liu 7- fungal disease + antifungal agents

what are examples of fungi?

which are distributed widely in the air, dust, fomites (inatimate objects), and normal flora?

are humans incredibley susceptible?

1. mold

2. yeast

3. mushrooms

4. toadstools

5. puffballs

mold and yeast widely distributed!

humans are actually relatively resistant

Fungi as Infectious Agents:

• are fungi primarily pathogenic/ nonpathogenic?

• of the 100,000 fungal species, how many habe been linked to disease in humans and animals?

• fungi are the most common ______ pathogen

• human mycoses (fungal diseases) are caused by _______ pathogens and ______ pathogens

primarily NONpathogenic

• only 300 are actually infectious

most common PLANT pathogen

human mycoses caused by true and oppurtunistic pathogens

Molds grow in the form of branched filaents known as _______ or _______

branches = mycelium or hyphae

True hyphae (mold branahes) are divided into individual cells by _______.

Psuedophae have incomplete ______ allowing exchange of nuclei and cytoplasm along the hyphae.

Many pathogenic fungi show ______ growth: hyphae state when in natural environemnet and ______ state when in humans or animals

• septa

• psuedophae have incomplete septa - allow exchange of nuclei and cytoplasm along hyphae

• pathogenic= dimorphic growth

• dimorphic growth happens to hyphae (mold) in environment

• dimorphic growth happens to yeast INSIDE humans or animals

in stressful enviornemnts

• increased temperaure (35-40 C)

• reduced O2

• suboptimal nutrients

fungal ______ form in the environment gain entrance into a _______ animal where they germinate into _______ and remain in this phase in the host

ENDOSPORES enter warmblooded animals where they generate into yeast

in stressful environments

in optimal environement

• decreased temperature (less than 30 C)

• optimal O2 content

• imporved nutrients

_____ leave the animal host and return to the environment and revert to __________ state.

Can these converstions be demonstrated on artificial media in the labratories?

yeast leave animal host revert to sporulating hyphae state

YES converstions can be demonstrated on artificial media

Natural Habitat of Fungus:

• ______ (free-living)

• _______ phase

• temperate ________

• reproduction through _________

Animal Habitat of Fungus:

• _______ phase

• temperature _______

• reproduction through ___________

naturally

• saprobic (free living)

• mycelial phase (branched hyphae)

• temperate less than 30 C

• reproduction through SPORULATION

animal habitat:

• yeast phase

• heat 35-40

• reproduction through BUDDING or ENDOSPORES

Mycoses:

• do most fungal pathogens require a host to complete their life cycles?

_______ and ________: naturally inhabit human body and are trasnmissible

_______ are the most prevelant (most cases mis or undiagnosed)

• cutaneous, subcutaneous, systemic, or superficial infections

• NO fungal pathogen dont require host!

dermatophytes and candida

• dermatophytes most prevalent

immunity to fungal infections consist of ______ ______, ______, and ____ ______ defensces

diagnosis and identification require microscopic examination of ______ specimens, _______ in selective and enriched _______ and __________ tests

• nonspecific barriers

• inflammation

• cell mediated

• microspic evaluation of STAINED specimens, cultured in selective and enriched BIOCHEMICAL and SEROLOGICAL tests

which drugs are involved in the control of fungal infections by working as

• nonspecific barriers

• against inflamation

• cell mediated defences

1. amphotericin B

2. -azoles

3. allylaines

4. griseofulvin

5. nyastatin

6. flucytosine

7. echinocandins

what are the layers of tissues from superficial —> cutaneous→ subcutaneous?

1. epidermis

2. stratum corneum

3. dermis

4. subcutaneous

infections strictly confined to keretinized epidermis (skin, hair, nails) are called ___________

what are some examples?

what are the 3 species in the genera that are responsible?

dermatophytoses

ex. ring worm and tinea

3 species responsible:

1. trichophytom

2. microsporum

3. epiidermophyton

Dermaphotysos (keratinized epidermal infection):

communicable among _____, _____ , and ______

infection facillitated by _______ and ____ skin

_______ of the nails is a persistent colinization of the nails of the hands and feet that disorts the nail bed (tinea pedis and unguium)

communicable among humans, animals, and SOIL

moist and chafed skin allow infection to pread

ringworms

Which drugs can be used to treat dermatophytoses (keratinized epidermal infection)?

