Fungal Infections
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Table of Contents
Overview
Fungal Infections
Antifungal Agents
References



 
OVERVIEW
Objectives
    • 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.

Introduction
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.

Fungi
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.

Ergosterol Synthesis
Acetyl CoA  —>  Squalene  —(squalene epoxidase)—>   —(cyclase)—> 
—> Lanosterol   —(14-α-demethylase)—> —>  Ergosterol




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FUNGAL INFECTIONS
Introduction
    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.
  • Pityriasis (Tinea) Versicolor
    • Organism: Pityrosporum orbiculare (formerly 1ssezia furfur)
    • A common skin condition that produces patches of white, brown or salmon-colored finely flaking skin over the trunk and neck.  Primarily effects young and middle-aged adults and is more common in men.
    • Treatment: selenium sulfide lotion or shampoo (Selsun), topical or PO azoles.
  • Tinea Nigra
    • Organism: Exophiala wernickii
    • Characterized by discolored spots on the skin that are not raised above the surface.  Brown or black lesions are most commonly seen on the palms of the hands and soles of the feet.
    • Treatment:  selenium sulfide lotion or shampoo (Selsun), topical or PO azoles.
  • Black Piedra
    • Organism: Piedraia hortae
    • A superficial hair infection characterized by small, hard nodules on the hair shaft.
    • Treatment: shave or crop the infected hair.
  • White Piedra
    • Organism: Trichosporon beigelii
    • Affects hair of the scalp, mustache and beard.  Characterized by a cream-colored pasty growth along the hair shaft.
    • Treatment: shave or crop the infected hair.

Cutaneous Mycoses
- infections that extend deeper into the epidermis, as well as invasive hair and nail disease.
  • Candidiasis (Thrush, Vulvovaginitis, Moniliasis, “A Yeast Infection”)
    • Organisms: Candida albicans (90%), Torulopsis glabrata, C. tropicalis
    • Occurs in the vagina (mostly), mouth, mucous membranes, moist skin, and fingernails.  Candida sp. are in ecologic equilibrium with bacteria that exist in the mouth and vagina.  Certain factors can throw off this balance and allow for the overgrowth of the fungus.  These factors include antibiotic use, change in immune system status, AIDS, immunosuppressant drugs, corticosteroids (especially inhalers), diabetes, oral contraceptives and pregnancy.  Vaginal candidiasis may produce a thick, white, “cottage-cheese” discharge accompanied by itching or irritation.  Oral thrush produces sore creamy-yellow raised patches in the mouth.
    • Treatment (Vaginal candidiasis): topical imidazoles or triazoles or nystatin (e.g. Gyne-Lotrimin®, Monistat 7®), PO fluconazole or itraconazole, pt should avoid wearing tight clothing.
    • Treatment (Oral Thrush): topical nystatin (swish & swallow) or clotrimazole, PO fluconazole.
  • Tinea (Dermatophytosis, Ringworm, Athlete’s Foot, Jock Itch, etc.)
    • Organisms: These fungi are referred to as dermatophytes and include Trichophyton sp., Epidermophyton fluccosum, Microsporum sp.
    • This is a group of common fungal infections involving the skin, hair and nails.  Tineal infections may be acquired from another person, an animal, the soil, or from an inanimate object such as a chair, shower stall or carpeting.  Tinea pedis, also called Athlete’s foot, presents as cracking and itching between the toes.  Tinea corporis, also called ringworm of the body, is characterized as itchy patches on the body with well defined circular edges.  Tinea cruris, commonly called jock itch, produces a reddened, itchy area spreading from the genitals outward over the inside of the thigh and is more common in males.  Tinea capitis involves round, itchy patches of hair loss on the scalp.  Tinea unguium is a type of fungal nail infection or onychomycosis in which the nails become thick and white or yellow with debris accumulating underneath.  The nail may be destroyed.
    • Treatment: Many options exist for the treatment of tinea.  Mild to moderate cases can be treated with topical drugs such as the azoles, ciclopirox olamine, naftifine, tolnaftate, undecylenic acid, or haloprogin.  More severe or resistant cases can be treated with griseofulvin which concentrates in the skin or with PO ketoconazole, itraconazole or fluconazole.  Treatment usually last 2-4 weeks.  For tinea unguium the first line drugs are itraconazole, fluconazole or PO terbinafine, all of which are as good or better than griseofulvin.  Treatment should last 3-6 months for fingers and 6-12 months for toes when using the azole, and 3-6weeks for finger and 2-3 months for toes when using terbinafine.  Oral treatment of nail fungal infections can be combined with urea nail solutions to promote debridement.

