UTA Medical Mycology Exam II

Histoplasmosis

Intracellular infection of reticuloendothelial system via inflation of fungus

All stages mimic tuberculosis

From soil enriched with chicken, starling, or bat poop

Histoplasmosis aetiological agent and location

Endemic to Ohio and Mississippi River valleys

Histoplasma capsulatum

Histoplasma capsulatum colonial morphology

SD: white suede-like, pale yellow-brown reverse

Histoplasma capsulatum microscopic morphology

Large, rounded single-celled tuberculate Macroconidia formed on short, hyaline, undifferentiated conidiophores

Disseminated histoplasmosis

Thin walled oval yeast

Dimorphic: filamentous in environment; yeast in tissue

Failure to activate macrophage fungicidal capacity is key immune defect

Disseminated histoplasmosis pathogenesis

Inflation of mycelial filaments

When microconidia reach alveoli, convert to yeast form

Activate PMN, macrophages, lymphocytes, NK cells

Phagocytosed by macrophages in an attempt to clear infection

Histiocytosis

Macrophage infiltration in affected tissues

The types of tissue response in disseminated histoplasmosis

Diffuse histiocytosis, focal histiocytosis, and tuberculoid granulomas (less common)

Lobomycosis

Chronic, localized, subepidermal infection

Keloidal verrucoid, nodular lesions or vegetating crusty plaques/tumors

Trauma or surgical incision

Found in humans and dolphins

Lobomycosis aetiological agent and distribution

Loboa loboi remains to be cultured

Amazon valley in Brazil

Malassezia infections

Pityriasis (Tinea) versicolor

Fluoresce pale greenish

Young adults affected most

Lesions on trunk, shoulders, and arms

Pityriasis (tinea) versicolor

chronic, superficial fungal disease of the skin characterized by well-demarcated white, pink, fawn, or brownish lesions

Malassezia distribution and aetiological agent

Worldwide, more common in tropical than temperate climates

Malassezia furfur: lipophilic yeast forming part of the normal flora of human skin

Pityriasis versicolor agents

Malassezia furfur, M. globosa, M. sympodialis, M. sloofiae, M. restricta

Seborrheic Dermatitis triad: the fungus

Malassezia globosa, M. restricta, M. furfur

Pityriasis versicolor microscopic morphology

Thick-walled round, budding yeast-like cells

Short angular hyphal forms 8um in diameter

Seborrheic dermatitis triad: sebum

Malassezia convert sebum triglycerides into irritating free fatty acids in vivo

Malassezia cause _____, _____ infections and occasionally _______ ________

Opportunistic, superficial; systemic infections

Common malassezia superficial infections (5)

Pityriasis versicolor

Seborrheic dermatitis

Atopic dermatitis

Folliculitis

Dandruff

Mycetoma (Madura foot)

Infection of humans and animals caused by fungi and actinomycetes (traumatic implantation)

Characterized by draining sinuses, granules and tumefaction

Sinus discharge contains granules of various size, color, & hardness

Mycetoma distribution and aetiological agents

Worldwide, most common in barefoot tropics

Actinomycotic: Nocardia, Actinomadura, Streptomyces

Eumycotic: Madurella, Acremonium, Pseudallescheria, Exophiala, Leptosphaeria, Curvularia, Fusarium, Aspergillus

Mycetoma colonial morphology

brown diffusible pigment

flat & leathery, white to yellowish brown

becomes brownish, folded

Mycetoma microscopic morphology

phialides, sterile cultures

2 conida isolates:

1. flask-shaped w/ round conidia

2. simple/branched conidiophores, truncated bases

Mycotic Keratitis

opportunistic infection of eye: ulceration and inflammation after trauma to cornea by surgery/vegetative matter/soil or prolonged treatment with corticosteroids

Mycotic Keratitis distribution and aetiological agents

Worldwide

saprophytic fungi: A. fumigatis, A. flavus, A. niger, Fusarium solani, C. albicans

and Alternaria, Curvularia, Pseudallescheria, Acremonium

Fusarium solani colonial morphology

fast growing

pale/bright colored

felty aerial mycelium

Fusarium solani microscopic morphology

Microconidia: cylindrical to oval, 1-2 celled, formed from long lateral phialides

