|Table of Contents
• To discuss the biology of fungal parasites.
• To present an overview of the common skin and systemic fungal infections.
• To present a brief overview of the antimycotic drugs used to treat fungal infections.
• To discuss the pharmacologic alternatives in treating fungal infections.
Four types of microorganisms can infect the human body: viruses, bacteria, fungi and parasites (protozoa). All of them offer unique challenges to treatment, and fungal pathogens can be particularly problematic.
There was a time not long ago when serious fungal infections were only rarely encountered. Most fungal infections consisted of minor, non-life threatening skin infections that could easily be dealt with. Nowadays serious fungal infections are on the rise. This can, in part, be attributed to the increasing number of immunocompromised individuals that are a result of cancer chemotherapy, organ transplants, and the AIDS epidemic.
In a normal, healthy individual most fungal pathogens are prevented from multiplying by competition from normal bacterial flora or the body’s immune system. When either of these two factors are compromised (e.g. broad-spectrum antibiotic use, immunosuppressive drugs, etc.) there is an increased likelihood of a fungal infection.
Fungal infections can be from endogenous or exogenous sources. Only a few fungi are harmlessly present all of the time in areas of the body such as the mouth, skin, intestines and vagina. While the vast majority come from sources outside of the body.
So what are fungi? They are simple eukaryotic organisms that reproduce by sporulation and exist in two different forms: filamentous molds and unicellular yeasts. They differ from bacteria in that their DNA is housed in a nuclear membrane. Since mammals and fungi are both eukaryotes, they have very similar cellular machinery. This makes it very hard to design drugs that will damage the fungi and not harm humans. Thankfully, some differences do exist. Fungal cell membranes contain ergosterol instead of cholesterol, the major sterol found in the tissues of mammals. This is important because most antifungal strategies are currently based on the presence of ergosterol in fungal membranes. This is also a source of many drug adverse reactions because ergosterol does not differ much from cholesterol. Many of the drugs that attack ergosterol also effect cholesterol to a lesser extent. And the drugs that affect ergosterol synthesis also have some impact on mammalian metabolism.
Acetyl CoA —> Squalene —(squalene epoxidase)—> —(cyclase)—>
—> Lanosterol —(14-α-demethylase)—> —> Ergosterol
Fungal infections can be classified by the area of the body infected.
Superficial Mycoses - infections limited to the outer most layers of the skin and hair.
Cutaneous Mycoses - infections that extend deeper into the epidermis, as well as invasive hair and nail disease.
Subcutaneous Mycoses - infections involving the dermis, subcutaneous tissues, muscle, fascia; usually due to puncture wounds.
Systemic Mycoses - infections that originate primarily in the lung but may spread to many other organ systems in the susceptible host.
Opportunistic Mycoses - infections occurring in immunocompromised host (usually due to organ transplants, chemotherapy, AIDS).
|Sterol Binding Agents (Polyenes)
- MOA: binds to membrane sterols (high affinity for egosterol) causing ↑ membrane permeability, leakage of cytoplasmic contents & death.
• Amphotericin B (Fungizone®): Tx of severe systemic fungal infections, gold standard of antifungals, broad spectrum of activity; Admin: IV, topical; SE: nick-named "amphoterrible" b/c of numerous adverse rxns, nephrotox (common), fever, chills, HA, N/V, hypokalemia, hypomagnesemia, blood dyscrasias, anorexia, malaise, generalized pain, renal tubular acidosis, topical will discolor skin; premedication w/ APAP, diphenhydramine & meperidine to ↓SE; Interaxns: other nephrotox drugs, ↑hypokalemia w/ corticosteriods →(↑tox of digitalis, skeletal muscle relaxants);
• Amphotericin B lipid complex (Abelcet®): supposedly less toxic than amphotericin B.
• Nystatin (Mycostatin®): more toxic than Amphotericin B so not used systemically, not absorbed from GIT; Admin: topical, vaginal, oral-local; SE: N/V, diarrhea, stomach pain.
Ergosterol Synthesis Inhibitors (Azoles)
- MOA: Inhibition of sterol 14-α-demethylase enzyme (a Cyt P450 enz.) → interferes with the synthesis of ergosterol (an important fungal membrane component) and results in cell membrane damage via alteration of permeability & function. Many drug interaxns because of Cyt P450 inhibition.
