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

MECHANISM OF ACTION OF ANTIFUNGALS Drugs interacting with ergosterol (polyenes) Drugs inhibiting ergosterol synthesis (azoles,squalene oxidase inhibitors) Inhibitors of fungal cell walls (echinocandins) Inhibitors of fungal mitosis (griseofulvin) Inhibitors of fungal nucleic acid synthesis (5- flucytosine)

DRUGS INTERACTING WITH ERGOSTEROL Polyenes-AmphotericinB, nystatin

SELECTIVITY Selective for fungi and not bacteria. Some selective toxicity towards fungal membranes vs mammalian.

RESISTANCE Uncommon. Probably results from changes in sterol content.

INHIBITORS OF ERGOSTEROL SYNTHESIS Azoles (Demethylase inhibitors) Terbinafine (Squalene oxidase inhibitors)

MECHANISM OF ACTION Share similar mechanism of action. Either fungistatic or fungicidal.

X Lanosterol Ergosterol Sterol Demethylase- Cytochrome P450 Imidazole or Triazole X Lanosterol Sterol Demethylase- Cytochrome P450 dependent enzyme CH3 Ergosterol Mechanism of Action of Imidazoles and Triazoles

AZOLES Inhibition of the demethylase leads to accumulation of 14--methylsterols. Disrupts the close packing of phospholipids, impairing the functions of certain membrane bound enzyme systems.

AZOLES Selective toxicity towards fungi . Imidazoles (ketoconazole) but not the triazoles (itraconazole) interact with the mammalian CYTOCHROME P450 system.

RESISTANCE Common with the newer triazoles. The primary mechanism is accumulation of mutations in erg11 the gene coding for the demethylase. Cross resistance to all azoles.

TERBINAFINE (Lamasil) Synthetic allylamine compound that inhibits ergosterol synthesis. Inhibits squalene epoxidase.

Terbinafine

INHIBITORS OF THE FUNGAL CELL WALL

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

Glucan synthase UDP-glucose β-1,3 glucan Caspofungin

FUNGAL MITOTIC INHIBITORS

INHIBITORS OF FUNGAL NUCLEIC ACID SYNTHESIS

FLUCYTOSINE (Ancobon) Flucytosine is a fluorinated pyrimidine related to 5-FU. Originally synthesized in 1957 as an antileukemic agent.

5-FdUMP Flucytosine NH2 F N Permease O N H Fungal Cell NH2 NH3 F N Deaminase H dUMP dTMP

MECHANISM OF ACTION RNA 5-FC 5-FU 5-FUTP

RESISTANCE Extensive if used alone.

POLYENE ANTIFUNGALS

ANTIFUNGAL ACTIVITY Most species of fungi causing human infections are susceptible. Fungistatic or fungicidal. Several different kinds of fungi are sensitive to amphotericin. pathogenic yeasts pathogenic yeast-like fungi dimorphic fungi molds or filamentous fungi

DRUG FORMULATIONS Amphotericin B deoxycholate (DOC) administered IV as a colloidal dispersion. Lipid drug formulations for IV infusion are now available.

DEOXYCHOLATE-PHARMACOKINETICS Poorly absorbed from GI tract. Prepared in dextrose, given IV. Distributed to many tissues. It is sequestered in tissues and slowly released.

THERAPEUTIC USES Systemic fungal diseases (DOC in the immunosuppressed). Selected patients with profound neutropenia and fever unresponsive to broad-spectrum antibacterial agents.

DRUG INTERACTIONS Nephrotoxic Drugs (e.g. cyclosporine, aminoglycosides). Azole antifungals.

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

LIPID FORMULATIONS Amphotericin B lipid complex (ABLC). Amphotericin B colloidal dispersion (Amphotericin B cholesteryl sulfate complex, ABCD). Liposomal amphotericin B (Ambisome).

LIPID FORMULATIONS Indicated for systemic infections in patients unresponsive to the deoxycholate or who are intolerant of it. Less nephrotoxicity (and less infusion related events) than the deoxycholate. 20-50X as expensive.

Amphotericin Lipid Formulations Product Size (mean diameter) Configuration AmBisome 45-80 nm Small spherical unilamellar liposomes Amphocil (Amp B colloidal dispersion), ABCD 115 nm, 4 nm thickness Disc shaped complexes, with Amp B attached. Colloidal dispersion of a stable complex of amp with cholesteryl sulfate. Abelcet (Amp B lipid complex), ABLC 1.6-11.1 m Ribbons of lipid with Amp B attached.

