Fungal Structure, Diagnosis, Therapeutics Flashcards
pathenogenic funcal phyla
Ascomycetes
Zygomycetes
Blasidiomycetes
differences between fungi and bacteria
size (bigger)
mode of reproductin
multicellula rstructures
cell structures have nucleus, mitochondria, ER, cell wall (chitin vs. murein) and polysaccharides
fungal disease pathogenesis
adherence to tissues
invasion of tissues
local tissue destruction by pathogen/inflammatory response
allergic/hypersensitivity responses due to immunogenic cell wall
polyenes
membrane disruption, binds directly to ergosterol in cell membrane, permitting loss of electrostatic potential through electrolyte leakage
azoles
sterol synthesis inhibitor
inhibits fungal cytochrome p450 enzymes to interrupt proper sterol synthesis
results in depletion of necessary membrane substrates and accumulation of toxic intermediates
p450 inhibitor
allylamines
sterol syntehsis inhibitor
inhibits squalene epoxidase, earlier step in sterol synthesis
flucytosine
DNA syntehsis inhibition
a pyrimidine analog, transported by a fungal-specific permease
incorporated into RNA and DNA
echinocandins
glucan synthesis inhibition
impair beta-1,3, glucan production, impairing cell wall stress tolerance
griseofulvin
microtubule assembly inhibition
forms a complex with keratin-producing cells resulting in site-specific anti-fungal properties
binds tubulin in fungal cells, impairing mitosis
also an inducer of p450, therefore can have off-target effects
mechanisms of action of antifungal agents
membrane disruption
ergosterol synthesis
nucleic acid synthesis
glucan synthesis
microtubules
classifications of fungal diseases based on site of infection
superifical
cutaneous
subcutaneous
systemic
opportunistic
superficial mycosis
mostly caused by members of the Malassezia genus
Clinical Disease
- chronic in nature, involves the stratum corneum
- hypo and hyper-pigmented regions of skin, generally without inflammation, creating cosmetic disorders
- pityriasis versicolor
Diagnosis
- skin scrapings with KOH
- fluorescence under Wood’s lamp
- topical treatments, azoles
cutaneous mycoses
most common fungal disease in humans
caused by Trichophyton spp, Microsporum spp., and Epidermophyton floccosum
Clinical Disease
- invades superficial keratinized tissue (skin, hair, nails)
- transmitted by direct contact
- characterized by inflammation of infected tissue with occasional distant manifestations
- representative infections are the tinea family, infections may cause systemic infection n the immuno-compromised host, and often spread within group settings
Diagnosis
- fluorescence with Wood’s lamp
- microscopically in 10% H2O2
- fungal culture after 1-3 weeks
- treat with cleaning, dry conditions
- use azole creams or systemics
subcutaneous mycoses
caused by Sporothrix schenkii
Clinical Disease
- fungi reside in soil and plants
- introduction during penetrating injury
- granulomatous
- sporotrichosis - spreads along cutaneous lymphatics
Diagnosis
- serologic or DTH testing
- imaged using fungal wall stains
- itraconazole or Amphotericin B are useful
endemic (systemic) mycoses
organisms are generally found in nitrogen-rich soil fertilized by bird droppings
disease acquired by inhalation of spores, usually asymptomatic and self-limiting
in some cases, dissemination of infection can occur to other organs
generally, suspected diagnosis may be confirmed with skin testing, serology, or direct vusalization of cultures
major diseases:
coccidioidomycosis
histoplasmosis
blastomycosis
paracoccidiomycosis
coccidioidomycosis
caused by Coccidioides immitis
Clinical Disease
- endemic in southern US and Latin America
- produces pulmonary infection, generally asymptomatic
- some 40% will develop influenza-like symptoms, and 15% will develop hypersensitivity reactions with rash and adenopathy
- severe pulmonary infection and systemic dissemination
- virulence factors are extracellular proteases
- treatment with itraconazole or amphotericin
histoplasmosis
Histoplasma capsulatum
Clinical Disease
- Ohio and Mississippi River Valleys
- primary pulmonary infection
- replication in alveolar macrophages
- high doses can result in pulmonary disease
- TB-like lesions
- immunosuppressed are at risk for serious disseminated infection
- bone marrow and lymphoid tissue can be effected
- virulence factor - alpha-1,3 glucan
- treatment with itraconazole or amphotericin B
blastomycosis
caused by Blastomyces dermatitidis
Clinical Disease
- found in Midwest and Eastern North America, widespread in Asia, Africa, South America
- similar to histo, but not in macrophages
- pneumonia - fungus ball
- dissemination to the skin, resulting in ulcerated granulomatous lesions
- other sites are CNS, gonads, and bone
- virulence factors - beta-glucan, alpha-1,3 glucan, WI-1
- treatment are azoles and Amphotericin B
paracoccidioidomycosis
caused by Paracoccidioides brasiliensis
Clinical Disease
- South American blastomycosis
- strong male predominance
- estrogens protective
- long dormancy with reactivation
- pulmonary, chronic cutaneous ulcers
- virulence - alpha-1,3 glucan, estrogen binding protein
- treatment azoles and amphotericin B
opportunistic mycoses
marginal pathogenicity
generally co-exist with their host
generally progress during conditions of host immunosuppression or alterations in the bacterial niche
diagnosis culture from a sterile site or serology or antigen detection
diseases:
candidiasis
cryptococcusis
aspergillosis
mucormycosis
pneumocystosis
candidiasis
caused by Candida albicans, tropicalis, parapsilosis
Clinical Disease
- most common of the systemic mycoses
- pseudohypahe
- mucosal surfaces
- superficial - thrush, vaginal
- chronic mucocutaneous
- systemic/disseminated - retina, kidneys, CNS
- germ tube test - 3 hours at 37 degrees C in serum
- treatment is local or systemic with azoles or AB
cryptococcosis
Cryptococcus neoformans
Clinical Diseaes
- soil contaminated with pigeon
- encapsulated - not phagocytosed
- inhalation and dissemination
- primary infection - influenza-like illness
- meningitis - lethal complication
- virulence factors - surface capsule, melanin synthesis genes, and myristoyl-CoA transferase
- treatment difficult to treat, AB + 5-FU
aspergillosis
caused by Aspergillus fumigatus
Clinical Disease
- inhaltional, pulmonary/air space invasive
- hypersensitivity reactions
- localized thrombosis and subsequent tissue infarctionrecurrentr asthma, peripheral eosinophillia
- space filling sesions in cavities known as aspergillomas
- branching septate hyphae on silver stain, conidial structure pathognomonic - long stalks with vesicles
- common nosocomial in immunocompromised
- detection by skin testing
- various toxins (aflatoxin) and proteases
- treatment with steroids, surgery, azoles, AB
mucormycosis
caused by the Zygomycosis phyla, Rhizomucor and Mucor genus
Clinical Disease
- ubiquitous saprophytes
- highly invasive local tissue infections
- starting in the nose and spreading through the face with potential direct extension to the CNS
- diabetic acidosis
- pulmonary or rhinocerebral disease
- GI Disease in AIDS
- culture/diagnosis difficult
- virulence by endoprotease Arp
- treatment is surgery and AB therapy
pneumocystosis
caused by Pneumocystic jiroveci
Clinical Disease
- resides in pulmonary tree, causes infecction in immunocompromised, notably premature or malnourished infants with HIV/AIDS
- causes increased barrier to gas exchange in intrapulmonary shunting (hypoxemia results) from growth on the surfactant layer of the alveolus
- treatment with trimethoprim-sulfamethoxazole or pentamidine isethionate
