Antifungal DrugsAntifungal Drugs

• Polyene antibiotics: Amphotericin B, nystatin• Antimetabolites: 5-Fluorocytosine • Azoles:

Imidazoles: Ketoconazole, miconazole (topical)

Trizoles: Itraconazole, Fluconazole • Griseofulvin• Topical antifungal agents: imidazoles, polyenes

and others.

Drug of Choice for most systemic fungal infections. Even those susceptible to others but where the disease rapidly progressive, in Immunocompromized or involves CNS.

Model for Amphotericin B induced Model for Amphotericin B induced Pore in Cell MembranePore in Cell Membrane

In fungi: ergosterol in membranes: higher affinity thanmammalian cholesterol for AmB

Adverse EffectsAdverse Effects• Acute: Infusion-related

– Chills, fever, dyspnea, nausea, vomiting, bronchospasm, hypotension, convulsions

• Chronic– Nephrotoxicity

azotemia, impaired concentration, impaired urinary acidification, K & Mg wasting with hypokalemia and hypomagnesemia

– Normochromic, normocytic anemia (↓ erythropoietin)

QA

SNGFRRE

RA

PGC

ΔP

PT

Kf

Influence of Amphotericin B Infusion on Influence of Amphotericin B Infusion on Determinants of Single Nephron GFRDeterminants of Single Nephron GFR

Influence of Amphotericin BInfluence of Amphotericin Bon intracellular Caon intracellular Ca++++ levels levelsin glomerular mesangial cellsin glomerular mesangial cells

Theory

Pore

↑ Na entry

Depolarization

Voltage-dep. Ca channels

Contraction

Calcium channel blockers are protective against AmB- nephrotoxicityin-vivo in rats

Salt loading is protective against nephrotoxicity in vivo in animals

Salt loading orSupplementsProtectAgainst AmB-NephrotoxicityIn Humans

Alternative Formulations to Decrease ToxicityAlternative Formulations to Decrease Toxicity

Lipid formulations:20-50 times more expensive than AmB-deoxycholate

Renal Effects of AmB-DOC & Liposomal AmB

f-AmBL-AmBf-AmB

L-AmB

AmB-DOC

Differential Effects of L-AmB on Mammalian Differential Effects of L-AmB on Mammalian and Fungal Cells, in Contrast to free AmBand Fungal Cells, in Contrast to free AmB

RBCFungal Cell

5-Fluorocytosine5-FluorocytosineA fluorinated pyrimidineA fluorinated pyrimidine

• Converted to 5 fluorouracil by a deaminase then to 5-fdUMP, which inhibits thymidylate synthase and DNA synthesis

• Selective toxicity to fungal cells (no deaminase in mammalian cells)

• Resistance is common. Do not use alone, but in combination with AmB cryptococcal meningitis

• Bone marrow toxicity – pancytopenia -reversible

The AzolesThe AzolesImidazoles and TriazolesImidazoles and Triazoles

• Triazoles newer with fewer side effects• Impair synthesis of ergosterol; inhibit sterol 14 α-

demethylase (of cyt. P450). Acumulation of precursors which inhibit growth.

• Mammalian cells can incorporate already formed cholesterol; fungi have to synthesize

• Adverse effects due to inhibition of mammalian steroid synthesis

• Drug interactions due to inbibition of cyt. P450 enzymes.

KetoconazoleKetoconazole(older, more toxic, replaced by itraconazole, but less costly)(older, more toxic, replaced by itraconazole, but less costly)

• Absorption variable (better in acidic medium)• Poor concentration in CSF• Metabolized by Cyt. P450 enzymes• Adverse effects:

- Nausea, anorexia, vomiting- Endocrine: menstrual abnormalities, gynecomastia, azoospermia, decreased libido and potency- Hypertension and fluid retention- Hepatitis (rare-fatal)- Drug Interactions (inhibition of cyt. P450)

• Therapeutic Use: coccidiomycosis, histoplasmosis if not severely ill or immunocompromized. Oral, esophageal, mucocutaneous candidiasis

TriazolesTriazoles

Itraconazole• Varied absorption.

Metabolized by cyt P450• Has less endocrine effects

but occur at high doses• Less hepatitis• Histoplasmosis and

blastomycosis• Many drug interactions

(due to inhibition of cyt P4503A4)

Fluconazole• Completely absorbed and

better tolerated• Renal excretion• Less endocrine effects • Penetrates well into CSF• Cryptococcal, coccidial

meningitis. Candidiasis.• Drug Interactions

Other Antifungal AgentsOther Antifungal AgentsGriseofulvin

• Binds to microtubules/ disrupts mitosis

• Deposits in keratin layers• Dermatophytes actively

concentrate it• Infections of skin, hair,

nails; Prolonged therapy.• Toxicity: headache, neuro

& hepatotoxicity, photo-sensitivity, carcinogenic.

Topical Antifungals• For stratum corneum,

mucosa, cornea by dermatophytes & Candida.

• Not for subcutaneous, nail or hair infections.

• Many azoles; Tolnaftate; nystatin (Candida only); naftifine; terbinafine; Whitfield’s ointment (Benzoic+Salicylic Acid).