1. griseofulvin

2. -azoles

3. alllylamines

which antigungal works by:

causing disruption of mitotic spindle by binding to to microtubules resulting in formation of multicucleate cells

griseofulvin

Fungiiostatic agents such as _______ and ________ accumulate in _______ precursor cells and perists in them as they differentiate making their _______ ressitant to fungal growth

grisofulvin and -azoles accumulate in keratin precursor cells —- make keratin resistant to fungal growth

which antigungal works by:

inhibitng ergosterol biosynthesis

azoles (fungistatic) and allylamines (fungiCIDAL)

work at different points of synthesis

allylamine (cidal) works in earlier step

MOA of azoles (fungazole, ketoconazole, itraconazole)

• blocks __________ which converts _____ to _____________ (next step would have been ergosterol synthesis)

prevents lansosterol —> 14-de methyl lansosterol by blocking a-C-14 demethylase

MOA of allylamines (naftidine + terbinafine- lamasil):

• blocks ________ which converts ______ to ________ leading to buildup of _____ which is toxic and leads to fungal death

block squalene epoxidase which converts

squalene—> squalene oxide

lead to buildup of squalene which is toxic to fungus

Candidiasis:

• candida are widespread _____ ________

• what is the most common?

infections can be ____-lived, _____ skin irritations to overwhelming, ______ _____ diseases

budding cells of varying size may form both _______ _________ and ______ _______

forms off-white _______ colony with a _____odor

dimorphic yeast

candida albicans

shortlived and superficial —> fatal systemic (wide range)

can form both true hyphae and elongate psuedophyphae

form pasty white colony with YEAST odor

Candidiasis:

• present in normal flora of which 4 places for 20% of humans?

• accounts for 80% of _____ fungal infections (30% of deaths)

• Candida cause _____ candidiasis

• _______ is commonly caused by candida

• candida cause _______ candidiasis (occurs in chronically ____ areas of skin and burn patients)

• skin, intestines, oral cavity, genetalia

• nosocomial (most hospital fungal infections caused by candiasis)

• ORAL

• vaginitis

• cutaneous - moist areas of skin and burn patients

_______ ( ) used to treat candidiasis

• structurally a _______

• binds to _________ like ________

bc/ it is toxic it is used to treat only _______ candiasis of the ______ and _______( )

NOT useful for ______ or ______ fungal infections

can it be used for ring worm?

Nystatin (mycostatin)

• polyene

• bind to ergosterol like amphotericin B

Only treat topically! skin and mucosal (oral thrush)

NOT used for subcutaneous or systemic

NOT used for ring worm

____ _____ ( ) appears as a thick white adherant growhth on the mucous membranes of mouth and throat

oral candidiasis (thrush)

Vaginitis ( _____ infection):

• painful ________ condition

• characterized by ____ _____ discharge

what are some predisposing factors?

is it easy to treat?

what has been used to treat?

yeast:

inflammatory

yellow milky

diabetes, pregnancy, antibiotics, use of contraceptives

NOT easy to treat

treatment:

• topicals = imidazoles and triazoles (powder, cream, lotion, tablet)

• systemic = oral imidazole/ triazole

candida auris:

• first isolated in _____ in 2009 — >US in 2013

• conidered _____ ______ ______ ( ) !

• spread in ______

• which patients are typically infected?

• first japan

multidrug-resistant fungus (superbug)

spread in hosptials

• typically patinets with pre-existing conditions already in hospitals, diabetes, or blood cancer

Candida Auris:

• symptoms of illness vary

• most notable are _______ and _____ (do these go away with treatment?) —- can cause ______ or ______ infections

• is this disease mild or life-threatening?

chills and fever (dont go away with treatment)

• can cause heart or bloodstream infections

FATAL: 1 in 3 people die

which states have highest cases of deadly candida aureas?

several cases were resistant TO ALL DRUGS in _______

new york

new jersey

illinois

high resistance in texas

systemic mycoses - ENDEMIC mycoses

caused by:

1. hisoplasma capsulatum

2. coccidioidies immitities

3. blastomyces dermatitis

Histoplasma Capsulatum (systemic mycoses):

• cause histoplasmosis

• typically ________

• grow in _____ _______ high in ____ content

• ______ conida produce primary ______ infection that can progress to systemic involvement of a variety of organs and chronic _____ disease

How can it be treated? Is treatment fungicidal or fungistatic

• dimorphic

• grow in moist soil high in nnitrogen content

• inhaled can lead to primary respiratory infection —> systemic —> chronic lung diseased

• Amphoterecin B (polyene)- bind to ergesterol and disruptsthe membrane- fungCIDAL

Hisplasma Capsulatum is also known as _______ _______ and ______ ______ _______

discovered in 1905 by _______ but only discovered to be widespread in 1930

before them many causes of histoplasmosis were mistakenly attributued to ________ and patients were mistakenly admitted to ________ sanatoriums

some patients actually CONTRACTED ______ in these sanatoriums !

