Mycology - study of fungi, approx 80,000 species but 400 medically important

- most fungi are beneficial to mankind (food production, medicine, etc.)

- eukaryotic with at least one nucleus and organelles

- most are obligate of facultative aerobes

- chemotropic (enzyme secreting)

Fungal Infections - called mycoses

- most are candidiasi/dermatophytosis (part of normal flora)

-classified as: a.) superficial

b.) cutaenous

c.) subcutaneous

d.) systemic

e.) opportunistic

- grouped by: portal of entry and initial site of involvement

- patients develop significant cellular and humoral immune responses

- difficult to treat as eukaryotes which have similar genes, etc with host

Definition of Terms:

Conidia - asexual reprodcutive structures (mitospores), may be formed on specialized

hyphae termed conidio spores. may be large (macroconidia)/small (micro)

Arthroconidia - conidia from fragmentation of hyphal cells

Blastoconidia - from budding process

Chlamydoconidia - large, spherical produced from terminal or intercalary hyphal cells

Phialoconidia - from "vase-shaped" Phialide (aspergillus)

Dematiaceous Fungi - walls contain melanin; black-brown

Dimorphic Fungi - two growh forms mold and yeast

Hyphae - tubular branching filaments (mold form) seperated by septa

- aerial hypha project above colony and bear reproductive structures

Imperfect Fungi - lack sexual reprodutcion (anamorph - mitotic state)

Mold - hyphal colony/form of growth

Mycelium - mass of mat of hyphae, mold colony

Perfect Fungi - capable of sexual repro (telemorph)

Pseudohyphae - elongated buds or blastoconidia

Septum - typically perforated hyphal cross wall

Sporangiospores - asexual structurees of zygomycetes within a sproangium

Spore - specialized poropagule with enhanced resitance and promoted dispersion

Ascospores - following meiosis, 4-8 meiospores form within ascus

Basidiospores - club shaped basidium upon which 4 meiospores form on surface

Zygospores - large thick-walled structure develops after meiosis

Yeasts - spherical to ellipsoid cells taht reproduce by budding

Classification:

Zygomycota - sexual: zygospore; asexual: sporangia

- sparsely septate, vegetative hyphae

Ascomycota - sexual: ascopores from ascus/sac; asexual: conidia

- septate hyphae

Basidiomycota - sexual: four progeny basidiospores supported by club shaped basidium

- have complex septa

- mushrooms, cryptococcus

Growh and Isolation: grow readily in simple sources of nitrogen and carbohydrate

Sabouraud's agad (glucose + modified peptone

Superficial Mycoses:

1.) Pityriasis Versicolor - chronic mild superficial infection; minimal responses

- discrete, serpentine, hyper or hypopigmanted maculae on skin usually on upper back, chest, arms, abdomen

- Malassezia Globosa lipophilic yeasts

- diagnosed by scarpings of infected skin

- short unbranched hyphae and spherical cells

- also implicated in SebDerm and Dandruff

2.) Tinea Negra - or tinea negra palmaris

- superficial chronic and asymptomatic

- caused by dermatiaceous fungus Hortaea werneckii

- dark discoloration on palm

- skin scrapings from periphery: branched septate hyphae and budding yeast cells with melaninized cell walls

3.) Piedra - nodular infection of the hair shaft (axillary, pubic, scalp)

- caused by Piedraia hortai (black piedra) and Trichosporon (larger, white piedra)

- endemic in tropical underdeveloped countries

Cutaneous Mycosis

Dermatophytosis - infect only superficial keratinized tissue (skin, hair, nails)

- dermatophytes: Microsporum, Tichophyton, Epidermophyton

- unable to grow at temp of 37, and in presence of serum

- most prevalent, persistent and troublesome but NOT life threatening

- hyaline, septate, branching hyphae, or chains of arthroconidia

- classified as geophilic, zoophilic, antrhopophilic-

- anthro--produce mild and chronic; more difficult to eradicate

- geo, zoo--acute that resolves more quickly

--> Morphology - colonial appearance and after growh of 2 weeks

- T mentagrophytes: cottony to granular

- T rubrum: white, cottony surface and deep red from reverse side

- T tonsurans: flat powdery to velvety colony; reddish brown on reverse

elongated macroconidia attached to supporting hypha

- Microsporum: distinctive multicellular macroconidia with ehinulate walls

- Epidermophyton floccosum (only pathogen): produces only macroconidia which are smooth walled, dlavate, 2-4 cells, in clusters

infects the skin and nails but not hair

--> Epidemiology - begin after trauma and contact

- host susceptibility enhanced by moisture, warmth, sebum+sweat, youth

- conidia can remain viable for long periods (in zoophilic, geophilic)

