FUNGAL INFECTIONSFUNGAL INFECTIONS

Traditionally have been divided into two Traditionally have been divided into two distinct classes: systemic and superficial.distinct classes: systemic and superficial.

MECHANISM OF ACTION OF MECHANISM OF ACTION OF ANTIFUNGALSANTIFUNGALS

Drugs interacting with ergosterol (polyenes)Drugs interacting with ergosterol (polyenes)

Drugs inhibiting ergosterol synthesis (azoles,squalene Drugs inhibiting ergosterol synthesis (azoles,squalene oxidase inhibitors)oxidase inhibitors)

Inhibitors of fungal cell walls (echinocandins)Inhibitors of fungal cell walls (echinocandins)

Inhibitors of fungal mitosis (griseofulvin)Inhibitors of fungal mitosis (griseofulvin)

Inhibitors of fungal nucleic acid synthesis (5-Inhibitors of fungal nucleic acid synthesis (5-flucytosine)flucytosine)

DRUGS INTERACTING WITH DRUGS INTERACTING WITH ERGOSTEROLERGOSTEROL

Polyenes-AmphotericinB, nystatinPolyenes-AmphotericinB, nystatin

SELECTIVITYSELECTIVITY

Selective for fungi and not bacteria.Selective for fungi and not bacteria.

Some selective toxicity towards fungal Some selective toxicity towards fungal membranes vs mammalian.membranes vs mammalian.

RESISTANCERESISTANCE

Uncommon.Uncommon.

Probably results from changes in sterol Probably results from changes in sterol content.content.

INHIBITORS OF ERGOSTEROL INHIBITORS OF ERGOSTEROL SYNTHESISSYNTHESIS

Azoles (Demethylase inhibitors)Azoles (Demethylase inhibitors)

Terbinafine (Squalene oxidase inhibitors)Terbinafine (Squalene oxidase inhibitors)

MECHANISM OF ACTIONMECHANISM OF ACTION

Share similar mechanism of action.Share similar mechanism of action.

Either fungistatic or fungicidal.Either fungistatic or fungicidal.

Lanosterol

Ergosterol

Sterol Demethylase-Cytochrome P450 dependent enzymeCH3

Mechanism of Action of Imidazoles and Triazoles

Imidazole or Triazole

X

AZOLESAZOLES

Inhibition of the demethylase leads to Inhibition of the demethylase leads to accumulation of 14-accumulation of 14--methylsterols.-methylsterols.

Disrupts the close packing of Disrupts the close packing of phospholipids, impairing the functions of phospholipids, impairing the functions of certain membrane bound enzyme certain membrane bound enzyme systems.systems.

AZOLESAZOLES

Selective toxicity towards fungi .Selective toxicity towards fungi .

Imidazoles (ketoconazole) but not the Imidazoles (ketoconazole) but not the triazoles (itraconazole) interact with the triazoles (itraconazole) interact with the mammalian CYTOCHROME P450 mammalian CYTOCHROME P450 system.system.

RESISTANCERESISTANCE

Common with the newer triazoles.Common with the newer triazoles.

The primary mechanism is accumulation The primary mechanism is accumulation of mutations in erg11 the gene coding for of mutations in erg11 the gene coding for the demethylase.the demethylase.

Cross resistance to all azoles.Cross resistance to all azoles.

TERBINAFINE (Lamasil)TERBINAFINE (Lamasil)

Synthetic allylamine compound that Synthetic allylamine compound that inhibits ergosterol synthesis. inhibits ergosterol synthesis.

Inhibits squalene epoxidase.Inhibits squalene epoxidase.

Terbinafine

INHIBITORS OF THE FUNGAL INHIBITORS OF THE FUNGAL CELL WALLCELL WALL

CASPOFUNGIN (Candidas)CASPOFUNGIN (Candidas)

EchinocandinEchinocandin

Blocks the synthesis of a polysaccharide Blocks the synthesis of a polysaccharide component of the cell wall in many fungi component of the cell wall in many fungi ((ββ-(1,3)-d-glucan)-(1,3)-d-glucan)..

UDP-glucose β-1,3 glucanGlucan synthase

Caspofungin

FUNGAL MITOTIC FUNGAL MITOTIC INHIBITORSINHIBITORS

INHIBITORS OF FUNGAL INHIBITORS OF FUNGAL NUCLEIC ACID SYNTHESISNUCLEIC ACID SYNTHESIS

FLUCYTOSINE (Ancobon)FLUCYTOSINE (Ancobon)

Flucytosine is a fluorinated pyrimidine Flucytosine is a fluorinated pyrimidine related to 5-FU.related to 5-FU.

