ANTIFUNGAL AGENTS
Outline

Overview

Drugs

• Drugs categorized multiple bases
  • Type of infection
    • Systemic (Deep) Fungal infections
    • Topical (Dermatophytic) Fungal infections
    • Mucous membranes -- Yeast infections
  • Route/Site of action
  • Mechanism of action
  • Chemical nature

Pathogens / typical drugs

• Typical systemic fungal pathogens
  • Systemic candidiasis -- Amph and/or Flu, Keto, Mic, Fluconazole
  • Cryptococcosis (meningitis) -- Amph + Flu, Mic, Fluconazole better
  • Systemic aspergillosis -- Amph and/or Flu
  • Aspergillosis -- sinusitis in dogs -- Enilconazole, Itraconazole?(**)
  • Blastomycosis -- Amph, Keto, Itraconazole
  • Histoplasmosis -- Amph, Keto, Fluconazole
  • Coccidioidomycosis - Amph, Keto, Itraconazole
  • Paracoccidioidomycosis -- Ampho, Keto, Itraconazole
• Typical dermatophytic pathogens (hair, skin, nails)
  • Epidermophyton spp
  • Trichophyton spp
  • Microsporum spp
• Moist Skin and Mucous Membranes (yeasts)
  • Candidosis

Key differences -- Pathogens / host

• Bacteria
  • Prokaryotes
  • Have cell wall
  • Key membrane lipid = hydroxylated glycerols
• Fungi
  • Eukaryotes
  • Have cell wall
  • Key membrane lipid = ergosterol
• Vertebrates
  • Eukaryotes
  • NO cell wall
  • Key membrane lipid = cholesterol

Amphotericin B (Fungizone^R)

Structure and chemical characteristics

• Poorly water soluble
• Unstable in saline -- must use 5% dextrose
• Large, charged molecule, polyene derivative
• Nystatin related and similar, but more systemic toxicity

Mechanism of action

• Affinity for membranes with ergosterol
• Forms channel through membrane
• Small molecules leak
• Cell dies
• Resistance is rare and slow to develop.

Pharmacokinetics

• Crosses membranes poorly by diffusion
• Must inject where need, e.g., intrathecal, IV

Adverse Effects

• Many adverse effects, some serious
• Hospitalization often required
• Nephrotoxicity -- A major toxicity
  • predictable and dose related
  • Usually reversible
  • Give in"courses" of therapy, e.g.,
    7 days on, 7 days off
  • Course of Rx -- 6 to 24 weeks
  • MONITOR RENAL FUNCTION

Azole Derivatives

Overview

• Much less toxic than amphotericin B

Mechanism of Action

• Inhibit ergosterol synthesis
  • Inhibits key cytochrome P450 step
  • Lanosterol C₁₄-demethylase
  • Affinity for cytochrome P450s varies with drug and species
  • Decreases conversion of 14-alpha-methylsterols to ergosterol
  • Accumulation of C₁₄-sterols changes membrane fluidity and function
• Also alters steroid synthesis vertebrates
  • Inhibits key cytochrome P450 step in vertebrates
  • Lanosterol conversion to cholesterol inhibited by some azoles
  • Especially ketoconazole at higher doses
  • Itraconazole and fluconazole weaker binding
  • Basis for use in hyperadrenocorticism and adrenal cortical tumors
  • Alters testosterone synthesis
• Candida albicans: Inhibit transformation of blastopores into invasive mycelial form

Ketoconazole (Nizoral^R)

Pharmacokinetics

• Can cross membranes
• Used PO for systemic effect
• Dose-related kinetics, PO doses
  • Hepatic biotransforming enzymes approach saturation
  • Half-life after stated oral dose
    • 6.5 hr -- 100 mg tablet
    • 8.1 hr -- 200 mg tablet
    • 9.6 hr -- 300 mg tablet

Adverse effects

• See reference for full list
• Most common -- anorexia, nausea, vomiting
  • divided doses have been used to reduce GI side effects
• Not recommended for pregnant or lactating animals
  • teratogenic in rat
  • stillbirths and mummified fetuses in dogs
• Hepatocellular toxicity
  • Cats more sensitive than dogs
  • Avoid in concurrent use with other hepatoxins
  • 1 in 10,000 human patients
  • Usually reversible
• Adrenocortical suppression
  • Doses higher than required for most fungi
  • Effect used therapeutically
    • Adrenal hypercorticism
  • Depresses serum testosterone
    • gynecomastia
    • azoospermia
    • sexual impotence
  • Menstrual irregularities

