Fungal Disease and Antifungal Agents (8/9)

Liu (Lecture 25)

what makes fungi infectious agents?

molds, yeasts: distributed in air, dust, fomites, normal flora

mushrooms, toadstools, puffballs

fungi are relatively ____ and humans are relatively ____

fungi are the most common ____

nonpathogenic; resistant

most common plant pathogens

human mycoses are caused by

true pathogens and opportunistics pathogens

molds grow in the form of…

hyphae or mycelium: branched filaments

true hyphae are divided into individual cells by septa — pseudohyphae have incomplete septa allowing exchange of nuclei and cytoplasm along hyphae

dimorphic growth

fungi show this term in hyphae state when in natural environment and in yeast state when in humans or animals

SEQ the dimorphic fungal cycle

1. fungal spores from environment gain entrance to warm blood animal: germinate into yeasts (remain in this phase)

   1. increased temperature, reduced O2, suboptimal nutrients

2. Yeast cells leave animal host, return to environment: revert to sporulating hyphal state

   1. decreased temperature, optimal O2 content, improved nutrients

What are mycoses?

Mycoses are fungal infections; dermatophytes and Candida naturally live on the human body and are transmissible without needing a host to complete their life cycle.

What are the most common types of fungal infections and how are they classified?

Dermatophytoses are the most prevalent fungal infections, many of which go undiagnosed, and they are classified as cutaneous, subcutaneous, systemic, or superficial.

How does the immune system defend against fungal infections? and how are fungi diagnosed?

Immunity relies on nonspecific barriers, inflammation, and cell-mediated defenses;

diagnosis requires microscopic examination, specialized culture media, and biochemical/serological tests.

What drugs are used to control fungal infections?

Antifungal control includes amphotericin B, azoles (imidazoles & triazoles), allylamines, griseofulvin, nystatin, flucytosine, and echinocandins.

Describe how deep superficial, cutaneous and subcutaneous is

superficial: epidermis

cutaneous: middle of dermis tissue

subcutaneous: the entirety of subcutneous tissue

what are cutaneous mycoses and what organisms cause them?

Cutaneous mycoses — dermatophytoses such as ringworm and tinea): infections of keratinized tissues

caused by 39 species in the genera Trichophyton, Microsporum, and Epidermophyton.

How are cutaneous mycoses transmitted and treated?

They are communicable among humans, animals, and soil—especially in moist, chafed skin—and are treated with griseofulvin, azoles (imidazoles & triazoles), and allylamines.

what is the mechanism of action for griseofulvin

causes disruption of mitotic spindle by binding to microtubules resulting in formation of multinucleate cells

what is the moa of fungistatic?

griseofulvin and other static agents (azoles) accumulate in keratin precursor cells and persists in them as they differentiate making their keratin resistant to fungal growth

How do azoles and allylamines differ in their mechanism of action against fungi?

imidazoles and triazoles AND allylamines: inhibit ergosterol biosynthesis

• Azoles block 14-α-demethylase, prevent conversion of lanosterol → ergosterol > disrupts fungal cell membrane synthesis.

• Allylamines (e.g., terbinafine) block squalene epoxidase, stopping squalene → squalene epoxide, an earlier step in ergosterol synthesis > toxic squalene accumulation and prevents ergosterol formation.

What are key features of Candida and Candida albicans? (candiasis)

Candida are widespread dimorphic yeasts; C. albicans is the most common species and can cause infections that can be shortlived, superficial skin irritation to overwhelming fatal systemic diseases

What are important morphological and cultural characteristics of Candida?

Candida forms budding yeast cells that may produce pseudohyphae and true hyphae, and grows as off-white, pasty colonies with a yeast-like odor.

where is candida present?

normal flora of oral cavity, genitalia, large intestine or skin

account for majority of nosocomial fungal infections, partial death toll

what conditions can candida cause?

oral candidiasis

vaginitis

cutaneous candidiasis: in chronically moist areas of skin and burn patients

What is one agent used to treat candidiasis

nystatin: poylene that binds to ergosterol (same as ampho B)

• topical treatment forskin and mucous membranes since its usually toxic

• NOT useful for SC or systemic fungal infections or ringworm

what is oral candidiasis?

thrush, thick white adherent growth on mucous membranes of mouth and throat

what is vaginitis? what are some treatments?

inflammation of female genital region

yellow milky discharge

Topical treatment: imidazole and triazole vaginal tablets, creams, lotions, powders

Systemic treatment: orally absorbed triazoles/imidazoles

What is candida auris? who are affected?

multi-drug resistant fungus (superbug) that can be spread in hospitals

infects pts with pre existing conditions who are already in hospitals/nursing home

vulnerable pts: diabetes or blood cancer

What are some symptoms of candida auris? is it deadly?

fever, chills that do not dissipate with treatment

can cause blood streatm or heart infections

high fatality rate

what causes systemic mycoses (endemic mycoses)?

histoplasma capsulatum

coccidioides immitis

blastomyces dermatitidis

cryptococcus neoformans

caused by opportunistic pathogens: Aspergillus

what is histoplasma capsulatum? where does it multiply? how is it spread?

