Antifungal Agents

SAMIR EL ANSARY

Wide-spectrum antibiotics

surgery

Immunosuppressant agents &

chemotherapyAIDS

Increase risk

Fungal infections = mycoses

• Opportunistic or primary

• Systemic or local

• Slow onset

• Long duration of therapy

• Difficult to diagnose & eradicate

• Symptoms vary from cosmetic to life threatening

Antifungal drugs

• Work by exploiting differences between mammalian and fungal cells to kill the fungal organism without dangerous effects on the host.

• Both fungi and humans are eukaryots.

• Difficult to find or design drugs that target fungi without affecting human cells. (side effects)

Fungal cell membranes have a

unique sterol, ergosterol, which

replaces cholesterol found in

mammalian cell membranes

Antifungal drugs

Systemic & topical

Some are fungistatic,

while others are fungicidal

• Amphotericin B.

• Azoles

• Flucytosine

• Echinocandins

systemic /systemic

• Griseofulvin

• TerbinafineSystemic

/mucocutaneous

• Nystatine

• Topical Azoles

• Topical Allylamines

Topical /mucocutaneous

Systemic antifungal drugs for systemic infections

AMPHOTERICIN B

• Broad-spectrum polyene macrolideantibiotic is the most potent antifungal agent for systemic mycosis, in clinical use since 1960

• Fungicidal drug at higher concentrations & static at lower levels.

AMPHOTERICIN B

Produced by Streptomyses nodosum

• CSF conc.= 2-3 % of blood conc.

• Highest concentrations in liver, spleen, bone marrow with less in kidneys and lungs.

Mechanism of Action

MECHANISM OF ACTION

• High affinity for fungal ergosterol, forms

“micropore” in fungal cell membrane

through which ions, amino acids, & other

water soluble substances move out.

MECHANISM OF ACTION

• Markedly increases cell permeability.

• Cholestrol, present in host cell

membranes, closely resembles fungal

ergosterol & thus explains the high

toxicity of AMB in humans

Clinical use

• Treatment of nearly all life threatening mycoticinfections.

• For systemic disease: slow IV

o Local:o Keratitis& corneal ulcers: drops, conjunctival irrigation,

o Candiduria: bladder irrigation

o Fungal arthritis: local injection

Side effects

• Infusion related

Fever & chills,

Dyspnea,

Nausea &vomiting,

Hypotension,

Convulsions

• Cumulative toxicity

Nephrotoxicity

K & Mg wasting

Anemia (↓erythropoietin)

• To reduce the severity of the infusion-related reactions, pretreatment with an antipyretic (acetaminophen), antihistamines, and antiemetics may be given.

Liposomal Amphotericin B

• New lipid formulations

• Amphotericin B is incorporated into lipid

formulations to reduce toxicity &

enhance efficacy.

• This allows higher dose to be used

without increasing the toxicity.

• Much more expensive than ordinary

AMB.

KEY POINTS

• AMB is not absorbed enterally; hence can be given orally for intestinal candidiasis.

• Drug concentration achieved in infected skin is very low, & hence ineffective against superficial fungal infections.

• Penetration in brain & CSF is poor (but extremely effective in fungal meningitis when combined with 5-FC)

FLUCYTOSINE (5-FC)

• Pyrimidine antimetabolite, narrow-spectrum fungistatic

• Water soluble• Oral only,

• Poor protein binding

• CSF conc. ≈ 75% serum conc.

• 5-FC (outside)

Cytosine permease enzyme

• 5-FC (inside)

• 5-FU (inside)

Inhibits thymidylate

synthase

• Inhibits DNA & RNA

synthesis

Flucytosine is taken up by fungal cells via the enzyme cytosine permease.

It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively.

Human cells are unable to convert the parent

drug to its active metabolites.

Clinical use at present is confined to

combination therapy, either with:

Amphotericin B for cryptococcal

meningitis , or

Itraconazole for chromoblastomycosis

Adverse Effects

• Bone marrow toxicity with anemia, leukopenia, thrombocytopenia,

(Mammalian bone marrow cell have the capacity to convert 5-FC to 5-FU)

• GI disturbances

• Mild & reversible liver dysfunction

KEY POINTS

• Since this is a narrow-spectrum fungistatic, it

is mainly used as an adjuvant drug & not

used as a sole therapy.

• CSF penetration is excellent, hence it is

combined with AMB in fungal meningitis.