Originally synthesized in 1957 as an Originally synthesized in 1957 as an antileukemic agent.antileukemic agent.

N

N

O H

F

NH2

5-FU 5-FdUMP

PermeaseN

N

OH

NH2F

dUMP dTMP

Flucytosine

Fungal Cell

Cytosine Deaminase

NH3

MECHANISM OF ACTIONMECHANISM OF ACTION

5-FU 5-FUTP RNA5-FC

RESISTANCERESISTANCE

Extensive if used alone. Extensive if used alone.

POLYENE ANTIFUNGALSPOLYENE ANTIFUNGALS

ANTIFUNGAL ACTIVITYANTIFUNGAL ACTIVITY

Most species of fungi causing human infections Most species of fungi causing human infections are susceptible. are susceptible.

Fungistatic or fungicidal.Fungistatic or fungicidal. Several different kinds of fungi are sensitive to Several different kinds of fungi are sensitive to

amphotericin.amphotericin.– pathogenic yeastspathogenic yeasts– pathogenic yeast-like fungipathogenic yeast-like fungi– dimorphic fungidimorphic fungi– molds or filamentous fungimolds or filamentous fungi

DRUG FORMULATIONSDRUG FORMULATIONS

Amphotericin B deoxycholate (DOC) Amphotericin B deoxycholate (DOC) administered IV as a colloidal dispersion.administered IV as a colloidal dispersion.

Lipid drug formulations for IV infusion Lipid drug formulations for IV infusion are now available.are now available.

DEOXYCHOLATE-DEOXYCHOLATE-PHARMACOKINETICSPHARMACOKINETICS

Poorly absorbed from GI tract.Poorly absorbed from GI tract.

Prepared in dextrose, given IV.Prepared in dextrose, given IV.

Distributed to many tissues. It is Distributed to many tissues. It is sequestered in tissues and slowly sequestered in tissues and slowly released.released.

THERAPEUTIC USESTHERAPEUTIC USES

Systemic fungal diseases (DOC in the Systemic fungal diseases (DOC in the immunosuppressed).immunosuppressed).

Selected patients with profound Selected patients with profound neutropenia and fever unresponsive to neutropenia and fever unresponsive to broad-spectrum antibacterial agents.broad-spectrum antibacterial agents.

DRUG INTERACTIONSDRUG INTERACTIONS

Nephrotoxic Drugs (e.g. cyclosporine, Nephrotoxic Drugs (e.g. cyclosporine, aminoglycosides).aminoglycosides).

Azole antifungals.Azole antifungals.

LIPID FORMULATIONSLIPID FORMULATIONS

These preparations differ in the amount These preparations differ in the amount of amphotericin as well as physical form, of amphotericin as well as physical form, serum clearance and acute toxicity.serum clearance and acute toxicity.

LIPID FORMULATIONSLIPID FORMULATIONS

Amphotericin B lipid complex (ABLC).Amphotericin B lipid complex (ABLC).

Amphotericin B colloidal dispersion Amphotericin B colloidal dispersion (Amphotericin B cholesteryl sulfate (Amphotericin B cholesteryl sulfate complex, ABCD).complex, ABCD).

Liposomal amphotericin B (Ambisome).Liposomal amphotericin B (Ambisome).

LIPID FORMULATIONSLIPID FORMULATIONS

Indicated for systemic infections in Indicated for systemic infections in patients unresponsive to the deoxycholate patients unresponsive to the deoxycholate or who are intolerant of it.or who are intolerant of it.

Less nephrotoxicity (and less infusion Less nephrotoxicity (and less infusion related events) than the deoxycholate.related events) than the deoxycholate.

20-50X as expensive.20-50X as expensive.

5-FC-ANTIFUNGAL ACTIVITY5-FC-ANTIFUNGAL ACTIVITY

Narrow spectrum of activity (some Narrow spectrum of activity (some Candida Candida speciesspecies and and Cryptococcus Cryptococcus neoformansneoformans).).

Most fungi causing systemic infections Most fungi causing systemic infections are resistant.are resistant.

PHARMACOKINETICSPHARMACOKINETICS

Rapidly and well absorbed after oral Rapidly and well absorbed after oral administration. administration.