Darlings Disease or Ohio Valley Fever

discsovered by Darling to be widespread

before people just throught it was tuberculosis and peopkle would be sent to tuberculosis sanatoriums where they wpuld actually GET tuberculosis

Spread of Histoplasma Capsulatum:

1. _____ containing bird droppings whipped by wind

2. ________ contracted via _______

3. patient develops mild _______ which might reoccur

4. in the tissue phase of infection, ______ phase develops, is phagocytosed and multiplies by budding INSIDE phagocyte (at this point patients still able to recover without complications)

5. in some cases phagocytes enter the ________ and cause _____ _____ in a number of organs

1. SOIL

2. microcondia contracted via INHALATION

3. mild pnueomonitis

4. yeast phase develops—> phagocyte eat-> STILL spreads inside phagocyte

5. phagocytes enter blood —> disseminated disease

Coccidioides Immitiis (Coccidiodomycosis):

• distinct morphology: ______like arthoconidia in the free living stage and _______ containing _______ in the LUNGS

• wheere do they live?

• arthrospores are _______ from dust, creates _____ and _____ in the lungs

• what can be used to treat?

blocklike arthconida - naturally

spherical containng endospores in host

alkaline soils, semiarid, hot climates

arthospores INHALED creating sphericle endospores and nodules

USE AMPHOTERECIN B to treat

what can be used to treat Coccidioides Immitis

also called

• Valley Fever

• Desert Fever

• San Joaquin Valley Fever

amphoterecin B

Cocccidiodes Immitis Infection Cycle:

1. _____ in _______ produces aerosol of arthospores

2. _____ arthospores lead to infection in _____

3. arthospores develop into ______ that produce _______ which are released into _____

4. compromised people can develop _______, _______, and skin _______

1. digging in dirt —> arthospores in air

2. inhaled arthospores —> infection in lung

3. arthospore develop —> spherules —> release endospores into lung

4. osteomylitis, meningitis, and skin granulomas

Coccidiodies immitis can present as _____ on _______

abcess on chest

Blastomyces Dermatitidis (Blastomycosis):

• _________

• free-living species live in _______

• ______ 10-100 conida convert to _____ in _________

• symtoms include ____ and _______—→ chronic _______, ____ and ______ system complications

• which drug can be used as treatment?

• dimorphic

• soil

• inhaled —> yeast in lungs

• fever and cough—> chronic cutaneous, bone, and nervous system

• Amphoterecin B

Blastomyces dermatidis was first discovered by Thomas Casper Gilchrist and can also be called ________ disease and also _______ disease

GilChrist didsease or Chicago Disease

how is Blastomyces Dermatita / Chicago Disease / Gilchrist’s Disease treated?

amphoterecin B

Cryptocococcus Neoformans (cryptococosis)

• ______ mycoses

• encapsulated ______ that inhabits _____ around pigeon roosts

• infection of ____ leads to fever, cough, ____ nodules

• common infection of ______, ______, or _____ patients

• why is it considered an oppurtunistic fungus?

systemic

yeast soil

lungs —> lung nodules

common in diabetes, AIDS, and cancer

considered oppurtunistic because doesnt have impact on healthy immune system

systemic mycosis (crytococcosis)

• disssemination to ______ and ______ can cause severe ______ disturbances —> DEATH

• ccrytococcus -__ is the leading cause of crypotococcal ______ which kills 180,000 people worldwide

• how can it be treated?

dissemination to brain and meninges —> neurological distrubrances—> DEATH

• neoformans —> crytococcal MENINGITIS

amphoterecin B

how can crytococcus neoformans be treated?

amphoterecin B

Flucytosin (5-flurocytosine (5-FC)):

• used in combination with _______ like ________ to treat serious life- threatening SYSTEMIC fungal infections

MOA:

• which enzyme helps it enter fungal cells?

• flucytosine is a prodrug, which enzyme activates it?

