Introduction To Fungi Flashcards
Mycoses - Basic Facts
Fungi do not require a host to complete their life cycles; usually not communicable, infection from environment
- Allergic mycoses - inhalation of spores: affects lungs or sinuses, patients may have chronic asthma or sinusitis
- Superficial mycoses - dermatophytes: affect the skin, hair and nails - ‘ringworm’, jock itch, athlete’s foot, these are communicable
- True fungal pathogens - can infect immunocompetent - only a few of these, can cause systemic infections in immunocompetent
- Opportunistic pathogens - vast majority of fungi are in this category, infect immunocompromised/debilitated individuals for the most part
Properties of Fungi- part 1
Eukaryotic - have nuclei, the usual organelles, and are larger than bacteria
- rigid cell wall composed of chitin and glucan - not peptidoglycan like bacteria
- no chlorophyll (they are not plants)
- cell membrane that has ergosterol instead of cholesterol
- relative to bacteria, grooow slowly with doubling times of hours rather than
- mycoses = fungal infection in or on a part of the body; disease caused by a fungus
Fungi more basic facts
Mycoses is a fungal infection in or on part of the body, or a disease caused by fungus
Fungi have chitin and glucan instead of peptidoglycan
Fungi have ergosterol instead of cholesterol
These components are targets for anti-fungals
Yeasts: unicellular fungi
Molds: multicellular fungi, reproduce by forming spores (fruiting bodies)
Dimorphism: some fungi can grow as yeast or molds (candida) depending on conditions
Properties of Fungi Part 2 - eg unicellular or multicellular
Properties of yeast
Properties of molds?
Dimorphic?
Yeast
- unicellular
- oval shaped or round
- reproduce by budding or fission
Molds
- multicellular
- threadlike structures; hyphae
- make spores
- some molds have hyphae that have regular, repeated septae, or walls between adjoining cells eg aspergillus
- some molds have only a few septae
Dimorphic
- exist as a mold in nature
- exist as a yeast at 37 degrees C in animals
- mold in the cold; yeast in the heat
All fungi can reproduce asexually
- molds release spores
- yeast undergo binary fission
**presence or absence of septae is helpful for diagnosis
More about molds, how do they grow etc,
Types of hyphae
Molds elongate at their tips: apical extension
- this is important becuase this is where new Cell wall material is produced, and drugs that target glucan production disrupt growth at the tips and thus tend to be fungistatic (prevent growth, but dont kill the fungus)
Hyphae are either septae (walls) or coenocytic (hollow and multinucleated)
Mold reproduction: Can produce spores (conidiophores or sporangispores; also called fruiting body) that are easily born and germinate on suitable substrates producing new hyphae
- produce specialized structures eg sporangiphores or conidiophores that have at their tips spores which can easily become airbornne, or quite stable and spread wide distances and be inhaled
Mold allergies due to inhalation of spores - just a hypersensitivity reaction
FRUITING BODY = aspergillus
Laboratory diagnosis of Fungal Infections
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SILVER STAIN IS BEST FOR VISUALIZING FUNGI
- lack of molecular tests; a few serology tests for some fungi
- culture of organism- most sensitive technique, but takes a lot of time (yeast grow in colonies but molds grow like molds, candida present as normal flora in 40% of people so culturing it by itself isnt enough
- **microscopic examination of tissue, sputum, etc. Fungi can appear as gram positive or negative depending on conditions but are not referred to in terms of gram staining, you should do silver stain (KOH prep used for silver stain)
NV cryptococcus is an unusual yeast in that it has a capsule (sort of like some forms of pneumococcus) formed of carbohydrate, and there is a good serologic test available to identify the presence of cryptococcal antigen
Treatment of Fungal Infections
what are the three targets for antifungal therapy?