Subcutaneous Mycoses - infections involving the dermis, subcutaneous tissues, muscle,  fascia; usually due to puncture wounds.
  • Sporotrichosis
    • Organism: Sporothrix schenckii.
    • Characterized by nodules, ulcers, and abscesses usually confined to the skin and developing along the lymphatics that drain the primary site of infection.  The fungi normally grows on moss and other plants; gardeners and florists are at particular risk.  Sporotrichosis can spread to the lungs and joints in immunocompromised individuals.
    • Treatment: for the cutaneous disease use a saturated solution of potassium iodide given orally.  For extracutaneous involvement use itraconazole or amphotericin B.
  • Chromoblastomycosis (Chromomycosis, Verrucous Dermatitis)
    • Organism: common soil fungi refered to as dematiaceous fungi
    • Characterized by verrucous (warty) nodules that appear at the site of inoculation.
    • Treatment: surgical excision is used when lesions are small and few, otherwise use itraconazole.
  • Phaeohyphomycosis (Black Molds)
    • Organism: common soil fungi referred to as dematiaceous fungi
    • Similar to Chromoblastomycosis but usually not as severe.
    • Treatment:  surgical excision is used when lesions are small and few, otherwise use itraconazole.

Systemic Mycoses - infections that originate primarily in the lung but may spread to many other organ systems in the susceptible host.
  • Histoplasmosis (Darling’s Disease, Reticuloendothelial cytomycosis, Cave Disease, Spelunker’s Disease)
    • Organism: Histoplasma capsulatum
    • This disease is  contracted by inhalation of a fungus which is found in soil, especially in areas contaminated by droppings of birds and bats.  It is endemic to the Mississippi and Ohio river valleys.  The infection presents itself as either an acute self-limiting pulmonary infection (fever, cough, malaise) or, if hematogenous spread is involved, as a progressive disseminated infection characterized by hepatomegaly, lymphadenopathy, splenomegaly, oral and GI ulceration, adrenal necrosis (producing a syndrome similar to Addison’s Disease) and anemia.  Advanced stages of the disease can present with pulmonary lesions similar to tuberculosis.   The disease can be fatal. The disseminated form is defining for AIDS.
    • Treatment: itraconazole or amphotericin B; second line agents are ketoconazole and fluconazole.  Therapy usually lasts 9 months.
  • Blastomycosis (Chicago Disease, Gilchrist Disease, North American Blastomycosis)
    • Organism: Blastomycces dermatitis
    • Contracted by inhalation of fungus which is found in soil and decaying wood.  It usually produces either an asymptomatic pulmonary infection or mild pneumonia.  If hematogenous spread occurs it usually involves the skin (ulcers and abscesses) and bone (swelling, heat, tenderness present over the lesion).  The fungus is endemic to the same areas as Histoplasmosis  It can infect dogs and epidemics among canines have been reported.
    • Treatment: itraconazole; second line agents are amphotericin B, ketoconazole, fluconazole.  Therapy usually lasts 6 months.
  • Paracoccidioidomycosis (South American Blastomycosis, Lutz-Splendore-Almeida’s Disease)
    • Organism: Paracoccidioides brasliensis
    • The disease is only found in Central and South America.  It is contracted by inhaling the fungus, but the pulmonary infection is usually asymptomatic.  It presents as ulcerations in the oral and nasal cavities.
    • Treatment: itraconazole (x6 months), ketoconazole (x6 to18 months), amphotericin B, sulfonamides.
  • Coccidioidomycosis (Posada’s Disease, San Joaquin Valley Fever, Dessert Rheumatism)
    • Organism: Coccidioides immitis
    • Inhalation of fungus laden dust usually causes an acute, self-limiting and benign respiratory infection.  If hematogenous spread occurs, it is often fatal and involves infection of the skin, lymph nodes, spleen, liver, bones, kidneys, meninges, and brain.  The fungus is endemic to the southwestern USA, especially the central valley of California (that’s us!).  The disseminated form is a defining disease for AIDS.
    • Treatment: fluconazole or itraconazole; second like agents are ketoconazole or amphotericin B.  Therapy usually lasts 12-18 months.  Relapse rate is 15-37%.
    • Treatment (meningitis): PO fluconazole and intrathecal or intraventricular miconazole or amphotericin B.
  • Cryptococcosis (Basse-Buschke’s Disease, Torulosis, European Blastomycosis)
    • Organism: Cryptococcus neoformans
    • The lung is the primary site of infection; however, the organism has a high predilection for systemic spread to the brain and meninges.  Cryptococcus is the leading cause of fungal meningitis.  Spread to the kidneys can also occur.  The disseminated form is fatal if untreated.  The  fungus has worldwide distribution.
    • Treatment (non-menigitis): use amphotericin B until clinical improvement is seen then switch to fluconazole (x8 to10 weeks).
    • Treatment (menigitis): use amphotericin B + flucytosine until afebrile and cultures are negative (~6 weeks) then switch to fluconazole.
  • Candidiasis (Candidosis)
    • Organisms: Candida sp.
    • Systemic candidiasis is the most common nosocomial fungal disease (70% of hospital fungal infections).  It is difficult to diagnose and less then 50% of patients with infections will have positive Candida blood cultures.  Unlike the other systemic mycoses, Candida sp. are a normal part of human oral and GIT flora.  These fungi gain hematogenous access from the oropharynx or GIT when the mucosal barrier is breached (e.g. inflamation secondary to chemotherapy) or through contaminated IV catheters and syringes.  The organs most often involved are the lungs, skin, spleen, kidney (pyelonephritis, UTI), heart (endocarditis), liver, bone, eye (endophthalmitis) and brain (meningitis).  Candida septicemia resembles a gram negative bacterial sepsis in the occurrence of fever, shock, hypotension, azotemia, oliguria, and renal shut down.  Risk factors for candidial infection include central venous catheters, parenteral nutrition, broad-spectrum antibiotic use, extensive surgical procedures, Candida colonization, neutropenia and immunosuppression (e.g. AIDS, chemotherapy, burn patients, premature infants).  It is considered a serious infection and potentially fatal if untreated.  Candidiasis involving the esophagus, trachea, bronchi, or lungs is a defining disease for AIDS.
    • Resistant Organisms: Candida krusei is resistant to the azoles and Candida lusitaniae is resistant to amphotericin B.
    • Treatment: fluconazole has been shown to be as effective as amphotericin B in immunocompetent patients and is less toxic.  Most clinicians still use amphotericin B as a first line agent, however.  In febrile neutropenic patients amphotericin B ± flucytosine is still the drug of choice.