Macroconidia: formed from short multi-branched conidiophores 3-5 septate, fusiform, cylindrical, moderately curved

Chlamydoconidia: hyaline, globose, smooth to rough, borne singly/in pairs

Alternaria colonial morphology

dark pigmented (black to olivaceous black)

suede-like to floccose

Alternaria alternata microscopic morphology

branched acropetal chains of dictyoconidia

Conidia: obclavate, obpyriform, often having short conical/cylindrical beak, pale brown, smooth walled

Curvularia lunata microscopic morphology

pale brown phragmoconidia formed through pore

Conidia: cylindrical/slightly curved, one of central cells is larger and darker

dichytoconidia

multicellular conidia

Acremonium microscopic morphology

long, hyaline, awl-shaped, simple, erect phialides

Conidia: one-celled, hyaline, globose to cylindrical, mostly aggregated in slimy heads at apex of phialide

Lasiodiplodia theobromae microscopic morphology

rare cause of mycotic keratitis

2 celled, pigmented, longitudinally striate pycnidioconidia

Paracoccidioidomycosis

chronic granulomatous disease

primary pulmonary infection (inapparent), disseminates to ulcerative granulomata of buccal, nasal, and occasionally GI mucosa

Similar to blastomycosis and coccidioidomycosis

Paracoccidioidomycosis distribution and aetiological agent

geographically restricted to Central/South America

Paracoccidioides brasiliensis

Paracoccidioides brasiliensis microscopic morphology

multiple, narrow base, budding yeast cells "steering wheels"

Penicillium marneffei infection

thermal dimorphism

disease in normal host and immunocompromised

opportunistic pathogen in HIV+ Indochina patients

"Molluscum contagiosum" like lesions

Penicillium marneffei distribution

Southeast Asia: northern Thailand, Vietnam, Hong Kong, Taiwan, southern China

Penicillium marneffei colonial morphology

Red diffusible pigment

suede to downy

white w/ yellowish-green conidial heads

become grayish-pink to brown

produce brownish-red to wine-red pigment

Penicillium marneffei microscopic morphology

hyaline, smooth-walled conidiophores

Conidia: globose to subglobose, 2-3um diam., smooth-walled, basipetal succession from phialides

Phaeophyphomycosis

infection of humans and lower animals

dematiaceous (brown-pigmented) fungi: tissue morphology is mycelial

localized superficial infection of stratum corneum (tinea nigra) to subcutaneous cysts (phaeomycotic cyst) to brain invasion

Phaeohyphomycosis distribution and aetiological agents

Worldwide

Cladophialophora bantiana, Curvularia, Bipolaris, Exophiala jeanselmei

Subcutaneous phaeohyphomycosis

Begins as single red nodule on extremities--> expansion of skin and subcutaneous tissue

Diagnosis: surgical excision/biopsy

Exophiala jeanselmei colonial morphology

Black mucoid, yeast-like streaked colonies

Greenish-gray suede-like aerial mycelium with age

Reverse: olivaceous-black

Exophiala jeanselmei microscopic morphology

Ellipsoidal, yeast-like, budding cells

Germinating cells give rise to short torulose hyphae changing into unswollen hyphae

Conidia: formed on lateral pegs arising at right/acute angles from undifferentiated hyphae/strongly inflated detached conidia

Pegs: 1-3um long, slightly tapering, imperceptibly annellate

Cladophialophora bantiana microscopic morphology

Conidia formed in long, sparsely branched, flexuous, acropetal chains, one-celled, pale brown, smooth-walled, ellipsoid to oblong-ellipsoid

Pseudallescheriasis and Scedosporium

Common soil inhabiting fungus

Spectrum of diseases similar to Aspergillus; mycetomas; infections of eye, ear, central nervous system, internal organs, and lungs

Pseudallesceriasis and Scedosporium distribution and aetiological agent

Worldwide

Pseudallescheria boydii (anamorph Scedosporium apiospermum)