Miconazole (Monistat^R, Conofite^R)

Pharmacokinetics

• Poor bioavailability PO
• IV infusion for systemic action
• Heavily used topically

Adverse effects

• No hepatotoxicity
• No effect on testosterone or adrenal gland
• Frequent Hypersensitivity
  • fever and chills
  • Skin rash or itching
• Phlebitis at injection site

Itraconazole (Sporanox^R

• Introduced 1992
• 5 - 100 times greater in vitro potency than ketoconazole
• Good activity against Aspegillus spp.
• Activity vs meningeal cryptococcus
• Fewer adverse side effects than ketoconazole

Pharmacokinetics

• PO for systemic effect
• Very lipophilic
  • PO bioavailability
    • Fasting = 40%
    • Meal = ~100%
  • Tissue levels high
• Eliminated in bile
• Also metabolized
• Half-life
  • Humans -- 17-25 hr (vs 8 hr ketoconazole)
  • Dogs -- Uncertain. Reported at 8-12 hr and 44-58 hr
  • Tissues very long -- detectable in --
    • vaginal epithelium -- 4 days
    • skin and nails -- 4 weeks
  • Non-linear kinetics
    • Half-life increases with dose and duration

Adverse effects

• Very few
• Not recommended for pregnant animals

Clinical uses

• List growing and important for animals
• See Heit and Riviere'95

Fluconazole (Diflucan^R)

• Introduced '90s
• In vivo potencies 100-fold ketoconazole

Pharmacokinetics

• More water soluble than ketoconazole & itraconazole
• Concentration in secretions similar to plasma
• Oral and IV doses identical for systemic effect; F >90%
• Oral absorption independent of food intake
• Linear absorption kinetics
• Penetrates into CSF even in absence of inflammation
• Primarily renal elimination
  • Reduce dose in renal insufficiency
• Half-life
  • ~ 14 hr dogs and cats
  • 22 - 30 hr humans

Adverse effects

• Dogs -- subacute toxicity studies @ 30 mg/kg
  • Slight increases in
    • liver wt
    • liver fat
    • plasma transaminases
• Avoid use in pregnant animals
  • Because of other azoles
  • Not shown to be mutagenic or carcinogenic, itself (yet)
• Alteration of hepatic biotransformation
  • cyclosporine
  • warfarin
  • phenytoin
  • rifampin

Clinical uses

• Growing in importance
• See Heit & Riviere'95

Clotrimazole

Mechanism of action

• Related to other azoles, but ...
• Acts on cell membrane
• Interferes with amino acid transport into organism

Pharmacokinetics

• Topical

Adverse effects

• Toxic if systemic
• Topical
  • May see erythema, urticaria, pruritus, stinging, and blistering

Uses

• cutaneous candidiasis
• candidal infections of mucous membranes and mucocutaneous junctions
  • perianal, intertriginous, and vulvovaginal areas
  • Treatment may require two to four weeks
  • Compliance problems has led to very high doses for 1-3 treatments

Griseofulvin (Fulvicin^R)

Application

• PO for topical infections
• Onychomycosis, Tinea capitis, Tinea pedis, etc.
• Many Trichophyton spp.,Microsporum spp. and Epidermophyton spp are susceptible

Structure and chemistry

• FromPenicillium griseofulvum
• Poorly water soluble
• Requires bile salts for solubilization and absorption

Mechanism of Action

• Disrupts mitotic spindle structure to lead to metaphase arrest
• Concentrates in newly formed cells of skin, hair, and nails and is carried with them as they continue their life history into keratinized structures
• Concentration -- static effect on fungi
• Fungi cannot invade
• Eventually slough off with keratin
• Long courses of therapy
  • hair covered skin -- 3 to 4 weeks
  • nails -- 3 to 4 months.