Widely distributed throughout the body Widely distributed throughout the body including the CNS.including the CNS.

Mainly excreted in the urine.Mainly excreted in the urine.

THERAPEUTIC USESTHERAPEUTIC USES

Usually used in combination with Usually used in combination with Amphotericin B for cryptococcal and Amphotericin B for cryptococcal and candidal infections.candidal infections.

PRECAUTIONSPRECAUTIONS

PregnancyPregnancy

DRUG INTERACTIONSDRUG INTERACTIONS

Immunosuppressive drugsImmunosuppressive drugs

Nephrotoxic drugsNephrotoxic drugs

AZOLESAZOLES

Synthetic compounds.Synthetic compounds.

The imidazoles, miconazole and ketoconazole The imidazoles, miconazole and ketoconazole were introduced around 1978.were introduced around 1978.

During the 1990s use of ketoconazole During the 1990s use of ketoconazole diminished because of the release of the diminished because of the release of the triazoles-fluconazole and itraconazole (2002-triazoles-fluconazole and itraconazole (2002-voriconazole).voriconazole).

TRIAZOLESTRIAZOLES

Enhanced therapeutic activity and less Enhanced therapeutic activity and less toxicity compared to imidazoles.toxicity compared to imidazoles.

ANTIFUNGAL ACTIVITYANTIFUNGAL ACTIVITY

Broad spectrum antifungal agents.Broad spectrum antifungal agents.

KETOCONAZOLE-KETOCONAZOLE-THERAPEUTIC USESTHERAPEUTIC USES

Effective against several systemic fungal Effective against several systemic fungal diseases when given orally (several diseases when given orally (several limitations to its use).limitations to its use).

Dermatophyte infections.Dermatophyte infections.

ITRACONAZOLE (Sporanox)ITRACONAZOLE (Sporanox)

GI absorption is somewhat erratic and depends GI absorption is somewhat erratic and depends on acidic environment. on acidic environment.

Available as capsules and a new oral solution Available as capsules and a new oral solution (about 30% better absorption).(about 30% better absorption).

IV preparation now also available.IV preparation now also available.

Metabolized primarily by CYP3A4.Metabolized primarily by CYP3A4.

THERAPEUTIC USESTHERAPEUTIC USES

Serious fungal diseases in patients Serious fungal diseases in patients intolerant or refractory to amphotericin .intolerant or refractory to amphotericin .

Oropharyngeal and esophogeal Oropharyngeal and esophogeal candidiasis.candidiasis.

Dermatophytoses and onychomycosis.Dermatophytoses and onychomycosis.

DRUG INTERACTIONSDRUG INTERACTIONS

Many can occur due to inhibition of CYP Many can occur due to inhibition of CYP 3A4 (e.g. PIs,NNRTIs,anticancer drugs).3A4 (e.g. PIs,NNRTIs,anticancer drugs).

FLUCONAZOLE (Diflucan)FLUCONAZOLE (Diflucan)

More favorable pharmacokinetic and More favorable pharmacokinetic and toxicity profiles than itraconazole.toxicity profiles than itraconazole.

Relatively narrow spectrum of activity.Relatively narrow spectrum of activity.

VORICONAZOLE (Vfend)VORICONAZOLE (Vfend)

Excellent oral bioavailability.Excellent oral bioavailability.

Good activity vs. many fungiGood activity vs. many fungi

CASPOFUNGIN-CASPOFUNGIN-PHARMACOKINETICSPHARMACOKINETICS

Given IVGiven IV

THERAPEUTIC USESTHERAPEUTIC USES

Invasive aspergillosis in patients Invasive aspergillosis in patients resistant to or who can’t tolerate resistant to or who can’t tolerate other antifungalsother antifungals..

Patients with oropharyngeal or Patients with oropharyngeal or esophageal candidiasis.esophageal candidiasis.

GRISEOFULVIN

OCH3

OCH3

CH3O

O

C

OO CH3

CL

ANTIFUNGAL ACTIVITYANTIFUNGAL ACTIVITY

Inhibits the dermatophytes (ringworm Inhibits the dermatophytes (ringworm fungi).fungi).

Fungistatic or fungicidal.Fungistatic or fungicidal.

PHARMACOKINETICSPHARMACOKINETICS

Variable oral absorption (Griseofulvin Variable oral absorption (Griseofulvin only works orally).only works orally).

Micronized preparations have the best Micronized preparations have the best absorption.absorption.