causes histoplasmosis, typically dimorphic

grows in moist soil high in nitrogen

inhaled conidia produces primary pulmonary infection > progress to organs and chronic lung disease

how is histoplasmosis treated?

amphotericin B: polyene that binds ergosterol and disrupts cell membrane

• fungicidal, toxic

What is Darling’s disease? what happened before it was discovered?

aka histoplasmosis, ohio valley fever

beforehand, pts were misdiagnosed at tuberculosis patients

what is coccidioides immitis? describes its morphology

causes coccidioidomycosis

morphology: blocklike arthroconidia in free living stage and spherules containing endospores

where does coccidioides immitis live? how is coccidiodidomycosis spread?

lives in alkaline soils in semirid, hot climates

endemic to southwest US

arthrospores inhaled from dust that creates spherules and nodules in the lungs

how is coccidioidomycosis treated?

amphotericin B c

what are other names for coccidioidomycosis?

valley fever, san joaquin valley fever, california valley fever, desert fever

what is blastomyces dermatitidis? where does it come from and how is it spread?

causes blastomycosis, dimorphic

freee living species distributed in soil of midwest/southeast US

inhalted 10-100 conidia convert to yeats and multiply in lungs

what are some symptoms, complications and treatments for blastomycosis?

symtoms: cough and gever

complications: chronic cutaneous bone and NS

treatment: amphotericin B

what is blastomyces dermatitidis also known as?

gilchrist’s disease or chicago disease

what is cryptococcosis? what are some symptoms? what are severe complications?

caused by cryptococcus neoformans

encapsulated yeast that inhabits soils around pigeon roots

symptoms: cough, fever and lung nodules

dissemination to meninges, brain > severe neurological damange and death (cryptococcal meningitis)

what type of pt is cryptococcosis a common infection in

AIDS, cancer, or diabetes patients

rare in functioning immune systems > opportunisitc fungus

how do you treat cryptococcosis

amphotericin B

what is flucytosine?

5-FC is primarily used in combo with other antifungals (amphotericin B) to treat serious, life-threatening systemic fungal infection

what is the MOA of 5-FC?

MOA: enter sensitive fungal cell via specific enzyme calle dcytosine permease, not presen in mammalian cells

• cytosine deaminase converts 5-FC to 5-FU

• 5-FU interferes with synthesis of fungal DNA and RNA

what is the state of fungal vaccines today?

no fungal vaccines have been approved for humans or animals so far

breakthrough example: live attenuated strain of blastomyces dermatitidis — produced by locating gene that codes for adhesive surface and eliminating it

what is aspergillus? how is it spread?

common airborne soil fungus

do not cause infection in humans except in pts with specific risk factors (diabetes, leukemia, lymphoma, immunosuppressed)

spread: inhalation of spores causes fungus balls in lungs and invasive disease in the eyes, heart and brain

fungemia may be due to

Aspergillus (pts with risk factors)

How can you treat aspergillus?

invasive pulmonary aspergillosis (fatal): amphotericin B or azoles

resistant to amphotericin B: echinocandins (caspofungin)

what are echinocandins? moa?

antifungal agent (such as caspofungin): large cycle peptides linked to long fatty acid

moa: block synthesis of polysaccharide component of cell wall in some fungi > inhibit glucan synthesis of cell wall

Echinocandins are ___ against most species of ___

fungicidal; candida

what are achinocandins used for?

2nd line treatment for aspergillosis that is resistant to amphotericin B or azoles

has no activity against cryptococcus, minimally active against Blastomyces and histoplasma

what is aflatoxin? why are they necessary?

aspergillus toxin, very potent hepatoxin and liver carcinogen

product of aspergillus flavus and aspergillus paraciticus growing on grains, corn and peanunts

necessary for constant monitoring of peanuts, grains, nut, vegetables oils, animal feed and milk

fungal meningitis outbreak in 2012

also includes paraspinal/spinal infection, stroke, peripheral joint infection

outbreak was linked to steroid shots for back pain (epidural or para spinal injection)

fatalities: 100 ppl

illness: 793

what were the suspected contaminated lots in the fungal meningitis outbreak? how do you treat this fungal infeciton?

presence of exserohilum rostratum, aspegillus fumigatus, Cladosporium

treatment: voriconazole (triazole)

what is exserohilum?

common mold found in soil, on plants likes grass, and thrives in warm and humid climates

plant pathogen

rarely causes infections in people, usually sinusitis and skin infections

What is Cladosporium

most common indoor and outdoor molds

rarely pathogenic in humans

what are 3 types of superficial mycoses?

discoloration/disfiguration of the skin

tinea versicolor: mild scaling, mottling of skin

white piedra: whitsh or colored masses on long hairs of the body

black piedra: dark, hard concretions on scalp hairs

what are fungal allergies?

most important: seasonal asthma, chronic respiratory conditions that occur after exposure to airbone mold spores

Farmer’s lung, teapicker’s lung, barkstrippers disease

What can cause sick building syndrome?

inhalation of toxins from building heavily contaminated black molds such as stachybotrys chartarum (requires high moisture to grow)

T/F: it is alway possible to link outbreak to a specific fungus or toxin

false