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Block 6 - week 5 > Basic mycology and fungal pathogens - Kozel > Flashcards

Basic mycology and fungal pathogens - Kozel Flashcards

1
Q

Are fungi human pathogens?

A

Yes, about 300 of the 1.5 million species are human pathogens, of which about 50 are common species.

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2
Q

Why are there so few species of fungi that are human pathogens?

A

Mammals are intrinsically resistant because of intact immune systems and because of the ability to generate and regulate our body temperature. Every degree above about 30 degrees celsius (normal body temp about 37 degrees celsius) excludes 6% of fungal species.

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3
Q

The emergence of fungi as human pathogens is fairly recent - why?

A
  1. the introduction and increased use of antibiotics
  2. the emergence of HIV and its effect on the immune system
  3. the emergence of immunosuppressive therapies
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4
Q

Describe the basic components of the fungal cell wall and plasma membrane.

A
  1. Fungi have a lipid bilayer plasma membrane that contains a sterol called Ergosterol. This sterol is unique to fungi and is therefore a target for anti-fungals.
  2. Fungi have a very thick cell wall made of chitin, B-(1,3) glucan, B-(1,6) glucan and mannoproteins.
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5
Q

Mannoprotein components of fungal cell walls can differ from fungi to fungi. Give 2 examples.

A
  1. Saccharomycetes cell walls contain Mannan

2. Euascomycetes cell walls contain Galactomannan

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6
Q

What are yeast?

A

A unicellular fungus that reproduces vegetatively by budding or fission.

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7
Q

What are pseudohyphae?

A

String of budding cells marked by constrictions rather than septa at the junctions. Part of the filamentous growth structure of some fungi.

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8
Q

What are hyphae?

A

Multicellular structures that elongate at the tips by apical extension. These are part of the filamentous growth structures of some fungi.

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9
Q

What are coenocytic hyphae?

A

These are hyphae that are hollow and multinucleate with no septa.

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10
Q

What are septate hyphae?

A

These are hyphae divided by partitions or cross walls.

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11
Q

What are Conidia?

A

Asexual reproductive elements produced by fragmentation of hyphae.

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12
Q

What are Sporangiospores?

A

Asexual spores produced inside a containing sack-like structure called a sporangium.

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13
Q

Fungi have many different mechanisms of growth. Give some examples.

A
  1. Mucorales - form sporangium with sporangiospores.
  2. Penicillium and Aspergillus species - for conidia.
  3. Coccidioides immitis- forms Arthroconidia.
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14
Q

Which fungi form broad, thin walled coenocytic hyphae and sporangiospores.

A

The group Mucormycetes of which Rhizopus and Mucor are examples.

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15
Q

Which fungi group has genera that include fungi that form septate hyphae with clamp connections, arthroconididia and budding yeasts?

A

The group Basidiomycetes of which Cryptococcus, Malassezia and Trichosporon are examples.

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16
Q

Which group of fungi forms cystlike structures and trophic forms?

A

The group Pneumocystidiomycetes of which Pneumocystis jirovecii is an example.

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17
Q

Which group of fungi includes genera that form hyphae, pseudohyphae and budding yeasts?

A

The group Saccharomycetes of which Candida and Saccharomyces are examples.

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18
Q

Which group of fungi includes genera that form septate hyphae (rare), asexual conidia on specialized structures, arthroconidia, and budding yeasts?

A

The group Euascomycetes of which Dermatophytes, Blastomyces, Histoplasma, Aspergillus and Coccidioides are examples.

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19
Q

What are some of the general mechanisms by which fungal infections are diagnosed?

A
  1. Culture
  2. Direct microscopy
  3. Histopathology
  4. Serology
  5. Molecular methods
  6. Antigen detection
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20
Q

Describe Culturing as a method of diagnosis.

A
  1. This is the Gold Standard for fungal infections
  2. Not easy in most cases and takes a highly skilled laboratories
  3. takes days to weeks to get results
  4. allows for sensitivity testing
  5. often negative for disseminated disease
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21
Q

Describe direct microscopy as a method of diagnosis.