- in anthropophilic, transmitted by direct contact or through fomites

- Tirchophytin: antigen to detect hypersensitivity to dermatophytic

--> Clinical Presentations

1.) Tinea Pedis - athelte's foot; most prevalent

- chronic infection of toe webs (may be vesicular, hyperkeratotic, etc)

- itching between toes, then dev't of vesicles with fluid

- skin becomes macerated and peels, cracks appear

- pain & pruritus

2.) Tinea Unugium - onychomycosis/nail infections (follows tinea pedis)

- nails becme yellow, brittle, thickend, crumbly

3.) Tinea Corpori - annular lesions of ringworm with clearing scaly center surrounded by red advancing border (dry/vesicular)

- lesions expand centrifugally and active hyphal growth in peripher.

- jock itch/tinea cruris in groin area

- tinea manus in hands or giners

4.) Tinea Capitis - ringworm of scalp or hair

- hyphal invasion of skin/scalp to hair follicle just above root

- dull gray circular patches of alopecia, scaling, and itching

- production of ectothrix- sheath of spores around hair shaft

- in T tonsurans, spores inside the hair shaft: endothrix

- Kerion - combined inflam and hypersenstiivity rxn

- Favus - acute inflamm infection of hair follicle

- formation of scutula around follicle

- tinea barbae - ringworm of beart

5.) Tirchophytid Reaction - hypersensitivity to fungus products which can have allergic manifestations called dermatophytids: vesicles on body

--> Diagnostic Tests

1.) Specimens - gross scrapings

2.) Microscopic Examinations - of scrapings are plated on slides

3.) Culture - for dermatophyte species (mold agad/Sabourad's agar + cycloheximide)

--> Treatment - removal of infected/dead epith and application of topical antifungals

- area should be kept dry, sources of infection should be avoided

1.) Tinea Capitis - oral administraition of griseofulvin/terbinafine

- frequent shampoos and miconazole cream

- ketoconazole/itraconazole

2.) Tinea Corporis, Pedis, etc - itraconazole and terbinafine

- 2-4 weeks of applicaitons have cure rate of 70-100%

- treatment should be continued 1-2 weeks after clearig of lesions

3.) Tinea Unguium - most difficult to treat

- months of oral itraconazole/terinafine + surgical removal

- relapses common

Subcutaneous Mycoses - normally reside on soil or vegatation; enter through trauma

- lesions become granulomatous and expand slowly

- extension via lymphatics is slow except in sporotrichosis

- rarely become systemic and fatal

Sporotrichosis - Sporothrix shenchkii; assoc. with vegetation (grasses, trees, rose bush)

- thermally dimorphic: 35-37 exist as yeast, otherwise mold

- produces chronic granulomatous infxn with secondary spread via lymphatics

--> Morphology - young colonies are blackish and shiny, becoming wrinkled and fuzzy w/age

- branching, septate hyphae and distinctive small conidia clsutered

- at 35temp conversts to small budding yeast cells usually fusiform

--> Antigenic Structure - sporotrichin (carb fractions) elicit postive delayed

- some normal have specific/x-reactive antibodies

--> Pathogenesis - introduced by trauma assoc. w/outdoor activites and plants

- initial lesion on extremities

- about 75% lymphocutaneous: initial lesion granulomatous then becomes

necrotic/ulcerative and draining lymphatics become thickened

- multiple nodules/abscesses along lymphatics

- may be fixed (involving single nonlymphangitic nodule)

- in rare cases, primary pulmonary spirotrichosis (mimics cavitary TB)

--> Diagnostics/

1.) Specimens

2.) Microscopic Examination - Gomori (black walls) or PAS stain (red walls)