Cell membrane: fungi use principally ergosterol instead of cholesterol (target this and bind and damage membrane or prevent its synthesis)
Cell wall
- unlike mammalian cells, fungi have a cell wall
DNA synthesis
- some comps may be selectively activated by fungi, arresting DNA synthesis - FLUCYTOSINE
DNA synthesis and cell membrane are most important
Class 1: Antifungals that directly damage the cell membrane
Polyene antibiotics
- bind directly to ergosterol forming channels in the cell membrane that disrupt osmotic integrity of the cell
Drugs in This class:
Amphotericin B, lipid formulations, broadly antifungal and you use it for serious infections
Nystatin (topical) *topical for athletes foot
Amphotericin B- polyene Abx given IV
Nystatin - polyene ABC used topically
Broad activity - effective against most of the important fungi
Fungicidal- used for most systemic infections
Some resistance due to reduced levels of ergosterol in the Fungal membrane
Poor penetration into joints, CNS
Administered IV
Very toxic: (bc it binds to ergosterol but can also bind to our own cholesterol)
- nephortoxicity***
- fever chills myalgia
- hypotension
- bronchospasm
Lipid formulations
- more expensive, reduced side effects
Class I continued: Antifungals that indirectly damage the the cell membrane
Azole Antifungals
- ketoconazole
- voriconazole *** primary treatment for invasive aspergillus
- itraconazole
- fluconazole *** used extensively; active against most candida cryptococcus, histoplasmosis, coccidioides. NOT active against aspergillus
- miconazole, clotrimazole (and other topicals)
Inhibit ergosterol production—> fungistatic rather than fungicidal (like polyenes)
Both can be given orally or IV, both have good absorption; fluconazole is very well tolerated
Azole mechanism of action
Azoles prevent ergosterol synthesis (polyenes bind directly to ergosterol) so azoles are fungistatic
Triazoles all end in ‘azole’: Fluconazole, Voriconazole, (and ketoconazole)
- fluconazole is used a lot, voriconazole is a newer drug
- both can be given orally or IV, both have good absorption; fluconazole is very well tolerated and voriconazole also has a good side effect profile
- fluconazole; used extensively, active against most Candida, Cryptococcus, Histoplasma, Coccidioides. NOT active against aspergillus
- foriconazole: primary treatment for invasive Aspergillus
Often drugs of choice for localized infections and for prophylaxis. More serious infections usually amphotericin, sometimes with an azole as well
Class 2: cell wall active Antifungals
Echinocandins
- caspofungin is mostly used
Fungal Cell wall
- complex cell wall
- major constituent is glucan (polymer of glucose and can be linked together in different ways), produced by action of enzyme beta 1,3 glucan synthase
- chitin (long chain polymer of N acetylglucosamine)
Caspofungin inhibits beta 1,3 glucan synthase —> damage to the cell wall—> osmotic fragility—> fungicidal drugs
Caspofungin- most important echinocandin
IV only, used for
- invasive candidiasis (as good as amphotericin, cheaper)
- invasive aspergillosis refractory to other therapies
**not used much, but sometimes instead of amphotericin for systemic infections
Side effects are infusion related: IV irritation, fever headache, flushing rash, symptoms consistent with histamine release
Class 3: DNA synthesis inhibitors
DNA synthesis
- pyramiding analogues
- flucytosine most used
Flucytosine
- transported into fungal cell wall where it is deaminated converting it to 5 Fluorouracil—> inhibits pyramiding synthesis (and DNA synthesis)
- resistance happens a lot so it is not used alone
- used for Cryptococcus and Candida
Side effects
- bone marrow suppression
- hepatotoxicity
Flucytosine
Actively transported across fungal membrane
Converted to 5 fluorouracil by cytosine deaminase
- essentially functions like a prodrug to go into cell and then get modified by enzyme unique to fungus to have an effect
Our cells lack cytosine deaminase giving it specificty
Further modified and inhibits thymidylate synthase, which is needed to produce thymidine, and hence DNA synthesis
Used with amphotericin to treat crypto and candida
Resistance arises readily
Side effects with prolonged use: bone marrow suppression, hair loss, abnormal LFTs
Summary - the drugs most commonly used for severe systemic fungal infections
USED THE MOST
Polyenes - amphotericin B**first choice for systemic infection
- bind ergosterol and disrupt cell membrane structure
Azoles - fluconazole, voriconazole **first choice for more localized infections, sometimes with amphotericin for more serious infections
- inhibit synthesis of ergosterol
USED LESS
Echinocandins- caspofungin