A
  1. Scrapings are taken and KOH is used to digest tissue before the fungi is looked at.
  2. A negative stain of CFS is used for detection of encapsulated cryptococci.
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22
Q

Describe Histopathology as a method of diagnosis.

A
  1. cytologic preparations, fine needle aspirates, body fluids and exudates can all be look at.
  2. usually requires invasive sample taking.
  3. routine stains - H&E
  4. special stains - PAS, mucicarmine, Gomori methenamine silver. These stain for things like carbohydrates, fungal cell walls and capsules.
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23
Q

Describe Serology as a method of diagnosis.

A
  1. detects antibody to fungal antigen
  2. complement fixation (can detect specific antibody or specific antigen) assay and other immunoassay formats are used.
  3. may not reflect active infection - would have to know if antibody is IgM or IgG.
  4. this method is most useful for coccidioidomycosis and histoplasmosis.
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24
Q

Describe Molecular Methods as a method of diagnosis.

A
  1. detect nucleic acids via PCR
  2. most useful for identification of cultured fungi
  3. problematic for identification in blood or tissue
  4. no FDA-cleared test
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25
Q

Describe antigen detection as a method of diagnosis.

A
  1. detects circulating antigen
  2. cryptococcal antigen (CrAg) very useful for cryptococcosis
  3. detects Beta glucan in blood - variable sensitivity since B-glucan can be found in other places in the medical setting
  4. detects Galactomannan
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26
Q

What class of drug are Azoles?

A

These are anti-fungals that contain an azole ring with variable amounts of nitrogen within the ring.

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27
Q

What is the mechanism of action of the Azoles?

A

They inhibit lanasterol 14-a-demethylase which in turn blocks ergosterol synthesis. Ergosterol is necessary for the formation of fungal plasma membranes.

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28
Q

In what way can fungi be resistant to Azoles?

A
  1. they can evolve targets with decreased affinity for the drug
  2. they form efflux pumps that pump the drug out
  3. they overexpress the drug target to bind up the drug
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29
Q

Describe the pharmacodynamics of the azole drugs.

A
  1. most have excellent oral bioavailability
  2. generally exhibit low rates of protein binding
  3. good distribution to organs and tissues including the CNS
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30
Q

Describe the toxicity and side effects of the azole drugs.

A
  1. Fluconazole has low toxicity
  2. other azoles have variable toxicity
  3. many adverse interactions with other medications
  4. need to monitor other medications because the azoles are a substrate and inhibitor of cytochrome P450
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31
Q

How are the azole drugs with 2 nitrogens in the azole ring classified?

A

As Imidazoles. Examples are:

  1. ketoconazole
  2. miconazole
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32
Q

How are the azole drugs with 3 nitrogens in the azole ring classified?

A

As Triazoles. Examples are:

  1. Fluconazole
  2. Itraconazole
  3. Voriconazole
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33
Q

What is the clinical use of Ketoconazole?

A

It has limited use due to toxicicity and low efficacy.

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34
Q

What is the clinical use of Fluconazole?

A

This drug is used ubiquitously and has low toxicity. Especially useful for candidiasis and cryptococcosis.

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35
Q

What is the clinical use of Itraconazole?

A

This a broad spectrum anti-fungal used for many fungal infections.

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36
Q

What is the clinical use of Voriconazole?

A

This is a broad spectrum anti-fungal and is especially used to treat invasive aspergillosis.

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37
Q

What are the two types of Allylamine anti-fungal drugs?

A
  1. Terbinafine

2. Naftifine

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38
Q

What is the mechanism of action of the Allylamines?

A

They inhibit squalene epoxidase which is an enzyme in the pathway of ergosterol synthesis.

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39
Q

Describe the pharmacodynamics of the Allylamines?

A
  1. well absorbed but rapidly metabolized in liver
  2. exhibit high concetrations in fatty tissue, skin, hair and nails
  3. well tolerated if given orally
  4. Category B drug for pregnant women
40
Q

What is the clinical use of Terbinafine and Naftifine (the Allylamines)?