5-FC-ANTIFUNGAL ACTIVITY Narrow spectrum of activity (some Candida species and Cryptococcus neoformans). Most fungi causing systemic infections are resistant.

PHARMACOKINETICS Rapidly and well absorbed after oral administration. Widely distributed throughout the body including the CNS. Mainly excreted in the urine. More than 90% excreted in the urine

THERAPEUTIC USES Usually used in combination with Amphotericin B for cryptococcal and candidal infections. Use as a single agent is usually precluded

PRECAUTIONS Pregnancy

DRUG INTERACTIONS Immunosuppressive drugs Nephrotoxic drugs

AZOLES Synthetic compounds. The imidazoles, miconazole and ketoconazole were introduced around 1978. During the 1990s use of ketoconazole diminished because of the release of the triazoles-fluconazole and itraconazole (2002-voriconazole).

TRIAZOLES Enhanced therapeutic activity and less toxicity compared to imidazoles.

ANTIFUNGAL ACTIVITY Broad spectrum antifungal agents.

KETOCONAZOLE-THERAPEUTIC USES Effective against several systemic fungal diseases when given orally (several limitations to its use). Dermatophyte infections.

ITRACONAZOLE (Sporanox) GI absorption is somewhat erratic and depends on acidic environment. Available as capsules and a new oral solution (about 30% better absorption). IV preparation now also available. Metabolized primarily by CYP3A4.

THERAPEUTIC USES Serious fungal diseases in patients intolerant or refractory to amphotericin . Oropharyngeal and esophogeal candidiasis. Dermatophytoses and onychomycosis.

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

FLUCONAZOLE (Diflucan) More favorable pharmacokinetic and toxicity profiles than itraconazole. Relatively narrow spectrum of activity.

VORICONAZOLE (Vfend) Excellent oral bioavailability. Good activity vs. many fungi

CASPOFUNGIN-PHARMACOKINETICS Given IV

THERAPEUTIC USES Invasive aspergillosis in patients resistant to or who can’t tolerate other antifungals. Patients with oropharyngeal or esophageal candidiasis.

OCH3 O CH3 C O O CH3O OCH3 CL GRISEOFULVIN

ANTIFUNGAL ACTIVITY Inhibits the dermatophytes (ringworm fungi). Fungistatic or fungicidal.

PHARMACOKINETICS Variable oral absorption (Griseofulvin only works orally). Micronized preparations have the best absorption. Deposited in keratin precursor cells, new keratin becomes resistant.

THERAPEUTIC USES Treatment of choice for ringworm infections (hair, nails, skin, hands etc). Length of therapy depends on location of the infection. Only effective orally. Use when topical therapy failed.

CONTRAINDICATIONS AND DRUG INTERACTIONS Pregnancy. Induces CYP3A4.

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

ADVERSE EFFECTS OF THE ANTIFUNGAL AGENTS

GI UPSET Griseofulvin Terbinafine Flucytosine Azoles

NEPHROTOXICITY

Hypomagnesemia and hypokalemia AMPHOTERICIN

EFFECTS ON THE BLOOD AND BONE MARROW

HYPOCHROMIC,NORMOCYTIC ANEMIA

HEMATOLOGIC EFFECTS Bone marrow depression is produced by 5-FC

HEPATOTOXICITY Ketoconazole, itraconazole, voriconazole Terbinafine

CNS EFFECTS Griseofulvin-headaches, dizziness

ENDOCRINE EFFECTS Imidazoles but not triazoles produce impotence, oligospermia etc

INJECTION OR INFUSION RELATED EFFECTS Amphotericin B produces fever and chills Caspofungin (phlebitis)

THERAPEUTIC USES OF THE ANTIFUNGAL AGENTS Amphotericin B Serious systemic fungal diseases Flucytosine Crytpcoccosis in AIDS patients, candidiasis Itraconazole Griseofulvin Dermatophyte Infections Terbinafine Caspofungin Invasive Aspergillosis and candidiasis

Summary of the Mechanisms and toxicity of the Antifungals Amphotericin B Bind to ergosterol, form pores in fungal membrane Fever and chills, Nephrotoxicity, Anemia and Neurotoxicity Flucytosine Inhibits fungal DNA and RNA synthesis GI, bone marrow depression Imidazoles and Triazoles Inhibit 14 demethylase (P450 enzyme) Ketoconazole-GI, endocrine Others-GI, liver

Summary of the Mechanisms and Toxicities of the Antifungals Griseofulvin Inhibits fungal mitosis GI, headache Terbinafine Inhibits ergosterol synthesis GI, hepatotoxicity Caspofungin Inhibits fungal cell wall synthesis Phlebitis