Pseudallescheria boydii colonial morphology

grayish-white, cottony colony

greenish-black reverse

Scedosporium apiospermum microscopic morphology

numerous single-celled, pale-brown, broadly clavate to ovoid conidia, borne singly or in small groups on elongate/branched conidiophores

Pseudallescheria boydii ascocarps

yellow-brown to black, spherical cleistothecia

submerged in agar: irregularly interwoven brown hyphae

release numerous, faintly brown ellipsoidal ascospores

Cleistothecia

non-ostiolate ascocarps

Scedosporium prolificans vs S. apiospermum

basally swollen, flas-shaped annellides, slower colony development on nutrient agar media, no growth on cycloheximide (actidione)

Rhinosporidiosis

Infection of the mucocutaneous tissue caused by Rhinosporidium seeberi

Chronic granulomatous disease characterized by large polyps, tumors, papillomas, or wart-like lesions

Nose is most commonly affected site

Unisolated and unclassified fungus

Sporotrichosis

Nodular lesions which may suppurate and ulcerate; elevated subcutaneous nodules

Caused by traumatic implantation

Secondary spread to articular surfaces, bone, and muscle, occasionally involve CNS, lungs, genitourinary tract

Sporotrichosis distribution and aetiological agents

Worldwide, particularly tropical and temperate regions

Sporothrix schenckii (soil and decaying vegetation)

Sporothrix schenckii colonial morphology

Moist and glabrous, wrinkled and folded surface

Varies from white to cream to black

Sporothrix schenckii microscopic morphology

Clusters of ovoid conidia produced sympodially on short conidiophores at right angles from septate hyphae

Budding yeast cells

Tinea nigra

Superficial fungal infection of skin: brown to black macules on palms

Lesions are non-inflammatory and non-scaling

Familial spread of infection

Tinea nigra distribution and aetiological agent

Worldwide, more common in tropics

Exophiala werneckii: saprophytic, in soil, compost, humus, wood in humid sub/tropical regions

Exophiala werneckii microscopic morphology

Brown to dark olivaceous (dematiaceous) septate hyphal elements

2-celled yeast cells producing annelloconidia, cylindrical to spindle-shaped, hyaline to pale brown, aggregate masses

Exophiala werneckii colonial morphology

Initially mucoid, yeast-like, shiny black

W/ age develop aerial mycelia, become dark olivaceous

Subcutaneous zygomycosis (Mucormycosis)

Result of a barrier break/traumatic implantation

Lesions include plaques, pustules, ulcerations, deep abscesses, ragged necrotic patches

Not associated with dissemination

Subcutaneous zygomycosis (Mucormycosis) distribution and aetiological agents

Worldwide

Rhizopus, Mucor, Rhizomucor, Absidia, Cunninghamella, Seksenaea, and Mortierella

Mucorales microscopic morphology

Distinctive infrequently septate thin walled hyphae w/ focal bulbous dilations and irregular branching

Apophysomyces elegans microscopic morphology

subcutaneous zygomycosis

funnel-shaped apophyses, conspicuous pigmented sub-apical thickening below apophysis

Saksenaea vasiformis microscopic morphology

Thin-walled hyphae with focal bulbous dilations and irregular, non-dichotomous, often right angled branching

Septa are solid cross walls without pores

Saksenaea vasiformis colonial morphology

white downy with no reverse pigment

Systemic Zygomycosis (Mucormycosis)

Involves rhino-facial-cranial area, lungs, GI tract, skin

Predilection for invading arterial vessels--> embolization and necrosis

Systemic Zygomycosis (Mucormycosis) distribution and aetiological agents

Worldwide

Mucorales: Rhizopus, Mucor, Rhizomucor, Absidia

Absidia corymbifera microscopic morphology

systemic zygomycosis

broad, infrequently septate, thin-walled hyphae, pyriform sporangium, conical columnella

Rhizopus oryzae microscopic morphology

sporangiospores are angular, subglobose to ellipsoidal, ridges on surface, up to 8 um long

no growth at 45C, good at 40C

Mucor sp. microscopic morphology

Systemic zygomycosis

erect, simple sporangiophores, terminal globose sporangium with well-developed subtending columnella

collarette (remnants of sporangial wall) usually visible at base of columnella after spore dispersal