A

They are used topically to treat dermatophyte infection and are used for systemic treatment of dermatophyte infection also.

41
Q

Describe the antifungal drug Flucytosine.

A
  1. It is a pro-drug that is activated when deaminated to active 5-fluorouracil in yeast cells.
  2. It works by acting as an antimetabolite. It competes with uracil and inhibits DNA and RNA synthesis.
  3. It is used in combination with Amphotericin B for the treatment of serious cryptococcal meningtitis.
42
Q

Describe the pharmacodynamics of Flucytosine.

A
  1. taken orally and is rapidly absorbed from the GI tract - but given in combo with IV administered Amphoterecin B
  2. widely distributed in body, good CNS penetration
  3. excreted unchanged in the urine
43
Q

Describe the toxicity and side effects of Flucytosine.

A
  1. Depresses bone marrow function

2. causes hepatotoxicity

44
Q

Describe the resistance of fungi to Flucytosine.

A
  1. develop decreased uptake
  2. develop mechanisms to block the conversion of the drug to its active form
  3. resistance is relatively common in monotherapy
45
Q

Describe Echinocandins.

A
  1. These are a class of antifungal drugs whose structure includes a cyclic lipopeptide An example is Caspofungin.
46
Q

Describe Caspofungin.

A
  1. an Echinocandin class of antifungal
  2. inhibits glucan synthesis
  3. resistance is currently rare but has been created in lab - altered target with decreased sensitivity
  4. used for fungi where 1,3 B-glucans are the dominant cell wall glucan
47
Q

Name some fungi that Caspofungin is prescribed for.

A
  1. Candida - causes invasive candidaisis

2. Aspergillus - causes invasive aspergillosis

48
Q

Describe the pharmacodynamics of the Echinocandins/Caspofungin.

A
  1. administered IV since exhibits poor oral bioavailability
  2. exhibits extensive protein binding
  3. has limited CNS penetration
49
Q

Describe the toxicity and side effects of the Echinocadins/Caspofungin.

A
  1. generally well tolerated

2. is a Category C drug for pregnant women

50
Q

Describe Amphotericin B.

A
  1. is a polyene class of anti fungal along with Nystatin
  2. it is an amphoteric molecule that can bind to sterol molecules
  3. Lipid formulations are less toxic
  4. works by binding to ergosterol and directly damaging the fungal membrane. Ergosterol is unique to fungal cell membranes
  5. broad spectrum
  6. resistance is rare but when occurs does so by many mechanisms
51
Q

What are some mechanisms of resistance to Amphotericin B?

A
  1. reduced ergosterol content in fungal membrane
  2. ergosterol with reduced binding to drug
  3. masking of ergosterol to block binding
52
Q

Describe the pharmacodynamics of Amphotericin B.

A
  1. negligible GI absorption - given IV
  2. pharmacokinetic properties differ with formulation
  3. conventional AmB remains in plasma, largely bound to protein
  4. lipid formulation of AmB has highest plasma concentration at therapeutic doses
  5. negligible excretion in urine
53
Q

Describe the toxicity and side effects of Amphotericin B.

A
  1. considerable nephrotoxicity - azotemia (nitrogen compounds in blood) in 80% of patients given conventional AmB
  2. reduced nephrotoxicity with lipid formulations
54
Q

Name some general types of fungal infections.

A
  1. superficial mycoses - limited to superficial surfaces of skin and hair, nondestructive but of cosmetic importance
  2. cutaneous mycoses - infections of keratinized layers of skin, hair and nails, pathology due to host response
  3. subcutaneous mycoses - infections of deep layers of skin, cornea, muscle and connective tissue
  4. infection can be via endemic or opportunistic mycoses
55
Q

Name some endemic (fungi found in nature) mycoses (fungal infection).

A
  1. blastomycosis
  2. histoplasmosis
  3. coccidiodomycosis
  4. penicilliosis
56
Q

Name some opportunistic (environmentally ubiquitous) mycoses.

