spp., Aspergillus spp,Lipid formulation of formation of aqueous channels, other filamentous fungi,amphotericin B. increased membrane permeability Coccidioides immitis,Nystatin. to univalent and divalent cations, Histoplasma capsulatum,

cell death. Blastomyces dermatidis.

+ a polyene

ergosterol

ergosterol with

pore


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Amphotericin B

Fungicidal, discovered in 1956 Streptomyces nodosus

Mechanism of Action

The selective effect is achieved because the sterolin highest concentration is ergosterol and polyeneshave a high affinity for ergosterol.

The membranes become leaky.

Ergosterol has two conjugated double bonds that islacking in mammalian membrane steroids (mainlycholesterol).


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Pharmacokinetics

not absorbed orally. It is given as a colloidaldispersion by slow iv infusion.

i.v, topical and intrathecal (never be givenintramuscular)

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. Painat site of injection and thrombophlebitis

Nephrotoxicity - chronic renal tox in up to 80%

of patients - most common limiting toxicity of thedrug.

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 liposomalpreparations

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 monilialovergrowth

Available in oral tablets, powder for suspension, vaginaltablets

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, chromoblastomycesand few Candida spp.

Given orally Penetrates into CNS


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5-flucytosine(outside)

permease5-flucytosine

(inside)Cytosine

deaminase

5-fluorouracil

5-dFUMPRNA

Phosphoribosyltransferase

5dFUMP

(inhibitsthymidylatesynthase)

d U M P d T M P


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Uses

used with amphotericin B (cryptococcalmeningitis) 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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AZOLEANTIFUNGALS


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Structure of Azoles

Imidazoles Triazoles

Clotrimazole, Econazole,Miconazole (topical)

Ketoconazole (systemic)

Itraconazole, Fluconazole,voriconazole

more potent, less toxic and provideeffective oral therapy for many

systemic fungal infections.


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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 albicanssp)


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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, vaginalcandidiasis

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 withcisapride, astemizole, terfenadine


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Adverse Effects

- Headache, rash, loss of appetite

- Endocrine: menstrual abnormalities,

gynaecomastia, azoospermia, decreased libidoand potency

- Hypertension and fluid retention

- mild hepatotoxicity (10%), fatal Hepatitis (rare1/10,000 )

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 Cryptococcalmeningitis

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

Indications

DOC for paracoccidiodomycosis andchromomycosis

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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Adverse Effects

nausea,

Gastric intolerance

Dizziness, pruritis, headache

rash

elevated transaminases; a few reports of severehepatotoxicity.

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 ofadministration

Oral, i.v

Bioavailability (%) 90

Half-life (hr) 6

Primary route ofelimination

Hepatic(Cyt P-2C19, 2C9, 3A4)

Adverse effectsTransient visual disturbances hepatic transaminases

Skin rash 1-5%

Drug interactions Many


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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 pointsof inhibition by antifungal agents

Squalene

AllylaminesSqualene epoxide

LanosterolAzoles

14-Demethyllanosterol

Zymosterol

Fecosterol

Ergosterol Polyenes


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Pharmacokinetics

Indications

Treatment of onychomycosis of the toenail orfingernail due to dermatophytes.

Candidiasis


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Adverse Effects

Gastric upset, rash, taste disturbance

monitor CBC and hepatic function in patientsreceiving long term therapy

now has a boxed warning on rarehepatotoxicity; 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 Penicilliumgriseofulvum.

Oral Fungistatic

Mechanism of action

Binds to microtubules/ disrupts mitosismultinucleated and stunted fungal hyphae

Dermatophytes actively concentrate it

incorporates into keratin precursor cells andultimately into keratin which cannot then supportfungal 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 3 weeks

Palm, soles 4-6 weeks

Finger nails 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 warfarinmetabolism 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 andosmotic instability.

Caspofungin

Micafungin Anidulafungin

Spectrum of activity Rapidly fungicidal against most Candidaspp. &

Aspergillusspp. Active against Histoplasma, Blastomycesand cyst

form of Pneumocystis carinii

Not active against Cryptococcus neoformans


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Pharmacokinetic Parameters

Caspofungin

Bioavailability

(%)

Poor (


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Caspofungin

Indications

Invasive aspergillosis.

Candidemia and the following Candidainfections:

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

Limitations of traditional antifungal


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Limitations of traditional antifungalagents

CLASS LIMITATIONS

POLYENESAmphotericin B Exhibits significant toxicities.

Frequent treatment failures.Chemically unstable.No oral formulation.

Lipid based Amphotericin B High cost (20-50 times).

Nystatin Only topical formulation.

AZOLESFluconazole Emergence of Resistance.Itraconazole Fungistatic.Ketoconazole Significant drug interaction potential.

Toxicity on long term use.

NUCLEOSIDE ANALOGUES5-Flucytosine Emergence of Resistance.

Narrow spectrum of activity.Toxicity.

CELL MITOSIS INHIBITORGriseofulvin Narrow spectrum of activity.

Fungistatic.


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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)

Tinea infections


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Tinea infections

FIGURE 1. Kerion, a

severely inflammatory,boggy, indurated,tumor-like mass thatmay occur in tineacapitis


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Tinea barbae


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Tinea Corporis


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Tinea cruris


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Tinea pedis involving the toewebs.


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antifungal lecture

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