Pharmacokinetics

• PO Absorption good if high fat meals
• Most absorbed drug biotransformed
• Small amount shed in dead skin and hair

Adverse Effects

• Not common
• Confusion
• Hypersensitivity
  • skin rash, hives, or itching
  • oral thrush (soreness or irritation of mouth or tongue)
• Photosenstivity.
• High doses / long therapy
  • hepatomas in mice and thyroid tumors rats
  • hepatitis
  • granulocytopenia or leukopenia
  • peripheral neuritis
    • (numbness, tingling, pain, or weakness in hands or feet

Terbinafine

• Allylamine
• Fungicidal
• Topical and PO for Topical effect
  • Better for Guinea pig T. mentagrophytes ringworm than ketoconazole or griseofulvin
• Cell membrane toxic
  • Decreases ergosterol synthesis
    • Inhibits squalene epoxidase
  • Fungicidal activity may be due to --
    • accumulation of intracellular squalene
    • secondary disruption of chitin synthesis
• Metaolized in liver

Adverse effects

• Humans -- 10% mild & self-limiting reactions
• GI disturbances
• rashes, pruritus
• Headache, dizziness
• Joint and muscle pains

Tolnaftate (Tinactin^R and others, OTC)

• Cidal
• Topical
• Trichophyton, Microsporum, and Epidermophyton spp.
• Not candidal infections
• Chronic, hyperkeratotic lesions may not respond well
• Cream or liquid should be used for active infections
• Powders for maintenance of remission
• Must apply treatment q12h.
• Refractory cases, may combine with griseofulvin
• Use of a keratolytic (e.g., Whitfield's ointment)
• Cure requires 1 to 10 weeks.

Whitfield's ointment

• Primary benefit -- keratolytic
• Old medication
  • 3% salicylic acid -- keratolytic
  • 6% benzoic acid -- some antifungal

Potassium Iodide

• Old drug
• Drug of choice for cutaneous-lymphatic sporotrichosis. (AMADE2:12)
• Actinomycosis (vet med)
• Use PO as saturated solution (1 mg/mL)
• Classified as expectorant most textbooks
  • Increases respiratory tract secretions within ~30 min

Adverse effects

• Hypothyroidism
• Iodism -- signs include --
  • brassy taste
  • (secretions) rhinitis, coryza, salivation, lacrimation
  • (irritation) sneezing, burning of mouth and throat, ocular irritation
  • sialadenitis
  • dermal lesions

Others

• Azoles
  • butaconazole nitrate [Femstat], econazole nitrate [Spectazole], oxiconazole [Oxistat], and Sulconazole [Exelderm].
• Triazoles
  • Terconazole [Terazol 3, Terazol 7]
• Haloprogin [Halotex]
• Allylamines
  • Naftifine hydrochloride [Naftin].

References

• USPDI15/95
• Heit/Riviere95-Adams95: Heit, M.C., and J.E. Riviere, 1995, Antifungal and Antiviral Drugs, Ch 44, in Veterinary Pharmacology and Therapeutics, 7th ed, ed. H. Richard Adams, Iowa State University Press, Ames, IA, pp. 855-869
• Moore'95: Moore, Cecil P., 1995, Ophthalmic Pharmacology, Ch 53 in Veterinary Pharmacology and Therapeutics, 7th ed, ed. H. Richard Adams, Iowa State University Press, Ames, IA, pp. 1115-1116.
• AMADE Section 14, Chapter 2: Topical drugs used in ear, skin, and mucous membrane infections. Updated quarterly. 1992.
• AMADE Section 15, Chapter 2: Drugs used for systemic mycoses. Updated quarterly, 1992.
• Rang & Dale87: Pharmacology. H.P. Rang and M.M. Dale, Churchill Livingstone, New York, 1987.
• Dallman, M.J., et. al. 1992. Disseminated aspergillosis in a dog with disk spondylitis and neurologic deficits. JAVMA 200(4): 511-513.
• Old GLC notes
• Frontiers in Biotechnology -- Resistance to Antibiotics. Special section in Science 264(5157):15 April, 1994. Series of articles including News Reports, Policy Forum, Perspectives, Scientific Articles. pp 359-393.
  • Georgopapadakou, N.H., and T.J. Walsh, Human Mycoses: Drugs and Targets for Emerging Pathogens p371... Has MOAs and nice illustrations of many drugs acting on fungi