A
  1. aspergillosis
  2. cadidiasis
  3. cryptococcosis
  4. mucormycosis
  5. pneumocystosis
57
Q

At what temperature do endemic mycoses grow?

A

37 degrees celsius.

58
Q

With which type of fungi are most people routinely exposed?

A

Opportunistic fungi.

59
Q

Name some superficial mycoses and the fungi that cause them.

A
  1. Pityriasis versicolor - Malassezia furfur
  2. Tinea nigra - Hortae werneckii
  3. Black piedra - Piedraia hortae
  4. White piedra - Trichosporan spp
60
Q

What are the three major genera of fungi that cause cutaneous mycoses?

A
  1. Microsporum spp
  2. Trichophyton spp
  3. Epidermophyton floccosum
61
Q

Name some cutaneous mycoses.

A
  1. Dermatophytoses - infections of skin
  2. Tinea unguium - infections of toes
  3. onychomycosis - infections of nails
62
Q

Name some genera of fungi that cause subcutaneous mycoses.

A
  1. Hyaline molds - Acremonium spp, Fusarium spp

2. Pigmented fungi - Alternaria spp, Cladosporium spp, Exophila spp

63
Q

Name some characteristics of subcutaneous mycoses.

A
  1. infection via traumatic inoculation
  2. cause abscess formation, nonhealing ulcers, draining sinus tracts
  3. localized - rarely disseminate
64
Q

What are the two growth forms (dimorphic) of endemic fungi?

A
  1. Saprobic -form that grows at room temp - such as in a lab.
  2. parasitic - form that grows at body temp.
65
Q

Describe Blastomyces dermatitidis.

A
  1. Dimorphic fungus:
    - tissue = broad based yeast
    - saprobic = nondescript mycelium
  2. found in decaying organic matter
  3. endemic to Ohio and Mississippi River valleys
  4. infections can sometimes be asymptomatic
66
Q

What diseases are caused by Blastomyces dermatitidis?

A
  1. pulmonary disease
  2. extrapulmonary - skin, genitourinary, CNS
  3. disseminated disease in imunocompromised patient
67
Q

Describe Histoplasma capsulatum.

A
  1. Dimorphic fungus:
    * tissue - intracellular budding yeast
    * saprobic - tuberculate macroconidia - diagnostic structure
  2. found in soil with high nitrogen content such as seen with bird and bat droppings
  3. endemic to Ohio and Mississippi River valleys, Mexico, Central and South America
  4. likes to grow in phagocytic cells
68
Q

What diseases are caused by Histoplasma capsulatum?

A
  1. acute pulmonary - 90% asymptomatic
  2. chronic pulmonary - mainly in patients with comorbidities
  3. progressive disseminated - a small number of patients may progress to this
69
Q

Describe Coccidioides immitis/posadasii.

A
  1. Dimorphic fungi:
    * tissue - endosporulating spherule
    * Saprobic phase - arthrocondidia
  2. found in soil and dust
  3. endemic to Southwestern US, Mexico, Central and South America
70
Q

What kinds of diseases are caused by Coccidioides immitis/posadasii?

A
  1. primary pulmonary - often asymptomatic
  2. progressive pulmonary
  3. Disseminated - usually in immunocompromised patients
71
Q

Describe Penicillium marneffei.

A
  1. Dimorphic fungus:
    * tissue - sausage-shaped yeast
    * saprobic phase - pigmented mold
  2. found in soil and the bamboo rat
  3. endemic to Southeast Asia
72
Q

What diseases are caused by Penicillium marneffei?

A
  1. disseminated infection - more common in AIDS

2. causes diseases similar to histoplasmosis, cryptococcosis or tuberculosis

73
Q

Describe Paracoccidioides brasiliensis.

A
  1. Dimorphic fungus:
    * tissue - large, multiple budding yeast
    * saprobic phase - nondescript mold
  2. found in soil
  3. endemic to South and Central America
74
Q

What diseases are caused by Paracoccidioides brasiliensis?