3.) Culture - most reliable

4.) Serology - agglutination of yeast cell suspensions (not always diagnostic)

--> Treatment - some are self limited; if not, oral potassium iodide in milk

- oral itraconazole is treatment of choice

- for systemic, amphoterecin B

--> Epidemiology - 75% occur 8in males (x-linked difference in susceptibility)

- higher among horticultural workers; occupational hazard

- prevent inoculation and use fungicides to treat wood

Endemic Mycoses - four primary: coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis

- each geographically restricted to areas of endemicity

- all are caused by thermally dimorphic fungi; most initiated in lungs following inhalation of conidia

Blastomycosis - B dermatitidis causes chronic infection with granulmoatous and suppurative lesions initiated in the lungs, which disseminate to any organ

- preferred sites of spread are bones and skin (endemic to US and Canada)

- thermally dimorphic: at 37 becomes large singly budding yeast cell

--> Morphology - branching hyphae bearing spherical, ovoid, or pyriform conidia on terminal or lateral conidiophores

- in yeast form usually thick walled, multinucleated spherical yeast that has single buds usually attached

--> Antigenic Structure - blastomycin

- low spec and sens on tests

--> Pathogenesis - initiated in lungs; most commonly pulmonary infiltrate (indistinguishable from lower respiratory infection--fever, malaise, cough, myalgias)

- can also present as chronic pneumonia

- histology: distinct pyogranulomatous rxn w/neutrophils (non-caseating)

- skin lesions: ulcerated verrucouse granulomas w/central scarring

- bone, genitalia, CNS lesions also occur

--> Diagnostics

1.) Specimens

2.) Microscopic Examination - broadly attached buds on thick walled yeast cells

3.) Culture - B-dermatitidis specific antigen A

4.) Serology - antigen A; not really useful

--> Treatment - amphotericin B for ystemic; 6-month itraconazole if confined

Opportunistic Mycoses - normal immune system is resistant (immunocompromised)

- susceptibility inversely correlated with CD4 lymphocyte count

Candidiasis - members of normal flora of skin, GI tract, mucous membranes

- most commonly C albicans, C tropicalis, C parapsilosis

- azole resistant species C krusei, C lusitaniae

--> Morphology - oval budding yeast cells

- also form pseudohyphae when buds grow but fail to detach

**long elongated cells that are pinched/constricted at septations

- produce soft cream colored colonies w/yeast ordor

- unlike other spec, C albicans produces true hyphae or germ tubes in nutritional media (serum for 90 min at 37temp)

- in deficient media, albicans produce large spherical chlamydospores

- C glabarata produces only yeast cells and no pseudohyphae

--> Antigenic Structure - two serotypes A and B

- other antigens include proteases, enolase, HSP

--> Pathogenesis - increased in local census and damge to skin permits local invasion

- systemic when Candida enters lboodstream and defenses inadequate

- can infect kidneys, attach to prosthetic heart valves, or infection anywhere

- varying inflammatory actions

- abundant budding yeast cells and pseudohyphae

- inc in # in intestine following administration of oral antibiotics

--> Cliniccal Findings

1.) Cutaneous&Mucosal - Aids, pregancy, diabets, OCP, trauma

- thrush on the tongue, lips, gums, or palate

- patchy whitish pseudomembranous (yeast+pseudohyphae+epithel)

- invasion of vag mucosa = vulvovaginitis (irritation, pruritus, discharge)

- contaneous candidiasis/onychomycosis (resembling paronychia)

2.) Systemic - indwelling catheters, surgery, aspiration, damage to skin/Gi tract

- normally eliminated by host defenses and candidemia is transient

- immunocompromised, develop everywhere especially kidney, skin, eye, heart, meninges

- most often assoc with chronic admin. of immunosuppresives (steroids)

- Candidal endocarditis with deposition of yeasts on prosthetic valves/veget

- Kidney infxns are systemic; UTI assoc. with foley caths, DM, pregnancy

3.) Chronic Mucocutaenous - rare; childhood onset

- assoc. w/cellular immunodef. and endocirnopathies

- disfiguring infxns on any or all areas of skin/mucosa

--> Diagnostics: Specimen, Microsocop , Culture, Serology

--> Immunity - basis incompletely understood; related to cell-mediated (CD4) responses