• Ketoconazole (Nizoral®): gastric acidity necessary for absorption of drug; Admin: PO, topical; SE: N/V, puritis, abdom pain, gynecomastia & impotence (↓hormone synth), photophobia, hepatotox; Interaxns: H2 blockers & omeprazole ↓absorption, Cyt P450 inhibitor (↑effect of sulfonylureas, warfarin, cyclosporine, terfenadine), isoniazid & rifampin ↓serum levels.
• Clotrimazole (Mycelex®, Lotrimin®, Gyne-Lotrimin®): Admin: topical, vaginal, oral-local; SE: abnormal liver fxn test, N/V (in pts using oral troche), mild burning or stinging.
• Miconazole (Micatin®, Monistat®): similar to Clotrimazole, also admin IV (v. rarely) for severe systemic fungal infections refractory to standard tx;Admin: topical, vaginal, oral-local; SE: fever, chills, rash, anorexia, diarrhea, N/V, anemia; Interaxns: ↑effect of warfarin & sulfonylureas.
• Butoconazole (Femstat®), Econazole (Spectazole®), Tioconazole (Vagistat®): similar to Clotrimazole.
— Triazoles - ↑affinity for fugal vs mammalian enzymes→ ↑efficacy & ↓toxicity.
• Fluconazole (Diflucan®): better absorbed from GIT than Ketoconazole, no antiandrogenic activity, one of the few anitfungals with significant penetration of the BBB; Admin: PO, IV; SE: hepatotox, N/V, HA, diarrhea, rash, hypokalemia, Steven-Johnson syndrome; Interaxns: ↑effect of (sulfonylureas, cycloserine, phenytoin, warfarin, terfenadine), rifampin ↓serum levels of Fluconazole, ↓effect of some PO contraceptive, HCTZ ↓renal clearance of Fluconazole.
• Itraconazole (Sporanox®): does not cross BBB, Admin: PO, food ↑'s absorption; Tx: Candidiasis, Histoplasmosis, Blastomycosis, dermatophytes; SE: N/V, HA, rash, diarrhea, pruritus, hypokalemia, ↓libido, hepatotox; Interaxns: ↓effect of Itraconazole (rifampin, isoniazid, phenytoin, phenobarb, carbamazepine), ↑effect of (sulfonylureas, cycloserine, phenytoin, warfarin, dig, terfenadine).
• Terconazole (Terazol®): similar efficacy to the toical imidazoles; Admin: topical-vaginal only.
• Flucytosine (Ancobon®, 5-fluorocytosine): used only in combination with Amphotericin B or the azoles because of high rate of resistance, use extreme caution in renal impairment (90% excreted unchanged in urine); MOA: converted to fluorouracil (an antineoplastic agent) inside of fungal cells, competes with uracil→ ↓nucleic acid & protein synth; Admin: PO; SE: N/V, bone marrow depression; Interaxns: synergism w/ Amphotericin B.
Squalene Epoxidase Inhibitors
- MOA: inhibits squalene epoxidase, a primary enzyme in ergosterol synth. → membrane damage & impaired fxn.
• Terbinafine (Lamasil®): Admin: topical (PO form pending approval for tx of fungal nail infections).
• Naftifine (Exoderil®, Naftin®): Admin: topical.
Cell Mitosis Inhibitor
• Griseofulvin (Grisactin®, Grifulvin®, Fulvicin®): used for cutanteous infections; MOA: inhibs fungal cell mitosis by disrupting mitotic spindle structure (interferes w/ microtubule fxn) arrests metaphase of cell division, distributes in the keratin precursor cells of skin, hair & nails, rendering the keratin resistant to fungal invasion; Admin: PO, take w/ fatty meals; SE: photosensitivity rxns, urticaria, oral thrush, N/V, HA, diarrhea, dizziness, fatigue, mental confusion, insomnia, leukopenia, hepatotox, nephritis; Interaxns: disulfiram-like rxn w/ EtOH, ↓effect of warfarin & PO contraceptive.
Miscellaneous Agents - used for cutaneous infections.
• Tolnaftate (Aftate®, Tinactin®): MOA: distorts hyphae & stunts mycelial growth; Admin: topical.
• Undecylenic acid (Desenex®, Cruex®): MOA: interferes w/ fungal cell membrane permeability; Admin: topical.
• Haloprogin (Halotex®): Admin: topical.
• Ciclopirox olamine (Loprox®): Inhibits transport of essential elements in the fungal cell causing problems in synth of DNA, RNA & protein; Admin: topical.
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