A
  1. self-limiting pulmonary disease
  2. progressive pulmonary disease
  3. disseminated infection
  4. infection more common in children and immune compromised patients
  5. acute disease is usually asymptomatic
75
Q

Describe the Aspergillus spp.

A
  1. has several species
  2. ubiquitous in air, soil and decaying matter
  3. infection by inhalation of spores
  4. tissue morphology - septate, branching hyphae
76
Q

What are the diseases caused by the Aspergillus spa?

A
  1. allergic reactions
  2. obstructive paranasal or bronchial symptoms
  3. invasive and disseminated pulmonary diseases - especially in neutropenic or immunodeficient (ie BMT or organ transplant), high fatality rate
77
Q

describe the Candida spp.

A
  1. multiple species but C. albicans the most common
  2. yeast-like forms with buds, pseudohyphae and germ tubes
  3. normal flora of humans
78
Q

What diseases does Candida cause?

A
  1. Oropharyngeal infection - thrush
  2. Esophagitis - seen in AIDS patients
  3. Vulvovaginal infection
  4. Hematogenous disseminated disease
79
Q

Describe Cryptococcus neoformans.

A
  1. encapsulated yeast -India ink stain of CSF or immunoassay for capsular antigen for diagnosis
  2. two clinically important species - C. neoformans and C. gattii
  3. ubiquitous saprophyte associated with pigeons and trees
  4. gains access to body via inhalation
80
Q

What diseases does Cryptococcus neoformans cause?

A
  1. pulmonary cryptoccosis
  2. cryptococcal meningitis
  3. opportunistic in AIDS and other immune suppressed patients
  4. major disease in AIDS in resource-limited countries
81
Q

Describe Mucormycocis.

A
  1. disease caused by Mucorales genera such as Mucor and Rhizopus fungi
  2. growth - coenocytic hyphae - diagnostic
  3. ubiquitous in soil, decaying vegetation
  4. acquired by inhalation of spores
82
Q

What diseases are caused by the Mucorales species?

A
  1. Rhinocerebal diseases - unique to diabetic ketoacidosis
  2. pulmonary diseases
  3. disseminated and angioinvasive diseases
  4. patients with metabolic acidosis and hematologic malignancies are at risk
83
Q

Describe Pneumocystis jirovecii.

A
  1. sexual and asexual life cycle
  2. tropic, sporocyst and cyst forms
  3. Cysts seen as empty collapsed balls in sample
  4. human reservoir most likely
84
Q

Name some characteristics about Pneumocystic jirovecii pathology.

A
  1. natural resistance very high
  2. likely infects most normal humans
  3. AIDS and other immune deficient patients and infants are susceptible to pathology
  4. causes interstitial plasma cell pneumonitis
  5. high morality if untreated
85
Q

What does a tissue culture of Blastomyces dermatitidis look like?

A

broad based, budding yeast

86
Q

What does a saprobic culture of Blasomyces dermatitidis look like?

A

nondescript mycelium

87
Q

What does a tissue culture of Histoplasma capsulatum look like?

A

intracellular, budding yeast

88
Q

What dos a saprobic culture of Histoplasma capsulatum look like?

A

tuberculate macroconidia

89
Q

What does a tissue culture of Coccidioides immitis/posadasii look like?

A

endosporulating spherule

90
Q

What does a saprobic culture of Coccidioides immitis/posadasii look like?

A

arthroconidia

91
Q

What does a tissue culture of Penicillium marneffei look like?

A

sausage-shaped yeast

92
Q

What does a saprobic culture of Penicillium marneffei look like?

A

pigmented mold

93
Q

What does a tissue culture of Paracoccidioides brasiliensis look like?

A

large, multiple budding yeast

94
Q

What does a saprobic cullture of Paracoccidioides brasiliensis look like?

A

nondescript mold

95
Q

What is the difference between mold and yeast?

A
  1. mold = fungi that contains multiple identical nuclei, grows in the form of hyphae of filaments
  2. Yeast = fungi that contain only a single cell
96
Q

What is a network of tubular, branching hyphae?

A

mycelium

Block 6 - week 5 (8 decks)

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