--> Treatment - Thrush: topical nystatin or oral ketoconazole/fluconazole

- Systemic: amphotericin B w/oral flucytosine

- clearing of lesions accelerated by eliminating moisture/antibacterials

--> Epidemiology - avoid disturbance of normal flora; not communicable

Aspergillosis - spectrum of disease caused by whole species

- A fumigatus most common human pathogen

- mold produces abundant small conidia that are easily aerosolized

- severe allergic rxns after inhalation

- may produce hyphae that invaide lungs in immunocompromised

--> Morphology - aerial hyphae that bear conidiophores with terminal vesicles on which phialides produce basipetal chains of conidia

--> Pathogenesis - alveolar macrophages normally able to destroy

- in immunocom. conidia swell and germinate and produce hyphae

- invade preexisting cavities (aspergilloma or fungus ball) and BVs

--> Clinical Presentations

1.) Allergic Forms - IgE antibodies elicit asthmatic reaction

- hyphae may also colonize bronchial tree and not lung parenchyma called allergic bronchopulmonary apergillosis

- normal host exposed to massive doses of conidia=extrinsic allergic alveolitis

2.) Aspergilloma - conidia enter existing cavity, germinate, produce hyphae in abnormal pulmonary space==Mass (previous cavitary disease)

- some are asymp. while some develop cough, dyspnea, hemoptysis

- rarely become invasive; noninvasive may involve nasal sinus, ear cornea, nails

3.) Invasive Aspergillosis - hyphae invade lumen and wall of BVs causing thrombosis, infaction, necrosis

- may spread to GI tract, kidney, brain producing abscess and necrotic lesions

- predisposed in immunocomp. (CD4<50cells/mm3)

--> Diagnostics - sputum culture and lung biopsies

- 80% precipitin serology

--> Treatment - itraconazole or amphotericin B and surgery

- often supplemented w/cytokine immunotherapy

Mycotoxins - poisonous substances can cause acute/chronic intoxication and damage

- seconadry metabolites, effects not dependent of fungal infxn

- variety produced by mushrooms: causes mycetismus

- aspergillus flavus produces aflatoxin w/c is a frequent contaminant of other food

Antifungal Chemotherapy - limited but increasing numbers

1.) Polyenes - bind ergosterol in fungal cell membrane

Amphotericin B - most effective for sever systemic mycoses

- formation os complex with ergosterol (membrane damage)

- low affinity with cholesterol (in mammalian membrane)

- packaging in liposomes and lipoidal emulsions (diminish adverse rxn)

2.) Antimetabolite - distrubing synth of pyrimidines and RNA

Flucytosine - oral antifungal; used in conj with amphotericin B

- converted by fungal enzyme to 5-florouracil w/c interferes with DNa synthesis (enzyme=cytosine deaminase not

present in mammals)

- side effects are bone marrow suppression, hair loss, abnormal liver fxn

3.) Azoles - inhibit ergosterol synthesis (fungistatic drugs)

- Ketoconazole, Itraconazole, Fluconazole, Voriconazole, Posaconazole

- block cyt. p-450 dependent 14alpha demethylation of lanosterol

- ketoconazole most toxic - may inhibit synth of testosterone and cortisol

4.) Allylamine -also inhibit ergosterol synthesis

Terbinafine - inhibits squalene epoxidase

- given orally agains dermatophyte infctions

5.) Echinocandins - perturb B-glucan synthase, stop cell wall synthesis

- inhibit 1,3-B-glucan synthase

- Caspofungin (IV), Micafungin, Adnidulafungin

6.) Griseofulvin - interferes w/microtubule assembly

- orally administerd antibiotic derived from penicillium

- poorly absorbed and concentrated in stratum corneum

- disruption of microtubule fxn, inhibit growth

- only actively dividing hyphae are affected

- side effect headache

Topical Antifungal Agents

1.) Nystatin - polyene antibiotic (like amphotericin B)

- treat local candidal infxns of mouth and vagina

- no systemic absorption and no side effects

- toxic for parenteral administration

2.) Cotrimazole, etc.- too toxic

- broad spectrum of activity

3.) Others - tolnaftate, naftifine, etc.