• what does this activated form of flucytosin do?

used in combo with antifungals such as amphoterecin B to treat SYSTEMIC fungal infections

• Enter using cytosine permease

• cytosine deaminase (flucytosine—> 5-flurorouracil - 5FU)

• 5-flurouracil intefere w/ synthsis of fungal DNA and RNA

has there been any vaccinations made for fungal infections?

no but they are working on it

so far have tried blastomyces dermatidis

sequenced fungal genome —> protective mechanism through elimination of adhesion surface

can be used in vets for pets!

a vaccine against which fungus is currently being worked on in rutgers newark medical school?

crytococcus neoformans

Aspergillus (systemic mycosis):

• very common ___ _____ fungus

• 600 species,only ___ have involved into human disease

• which populaiton is most infected? For this reason aspergillus is considered a _____ infection

airborne soil

8

diabetes, AIDS, cancer (leukemia, lymphoma) so considered oppurtunistic infection

inhalation of Aspergillus spores causes _____ ____ in the lungs and invase disease in the ____ , ___ ,and _______

• what can be used to treat aspergillus?

• what if that treatment is resistant?

spores cause fungus balls in lungs —> eyes, heart, brain

• amphotericin B or azoles

• if resistant use echinocandins (caspofungin)

what are the systemic mycoses?

which are considered opurtunistic?

Aspergillus (oppurtunistic)

Crytococcus Neoformans (oppurtunistic )

Echinocandins (caspofungins):

• newest class of antifungals

• large _______ ______ linked to a long _____ _______

• block the synthesis of _______ which is used to make the fungal ________

• are echinocandins fungiCIDAL or STATIC? against which species?

large cyclic peptide linked to fatty acid chain

block synthesis of polyascharide which is used to make 60% of fungal cell wall

CIDAL- cannot make fungus w/o glucan for cell wall

against candida

Echinocandins are fungicidal against most species of _______ (how does it compare to amphoterecin and azoles against yeast)?

Can it be used to treat Aspergillous?

What about Cryptococcus?

What about Balstomyces and Histpoplasma?

fungicidal against CANDIDA

more/same effectiveness as amphoterecin B and azole against yeast

second line for aspergillous if resistant to amphoterecin B and azole

cryptococcus CANNOT BE TREATED BY ECHINOCANDIDS

treats blastomyces and histoplasma minimally

Aspergillus ToxTI

Porduct of Aspergillus ______ and ________ growing on grains, corns, and peanuts

MAKE SURE TO MONITOR

• peanut

• grain

• nuts

• vegentable oils

• feed

• milk

aflatoxin is lung carcinogenic

• product of aspergillus FLAVUS and PARACITICUS

Fungal meningitis:

• _____/______ , stroke, _____ ___ infection

• linked to ___ shots for back pain (epidural or paraspinal injection)

• largest public health crisis ever caused by a contaminated drug

• which 3 fungal species were found in vials?

paraspinal/spinal peripheral joint infection

linked to steroid shots

• exserhilum rostratum

• aspergillus fungiatus

• cladosporium

Exserohilium (one of the fungi found in vials of steroid shots causing fungal meningitis) is a common mold found in ______ especially _______ and thrives in _____ and ____ climates

mainly a _____ pathogen

rarely causes infections for people, which present as _____ and ________

found in soil and plants especially grass

• humid and hot climates

mainly plant pathogen

• in humans —> sinusitis and skin infections

__________ found in vials of steroids causing fungal meningitis include the most common indoor and outdoor molds

are they usually pathogenic to humans?

Cladosporium

usually NOT pathogenic to humans

which treatment was used for the fungal meninigis outbreak caused by steroid shot?

which fungi were found in humans who had developed the meningitis?

voriconazole (triazole)

• aspergillus fumigatus

• exserohilum

• cladosporium

Superficial Mycoses:

• cause _____or disfiguration of the skin

• ______ _______ causes mild scaling, mottling of the skin

• ____ _____ is whitish or colored masses on the long hairs of the body

• _____ ______ causes dark hard concretions on scalp hairs

• discoloration

tinea versicolor - scaling+ molting

white piedra- long hair

black pierdra - scalp

what are examples of fungal allergies that occur after exposure to airborne mold spores?

named for the type of worker most likely afflicted

farmers lung

teapickers lung

barkstrippers disease

_____ _____ syndrome can be due to toxins (and spores) from building heavily contaminated by certain “black molds”

most notable cause: ______ ________

what allows this mold to grow?

sick building syndrome

most notably caused by stachybotyrs chartarum

moisture allows to grow

true/false: its always possivle to link an outbreak to a speicific fungus or toxin

whats an example?

NOT always possible

ex. sick building syndrome can be caused by other things other than stachybotyrs chartaryum