Block V, Fungus And Antifungals

Front 1

Sabouraud's agar

Back 1

Media similar to bacteriological but for fungus (lower pH)

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KOH mount

Back 2

tissue disintegrates, hyphae remain

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Calcofluor white tissue stain

Back 3

fungi fluoresce green or blue-green

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India Ink

Back 4

negative stain for capsule
for testing CSF for Cryptococcus neoforman

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PAS (Periodic Acid Schiff)

Back 5

stains chitin cell wall

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Gomori-Silver

Back 6

fungi stain black or deep brown

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Dermatophytes

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Fungal diseases on surface of skin
Molds
Adapted to specific species, but may spread to humans
Human-human transmission, animal-human
Usually self-limiting, can become chronic
Most common in moist areas or tight clothing

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Genera of Dermatophytes

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-Trichophyton
Skin, hair; lots of macroconidia, few microconidia, fluorescent
-Microsporum
Skin, hair, and nails; few macroconidia, lots microconidia, no fluorescents
-Epidermophyton
Skin and nails; Macroconidia in 2's and 3's, no microconidia, no fluorescents.

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TINEAS
Capitis (favus)
Barbae
Corporis
Pedis
Unguium
Cruris
Versicolor

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Head (yellowish cup-shaped encrustations)
Beard, neck, or face
Trunk, arm, hand, palm
Feet
Nails
Crotch
Skin

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Dermatophytid (ID) Reaction

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-Allergic reaction to circulating antigen
Called ID (identity) or autoeczematization
generalized acute cutaneous reaction
Appears as rash usually vesicles on fingers
Origin: a dermatophyte infection at a distant site (or other infection)
Culture at the site of dermatophytid reaction will be negative
Symptoms clear with treatment

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Subcutaneous Mycoses

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SPOROTRICHOSIS
Sporothrix schenckii
CHROMOYCOSIS
Fonsecaea, Phialophora, Cladophialophora
MYCETOMA
Dozens of fungal genera
Actinomycetes, Nocardia (bacteria)

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Sporotrichosis

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Agent: Sporothrix schenckii
Fungus present on vegetation
Primary lesion usually on hand or foot
“Gardener's disease“
most likely due to puncture wounds
Chain of lesions moves up the arm, along the lymphatics, over several days

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Systemic Mycoses

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Major causative agents:
Histoplasma capsulatum
Blastomyces dermatitidis
Coccidioides immitis

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Histoplasma capsulatum

Back 14

Endemic in midwestern US
-Mississippi and Ohio river valleys (80-90% test positive)
-associated with bird droppings
-present with flu-like symptoms progressing to pneumonia like.

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Blastomyces dermatitidis

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Endemic in Northeastern United States
-respiratory transmission
-Probably soil organism
Pulmonary disease, typically diagnosed from yeast in sputum

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Coccidiodes immitis

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Prevalent in San Joaquin Valley, CA (San Joaquin Valley Fever)
Free-living in dry southwestern deserts.
-inhalation of spores.
Most rapidly fatal of all systemics

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Opportunistic fungi

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Cryptococcus neoformans
Candida
Mucor, Rhizopus
Aspergillus
Penicillium
Pneumocystis carinii

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Candidiasis

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One of the most frequent fungal disease (33 species cause disease)
Candida albicans (60%) "Thrush"
Predisposing Factors
-AIDS
-Surgery
-Immunosuppresive drugs
-Antibiotic therapy
-malignacy, catherters, burns, diabetes.

Normal flora in mounth, large intestine, and vagina
-inoculated at birth.

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Invasive Aspergillosis

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Aspergillus fumigatis (and other species)
Filamentous "bread mold" fungus
Lung infections
Spreads to heart and CNS (~25% cases)
Diagnosis usually by lung biopsy
Treatment: amphotericin B
Prognosis poor

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Most common infection in AIDS

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Pneumocystis jirovecii (carinii)

70% of people have antibodies to.

Treated with contrimoxazole or pentamidine.

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Fungal membrane disrupting agents

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Amphotericin B, nystatin

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Ergosterol synthesis inhibitors

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Azoles, allylamines, morpholine

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Fungal nucleic acid inhibitor

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Flucytosine

Front 24

Anti-mitotic (spindle disruption) drug for fungus

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Griseofulvin

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Glucan synthesis inhibitor

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Echinocandins

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Chitin synthesis inhibitor

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Nikkomycin

Front 27

Fungal Protein synthesis inhibitors

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Sordarins, azasordarins.

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Amphotericin B Mechanism

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Irreversibly binds to ergosterol and forms pores to leak ions

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Amphotericin B Adverse effects

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Infusion reaction (70-90%) not hypersensitivity, causes fever, chills, and shaking
Nephrotoxicity (up to 80%), reversible most of the time, saline before may help.

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Nystatin

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Similar to Amphotericin B

Topical use only.

Used for thrush, vafinal and GI candidiasis.

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Flucytosine

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Fungus converts to 5-fluorouracil and inhibits RNA & DNA.

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Azoles mechanism

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Inhibit fungal CPY450 (lanosterol 14-alpha-demthylase) which leads to depletion of ergosterol.
Disrupts cellular growth and replication.

Inhibits mammalian CYP450
-each azole is different
-phenytoin, warfarin, statins...

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Clotrimazole

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Lotrimin

Front 34

Ketoconazole

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First systemic azole (oral)

***Potent inhibitor of CYP450 system***
Hepatotoxicity
Blocks both testicular and adreanal androgen biosynthesis.

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Intaconazole

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Greater spectrum and fewer side effects than ketoconazole

*Less potent CYP450 inhibitor than Ketoconazole*

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Fluconazole

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Gastic Acid not needed for absorption (>90% bioavailability)

Wide distrabution including CSF
->>>>>ketoconazole or itraconazole

Still a CYP450 inhibitor

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Voriconazole

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Very broad spectrum with very low MIC

1st line with invasive aspergillosis.

Phototoxiity in 1-6%
Visual disturbance in 30%

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Posaconazole

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Least hepatotoxicity of azoles

2nd line agent for prophylaxix of disseminated candidasis or aspergillosis in immunocompromised

Front 39

Griseofulvin

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Inhibits fungal mitosis & nucleic acid synthesis

For dermatophytes (no Candida activity)

Well Tolerated (headaches, GI, skin reactions, insomnia)

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Terbinafine

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Inhibits fungal squalene 2,3-epoxidase
-necessary for ergosterol synthesis

**Very active against dermatophytes**

Lipophilic and Keratophilic so high concentrations in
-Stratum corneum, sebum, and hair.

Front 41

Echinocandins

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Lipopeptides that are synthetically modified from fermentation broths of various fungi
-Inhibit cell wall synthesis

Caspofungin
Anidulafungin
Micafungin

Narrow Spectrum
-Candida (cidal), Aspergillus (static)