Deposited in keratin precursor cells, new Deposited in keratin precursor cells, new keratin becomes resistant.keratin becomes resistant.

THERAPEUTIC USESTHERAPEUTIC USES

Treatment of choice for ringworm Treatment of choice for ringworm infections (hair, nails, skin, hands etc).infections (hair, nails, skin, hands etc).

Length of therapy depends on location of Length of therapy depends on location of the infection.the infection.

CONTRAINDICATIONS AND CONTRAINDICATIONS AND DRUG INTERACTIONSDRUG INTERACTIONS

Pregnancy. Pregnancy.

Induces CYP3A4.Induces CYP3A4.

TERBINAFINETERBINAFINE

Used in the treatment of dermatophyte Used in the treatment of dermatophyte infections, especially onychomycosis.infections, especially onychomycosis.

ADVERSE EFFECTS OF THE ADVERSE EFFECTS OF THE ANTIFUNGAL AGENTSANTIFUNGAL AGENTS

GI UPSETGI UPSET

GriseofulvinGriseofulvin TerbinafineTerbinafine FlucytosineFlucytosine AzolesAzoles

NEPHROTOXICITYNEPHROTOXICITY

AMPHOTERICIN

Hypomagnesemia and hypokalemia

EFFECTS ON THE BLOOD AND EFFECTS ON THE BLOOD AND BONE MARROWBONE MARROW

HYPOCHROMIC,NORMOCYTIC ANEMIA

HEMATOLOGIC EFFECTSHEMATOLOGIC EFFECTS

Bone marrow depression is produced by Bone marrow depression is produced by 5-FC5-FC

HEPATOTOXICITYHEPATOTOXICITY

Ketoconazole, itraconazole, voriconazoleKetoconazole, itraconazole, voriconazole

TerbinafineTerbinafine

CNS EFFECTSCNS EFFECTS

Griseofulvin-headaches, dizzinessGriseofulvin-headaches, dizziness

ENDOCRINE EFFECTSENDOCRINE EFFECTS

Imidazoles but not triazoles produce Imidazoles but not triazoles produce impotence, oligospermia etcimpotence, oligospermia etc

INJECTION OR INFUSION INJECTION OR INFUSION RELATED EFFECTSRELATED EFFECTS

Amphotericin B produces fever and chillsAmphotericin B produces fever and chills

Caspofungin (phlebitis)Caspofungin (phlebitis)

Amphotericin BAmphotericin B Serious systemic fungal diseasesSerious systemic fungal diseases

FlucytosineFlucytosine Crytpcoccosis in AIDS patients, Crytpcoccosis in AIDS patients, candidiasiscandidiasis

ItraconazoleItraconazole Serious systemic fungal diseasesSerious systemic fungal diseases

GriseofulvinGriseofulvin Dermatophyte InfectionsDermatophyte Infections

TerbinafineTerbinafine Dermatophyte InfectionsDermatophyte Infections

CaspofunginCaspofungin Invasive Aspergillosis and Invasive Aspergillosis and candidiasiscandidiasis

THERAPEUTIC USES OF THE ANTIFUNGAL AGENTS

Amphotericin BAmphotericin B Bind to ergosterol, Bind to ergosterol, form pores in form pores in fungal membranefungal membrane

Fever and chills, Fever and chills, Nephrotoxicity, Nephrotoxicity, Anemia and Anemia and NeurotoxicityNeurotoxicity

FlucytosineFlucytosine Inhibits fungal Inhibits fungal DNA and RNA DNA and RNA synthesissynthesis

GI, bone marrow GI, bone marrow depressiondepression

Imidazoles and Imidazoles and

TriazolesTriazoles

Inhibit 14 Inhibit 14 demethylase (P450 demethylase (P450 enzyme)enzyme)

Ketoconazole-GI, Ketoconazole-GI, endocrineendocrine

Others-GI, liverOthers-GI, liver

Summary of the Mechanisms and toxicity of the Antifungals

GriseofulvinGriseofulvin Inhibits fungal Inhibits fungal mitosismitosis

GI, headacheGI, headache

TerbinafineTerbinafine Inhibits Inhibits ergosterol ergosterol synthesissynthesis

GI, GI, hepatotoxicityhepatotoxicity

CaspofunginCaspofungin Inhibits fungal Inhibits fungal cell wall synthesiscell wall synthesis

PhlebitisPhlebitis

Summary of the Mechanisms and Toxicities of the Antifungals