- inhibit synthesis of beta 1-3 D glucan
DNA synthesis inhibitors : Flucytosine (common resistance, dont do monotherapy)
Over the counter Antifungals
Azoles - inhibit ergosterol synthesis
- nystatin is topical polyene and is fungicidal (inhibit ergosterol synthesis) - topical only less effective than the azoles
Mycoses basic facts
Allergic
Superficial cutaneous mycoses- dermatophytes
Systemic (invasive)
Allergic- from inhalation of spores
- affect lungs or sinuses
- patients may have chronic asthma or sinusitis
Superficial/cutaneous mycoses - dermatophytes
- affect skin, hair and nails ‘ringworm’ jock itch, athletes foot (communicable)
Systemic (invasive) mycoses
- true fungal pathogens- can infect immunocompetent- only a few of these
- opportunistic pathogens- infect immunocompromised (debilitated), most are in this category
Fungal infections covered
Primary pathogens (all dimorphic)
Opportunistic pathogens
Cutaneous Mycoses
Primary pathogens (all dimorphic)
- histoplasma capsulatum (ohio valley fever)
- coccidiodes immitis (San juanguin valley fever, or valley fever)
- blastomyces dermatidis- can happy in healthy people
Opportunistic pathogens
- candida- mostly a yeast
- cryptococcus neoforman- yeast
- pneumocystis jiroveci- a yeast
- aspergillus- a mold (septae); mucosa is like aspergillus but without septae
Cutaneous Mycoses
True Fungal pathogens characteristics
Can infect immunocompetent
All dimorphic, live in hyphae state in the soil, yeast state at 37 C
Thermal dimorphism
Restricted to certain endemic regions of the world
Solid is the normal habitat
Infection by inhalation of spores—> pulmonary infections
- histoplasma - higher river valley and northeast - valley fever
- coccidioides - American southwest
- blastomyces
Histoplasmosis: Ohio Valley Fever
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Histoplasma capsulatum
Most common true fungal pathogen- causes histoplasmosis
Dimorphic fungus, produces spores that are inhaled
Associated with bird and bat dropping’s (high nitrogen soil)
Only intracellular fungus
Distributed worldwide, most prevalent in Ohio river valley
Most infections are asymptomactic
Histoplasma pathogenesis
Inhalation of spores from disturbed soil
Spores germinate to yeast in the lung
Usually stays localized or may spread via lymphatics within monocytes (taken up by macrophages and cause granulomatous inflammation)
Intensity of exposure and immune status are determinants of pathogenesis
Reactivation in immunocompromsied
Only intracellular fungal pathogen of significance
Histoplasma Clinical Presentations
Pic 24/69
70-90% infections asymptomatic
If large inoculum, most have Sx
Typically acute, self limited flu like syndrome, recover in 1 - 2 weeks, doesnt require treatment
Rarely progressive pulmonary disease develops with cavitary lesions and fibrosis
Can sometimes cause a chronic disease, and like TB can remain in your lungs for a long time and be reactivated later—> forms granulomatous like TB but not caseating
Disseminated hematogenous spread can present with overwhelming shock, disseminated intravascular coagulation, respiratory distress and high mortality
Histoplasma lab diagnosis and treatment
Microscopic/histologic identification of intracellular yeast
Culture can take 2 - 3 weeks
Urine antigen- detects histoplasma polysaccharide antigen in the urine of infected individuals - best with disseminated form of disease
Usually self limited so dont treat
Amphotericin for significant disease (targets ergosterol)
Long term itraconazole for immunocompromised such as aids patients for prophylaxis
Blastomyces Dermatitidis: North American blastomycosis
Picks slide 27
Causes blastomycosis in humans and other animals, particularly dogs
Distributed in soil of a large section of the midwestern and southeastern US
Inhaled conidiophores (spores) convert to yeasts and multiply in lungs - broad-based budding
Symptoms include cough and fever
Other systemic complaints are common
Can spread to other organs, particularly to skin and bone causing chronic granulomatous lesions
Skin lesions can be chronic—> crusted lesions on exposed skin surfaces
Detected microscopically with KOH prep of sputum—> broad-based budding yeast forms
Treatment: amphotericin B
Coccidioidomycosis: Valley Fever
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Like histoplasmosis, coccidiodomycosis is a primary pathogen - it can infect normal people - most virulent primary fungal pathogen**
- likes dry soil, distributed in the soil
Immitis - most common species
Distinctive morphology
- block like arthroconidia in the free-living stage and spherules containing endoscopes in the lungs, the spherules rupture, releasing the spores which spread and start process again