Opportunistic Mycoses - infections occurring in immunocompromised host (usually due to organ transplants, chemotherapy, AIDS).
  • Aspergillosis
    • Organisms: Aspergillus sp.
    • Aspergillus, a common fungus in the environment,  can be inhaled and the infection is almost always asymptomatic in immunocompetent people.  A chronic clinical situation may occur with little distress except occasional bouts of hemoptysis and  pathological changes in the lung that lead to formation of a “fungal ball.”  Hematological spread is possible in the severely immunocompromised host and appears similar to bacterial sepsis and can be rapidly fatal.  The fungal hyphael structures often penetrate blood vessels causing infarcts and hemorrhages.
    • Treatment: amphotericin B or itraconazole are drugs of choice, amphotericin B lipid complex can be used in patients refractory or intolerant to conventional amphotericin B therapy.
  • Zygomycosis (Mucormycosis, Phycomycosis)
    • Organisms: Rhizopus sp., Absidia sp., Mucor sp., Basidiobolus sp.
    • This infection originates in the nose, sinuses or ocular orbits and can spread to the brain.  It presents as pain in the associated areas, fever, orbital cellulitis, proptosis, purulent nasal discharge, and necrotic destruction of associated tissues.  Convulsions, aphasia, and hemiplasia can be seen when the brain is involved.  Risk factors include immunosuppression and diabetic ketoacidosis.  The disease is usually fatal.
    • Treatment: amphotericin B.



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ANTIFUNGAL AGENTS
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.

Imidazoles
        • 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.

Antimetabolites
        • 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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REFERENCES
1.    Facts and Comparisons.  St. Louis: Facts and Comparisons, Inc 1996.

2.    The Merck Manual. Sixteenth Edition. Merck Research Laboratories, Rahway, N.J., 1992.

3.    Young LY, Koda-Kimble MA, editors. Applied Therapeutics: The Clinical Use of Drugs. Sixth Edition. Vancouver, WA: Applied Therapeutics, Inc., 1995: 69.1 - 69-22.

4.    Murray PR, Kobayashi GS, Pfaller MA, Rosenthal. Medical Microbiology. St Louis: Mosby 1994:400-437.

5.    Sanford JP, Gilbert DN, Sande MA.  Sanford Guide: Guide to Antimicrobial Therapy, 26th Edition. Dallas: Antimicrobial Therapy, Inc 1996.

6.    Systemic Antifungal Drugs. The Medical Letter 1996 Feb;38(967):10-12.

 
 
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Copyright © 1996-2002 Scott Toste, Pharm.D., R.Ph.
Last updated: 12/15/02