Azoles

Azoles

Imidazoles

Ketoconazole

Miconazole

Clotrimazole

Triazoles

Itraconazole

Fluconazole

Voriconazole

Posaconazole

Mechanism of Action

Inhibition of fungal cytochrome P450 enzymes

Reduction of ergosterol synthesis

Clinical Use

BROAD SPECTRUM OF ACTIVITY –

Candida,

Cryptococcus,

Blastomyces,

Histoplasma,

Coccidiodes ,

Dermatophytes

Adverse EffectsRelatively nontoxic.

Minor GI upset

Abnormalities in liver enzymes

(inhibit cytochrome P450 enzymes)

Very rarely, clinical hepatitis

KETOCONAZOLE

•(older, more toxic, replaced by itraconazole, but less

costly)

•The first oral azole introduced into clinical use.

•It is less selective for fungal P450 than are the newer

azoles.

•Absorption variable (better in acidic medium)

•Penetration in brain & CSF is poor

•In high doses inhibits adrenocortical steroids and

testosterone synthesis, resulting in gynecomastia in

some males.

ITRACONAZOLE

•Broad-spectrum antifungal with fungistatic

action

•MOA: Inhibits fungal ergosterol synthesis like

other azoles

• Drug absorption is increased by food and by

low gastric ph.

•Penetration of drug in brain & CSF is poor.

• Much more selective than ketoconazole

FLUCONAZOLE

Broad-spectrum Fungicidal drug;

•It is also somewhat effective against some

Gram-positive & anaerobic bacteria

•Of the orally administered fluconazole 94% is

absorbed;

•Penetration in brain & CSF is good, hence

used for cryptococcal meningitis

Posaconazole

The newest triazole

It is the broadest spectrum member of

the azole family.

It is the only azole with significant

activity against the agents of zygomycosis

and mucormycosis.

ECHINOCANDINS

Caspofungin

Micafungin

Anidulafungin

ECHINOCANDINS

The newest class of antifungal .

Active against candida and

aspergillus, but not c neoformans or

the agents of zygomycosis and

mucormycosis.

Mechanism of Action

Inhibit the synthesis

of B glucan in the fungal cell wall

Disruption of the fungal cell wall and cell death.

Adverse Effects

Extremely well tolerated, Minor GIside effects

Flushing

Elevated liver enzymes (caspofungin + cyclosporine).

Histamine release during IV infusion.

Systemic antifungal drugs for Mucocutaneous infections

GRISEOFULVIN

Very insoluble, fungistatic

Derived from a species of penicillium.

Better absorption when given with fatty foods.

• It is deposited in newly forming skin where it binds to keratin, protecting the skin from new infection.

• Interferes with spindle formation in dividing cells and therefore with mitosis

Adverse effects

• Allergic reaction

• photosensitivity

• Hepatitis

• Teratogenesis

Terbinafine

• Synthetic allylamine.

• Orally Active.

• Dermatophytoses, especially onychomycosis .

• Keratophilic , fungicidal.

It interferes with ergosterol biosynthesis by:

Inhibiting the fungal enzyme squalene epoxidase

Accumulation of the sterol squalene,

• Like the azole drugs, it interferes with ergosterol biosynthesis, but rather than interacting with the P450 system, terbinafineinhibits the fungal enzyme squaleneepoxidase.

• This leads to the accumulation of the sterol squalene, which is toxic to the organism.

Adverse effects

Rare, mild, self-limiting

GI upset

Rash

Pruritis

Headache.

Topical antifungal

therapy

NYSTATIN

• Only used topically: creams, ointments, suppositories, and other

• Acts as amphotericin B

• It is not absorbed , unpleasant taste.

• Local candidal infections, oropharyngealthrush, vaginal candidiasis.

• adverse effects are rare.

TOPICAL AZOLES

• Clotrimazole , Miconazole;

• Vulvovaginal candidiasis, oral thrush , dermatophytic infections, including tineacorporis, tinea pedis, and tinea cruris.

• Absorption is negligible, and adverse effects are rare.

• Topical and shampoo forms of ketoconazolefor seborrheic dermatitis and pityriasisversicolor.

TOPICAL ALLYLAMINES

• Terbinafine and Naftifine

• Both are effective for treatment of tineacruris and tinea corporis.

• MOA: Inhibits the squalene epoxidase, leading to accumulation of intrcellular squalene & deficient ergosterol synthesis with subseqent fungal cell death.

• Terbinafine concentrates in skin and especially at nail beds, making it quite useful for fungal infection of nails

GOOD LUCK

SAMIR EL ANSARY

ICU PROFESSOR

AIN SHAMS

CAIRO

elansarysamir@yahoo.com