Arthrospores inhaled from dust, create spherules and nodules in the lung
Distinctive morphology = block like cells
Summary: sores inhaled—> grow and form large spherules that are full of new spores—> spheres rupture releasing spores that then go off and make new spheres
Coccidioidomycosis: epidemiology
Lives in alkaline soils in semarid, host climates and is endemic to southwestern US
San Joaquin valley fever
About 150,000 cases per year
60% asymptomatic
Reportable disease in California
When it causes symptoms, typically selflimited flu like like HIsto, but some people (immunosuppressed) get disseminated disease
Around 100 deaths per year, rate of infection has been increasing throughout the past decade
Coccidioidomycosis: Clinical
Chest film slide 32
Degree of dust exposure is important
Typical valley fever is self-limited
- 7 - 21 days after exposure-cough, fever, joint pain
- sometimes hemostasis, sometimes erythema nodosum (painful nodules on shins)
- can see eosinophilia
Chest film can show infiltrates with lymphadenopathy. Nodules if seen are a more specific finding, and sometimes peripheral, thin-walled cavities are seen
Infection confers immunity and a positive skin test
Disseminated disease (rare) can involve most any organ, especially meninges, fatal if not treated
Coccidioidomycosis: diagnosis and treatment
Often missed-non-specific Sxs
Sputum culture
- can take weeks
- lab hazard
Microscopic - large spherules in tissue/sputum
Self limited infection does not require treatment
Disseminated disease or patients with risk factors: amphotericin B plus an Azole, treat with azole for a year (targeting ergosterol)
SOUTHERN CALI
Candida: Candidiasis, opportunistic pathogen
Many species, but Candida albicans is the most important
Is a yeast but can form hyphae- not uncommon to see both in clinical specimens
Found as normal flora in mouth, gut- makes culture interpretation difficult
Most important and frequent opportunistic fungal pathogen
Candida common in GI tract so most forms of candida infection are endogenous- fungus is already there and if there is a predisposing condition it can spread and cause disease—> common cause of septicemia and has a high mortality rate
4th most common blood stream infection; 35% mortality; candida in blood is never a contaminant
Infections can be short-lived, superficial skin irritations to overwhelming fatal systemic diseases involving any organ
Hard to culture in throat becuase it is normal flora
Candida albicans- superficial infections
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Candida accounts for 80% of nosocomial fungal infections
30% of deaths from nosocomial infections
- THRUSH
Thick white adherent growth on the mucous, membranes of mouth and throat (common in AIDs pandemic)
- can scrape it off unlike Epstein Barr virus - Vulvovaginal Yeast infection - painful inflammatory condition of the genital region that causes ulceration and whitish discharge
- Esophageal candidiasis
Preferred treatment: fluconazole
Candida Albicans - Invasive Infections
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Risk factors - the usual suspects
- immunosuppresion
- neutropenia
- surgery
- also IV catheters, TPN, antibiotics
Typical clinical features
- fever, even on Abx
- skin lesions
- retinitis
- endocarditis
- microabscesses in any organ (see white center and red ring which is infectious, liver is ac moon place for abscesses)
Preferred treatment: fluconazole
Cryptococcus Neoformans
- opportunistic pathogen
Look at pic 39
Causes cryptococcosis
Widespread encapsulated yeast that inhabits soil (N rich) and is enriched around pigeon roosts
Oval cells surround by a halo, polysacccharide capsule
Common infection of aids, cancer or diabetes patients, often but not always associated with immune suppression
Cryptococcus Facts
Organism is inhaled
Amount of inoculum is important becuas eit isnt that virulent so the amount of exposure matters
Often relatively asymptomatic or with nonspecific symptoms
Infection of lungs leads to cough, fever, and lung nodules/cavities
Can spread via blood to most any organ, but the brain and meninges are favorite targets
Cryptococcal meningitis/encephalitis can be fatal
- cryptococcal meningitis is a significant problem for AIDs patients
Cutaneous involvement about 10%, painless nodules
Cryptococcal Meningitis/Encephalitis
Most often in AIDs pits - CD4 < 50
High burden of organisms/poor inflammatory response
Indolent meningitis ‘soap bubble’ lesions in brain
Stiff neck, photophobia - uncommon
Initial exam unimpressive—> can progress to mental status changes, visual, hearing, CNS findings