Syncephalastrum recemosum microscopic morphology

systemic zygomycosis

finger-like mersporangia and sporangiospores arranged in rows

Azole antifungals--> cell membrane

Ketoconazole

itraconazole*

fluconazole*

voriconazole

micronazole, clotrimazole

Azole mechanism

inhibit P450--> synthesis of ergosterol

unhindered N bind heme

2nd nitrogen of azoles interact w/ apoprotein of lanosterol demethylase

Ketoconazole

Target cell membrane

Given orally for thrush & systemic infections

Only member of imidazole class used for systemic infections

No activity against Apergillus

Ketoconazole adverse effects

anorexia, nausea, vomiting, gynecomastia, oligospermia, hepatoxicity is rare

Ketoconazole drug interactions

decreased absorption/increased metabolism

incr gastric pH=decr absorption

incr [cyclosporin, warfarin, astemizole, corticosteroid, theophylline]

Fluconazole

Target cell membrane

principally against Candida and Cryptococcus; dermatophytes, dimorphic fungi, some yeasts

C. krusei is intrinsically resistant; no activity against Aspergillus/mold

Fluconazole spectrum

(always resistant) C. krusei>C. glabrata>C. parapsilosis, C. tropicalis, C. kefyr (sometimes resistant)

Mechanisms of antifungal resistance (4)

Target enzyme modification

Ergosterol biosynthetic pathway

Efflux pumps

Drug import

Fluconazole absorption

>90% efficient, no effect form food/gastric pH

linear pharmokinetics

Fluconazole adverse effects

mild: nausea, headache, abdominal pain, rash, Stevens-Johnson syndrome (AIDS)

hepatotoxicity

Itraconazole

Target cell membrane

Oral/IV

No CSF

Activity against Aspergillus

Broken into large number of inactive metabolites

Voriconazole

target cell membrane

Oral/IV

Extensive hepatic metabolism

Widely distributed in tissues, including brain and CSF

Fluconazole spectrum vs Candida and Aspergillus

C. albicans, C. tropicalis +/- C. glabrata

No Aspergillus

Itraconazole spectrum vs Candida and Aspergillus

C. albicans, C. tropicalis, +/- C. glabrata

+ Aspergillus

Voriconazole spectrum vs Candida and Aspergillus

Broad, includes most Candida spp., Aspergillus, Fusarium sp.

Not Zygomycoses

Fluconazole, Itraconazole, Voriconazole CSF penetration

Excellent

Poor

Excellent

Fluconazole, Itraconazole, Voriconazole CYP 3A4 inhibition

Weak

Strong

Moderate-Strong

Fluconazole, Itraconazole, Voriconazole Adverse effects

N&V, hepatic

N&V, diarrhea (solution), hepatic, CHF

N&V, visual disturbances, hepatic, rash

Amphotericin B

Polyene antibiotic (target cell membrane)

Isolated from Streptococcus nodosus

Binds sterols in fungal cell membrane

Creates transmembrane channel and electrolyte leakage

Active against most except A. terreus, Scedosporium spp.

Poor oral absorption

Lipsomal Amphotericin B

drug is encapsulated in phospholipid-containing liposomes

Amphotericin B Colloidal dispersion

drug is packaged into small lipid disks containing cholesterol sulphate

Amphotericin B Lipid complex

drug is complexed with phospholipids to produce ribbon-like structures

Amphotericin B absorption spectrum

kidney>liver>spleen>lung>

heart>skeletal muscle>brain>bone>CSF>eye

AmB nephrotoxicity

80% patients, recovers after ending treatment

2 mechanisms of toxicity

Tubular: distal tubular ischemia, wasting of K, Na, Mg

Vascular: decrease renal blood flow dropping GFR, azotemia

AmB clinical uses

Cryptococcal meningitis

Mucormycosis (zygomycosis)

Invasive fungal infection not responding to other therapy

AmB resistant fungi

Aspergillus terreus, Scedosporium spp., +/-Candida lusitaniae, Paecilomyces, Maduralla spp.