Can be chronic, but invariably fatal if not treated
Clinically more mild than bacterial meningitis and can be indolent (slow developing)
Fatal if not treated
Microscopic image: macrophages infiltrating a blood vessel that contains the yeast - clear halo
Cryptococcus Diagnosis and Treatment
Direct microscopic examination - the appearance of crypto is quite characteristic in INdia Ink preparations of the CSF, see the halo very diagnostic but not that sensitive common test
Detection of cryptococcal antigen is method of choice- some of the polysaccharide capsule breaks off and you can detect this. Rapid, fast cheap
Systemic infection: amphotericin B and flucytosine for two weeks then 9 weeks of fluconazole
AIDs patients sometimes take fluconazole as prophylaxis
Pneumocystis
Pneumocystis Pneumonia is the first opportunistic infection recognized in AIDS patients and the most common cause of nonpacterial pneumonia in these individuals
Infection only in the immuunocompromised
Diffuse bilateral infiltrates - ‘ground glass’ appearance; looks more like a viral pneumonia than a bacterial pneumonia
Has trophozoites and cysts - the cysts are seen by silver stain
Treat with bacteria- only fungus treated with this
Aspergillosis: disease of the genus aspergillus
Ubiquitous, airborne soil fungus
A fumigatus most common
Serious threat to immunocompromised
Can cause allergic hypersensitivity
A mold; acutely branching hyphae with septae with fruiting bodies
Differentiate from Mucor; a mold without septae, right angle branching
Usually infects lungs - spores germinate, form fungal balls (aspergillomas); can colonize sinuses, ear canals, eyelids, and conjunctiva
Invasive aspergillosis can produce necrotic pneomnia and infection of brain, heart and other organs
Mucor
Similar to aspergillus, also an opportunistic mold, less common but presents in a similar way- lacks septae and has right angle branching
Have hyphae but these have very few septae
Aspergilloma
Pic 48
Noninvasive fungus ball in a cavity
Usually preexisting lung disease (sarcoidosis, TB)
Often asymptomatic, can cause hemostasis, chest pain, shortness of breath
Drugs ineffective (access) - need to respect - get poor drug penetration in any type of abscess situation, so surgical resection is called for as these can be locally invasive
Invasive Aspergillosis
49
Bad news
Incredibly destructive
Angio-invasive leading to infarction, necrosis
Lung infection most common, but can spread anywhere
Early diagnosis essential0 usually need tissue to visualize fungus- culture not usually effective
High mortality
Voriconazole is first choice Tx in most cases
Cutaneous Mycoses
51
Spreading ring of inflammatory reaction—> fungal infection, ring worm
Infection of nail beds, scalp etc
Cutaneous Mycoses
Infections strictly confined to keratinized epidermis (skin, hair, nails) fungi feed on keratin
39 species in the genera trichophyton, microsporangia, epidermophyton
Closely related and morphologically similar
Common name is ring worm
Causative agent varies case to case and is not that important
Natural reservoirs- humans, animals, and soil
Infection facilitated by moist, chafed skin (localized to keratinized epidermis as these fungi actually feed on keratin, can lead to chafing, itching, cosmetic issues)
Long infection period followed by localized inflammation and allergic reactions to fungal proteins
Infections elicit cellular response; leading to inflammed, outward spreading lesions
Tinea names of Cutaneous Mycoses
Tinea plus modifier indicates site
- Tinea capitis- scalp
- Tinea Cruris - groin (jock itch)
- Tinea pedis - feet (athlete’s foot)
- Tinea unguided - nails
Branching, septae hyphae seen on KOH preps
Treatment: topical Azole Antifungals, nystatin
Guess the Fungus:
HIV+ man with white patches on the tongue
After vacationing in the desert areas of NEw Mexico, 50 yo woman develops respiratory symptoms with infiltrates and has red, painful, modular lesions on her shins
35 yo man has chronic respiratory symptoms. He exhibits hemostasis (blood tongued sputum) chest film shows a circular abscess with a partially opaque center
Immunosuppressed individual has neck stiffness. India ink preparation of her CSF shows encapsulated yeast cells
Candida
Coccidiamycosis
Aspergillosis
Cryptococcus
68 yr old man presents with fever of 39.5 C cough with productive sputum, and with a chest film that shows a consolidated right middle lobe
3 week archeological dig in southwestern candida
Influenza Coccidioides immits Histoplasma capsulatum Strep pneumo RSV
Strep pneumo
Look at image of chest film 61
Sputum of 75yo pneumonia, nodules,
Treat with amphotericin used with azole for aspergillus
