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1

When did fungus infections become a big deal for humans? Why was this the time of fungal blooming?

1950s
antibiotics were being used a lot-disrupt normal flora
HIV
immunosuppressive therapies

2

More fungi infect plants & insects than humans--by a lot! Why do humans get away so easily?

our neutrophils do well with fungi
fewer infections!
also our temp is relatively high at 37 degrees Celsius
**Every 1°C above 30°C excludes 6% of fungal species

3

What is the unique sterol found in the fungal plasma membrane?

ergosterol
**often targeted by anti fungal agents

4

Outside of the plasma membrane of the fungus is a huge cell wall. WHat is found here?

chitin
beta 1,3 glucan
beta 1,6 glucan
mannoproteins

5

The content of mannoproteins can vary a lot from one fungus to another. What type of mannoprotein is found in saccharomycetes? Candida albicans? Euascomycetes?

Saccharomycetes-mannan
Candida Albicans--mannan
Euascomycetes--Galactomannan

6

To check for various fungal infections which component of the fungal structure is tested for?

mannoproteins--differentiate between different types of fungal infections

7

What is yeast?

a unicellular fungus that reproduces vegetatively by budding or fission
**doesn't reproduce sexually

8

What is pseudohyphae?

String of budding cells marked by constrictions rather than septa at the junctions
**can be seen in vaginitis

9

What is hyphae?

multicellular structures that elongate at tips by apical extension

10

What are coenocytic hyphae?

– hollow, multinucleate hyphae
no septa! nuclei are just floating around.

11

What are septate hyphae?

hyphae divided by partitions or cross-walls

12

What are conidia?

asexual reproductive elements (spores) produced by budding at the tip or side of a hypha

13

What are arthroconidia?

– asexual reproductive elements produced by fragmentation of hyphae

14

What are sporangiospores?

asexual spores produced inside a containing sack-like structure (sporangium)

15

Give some examples of asexual spores.

mucorales
coccidioides immitis
penicillium spp.
aspergillus spp.

16

What is a sporangium filled with?

spores

17

What do septate hyphae break apart to form?

arthroconcidia

18

Which part of the aspergillus is infectious?

the conidia on top of them.

19

What are several genera in the group mucormycetes?

rhizopus
mucor

20

What is the morphology of mucormycetes?

broad, thin walled hyphae with multiple nuclei (coenocytic), septa are rare, sporangiospores are present

21

What are several genera in the group basidiomycetes?

cryptococcus
malassezia
trichosporon

22

What is the morphology of basidiomycetes?

budding yeasts
septate hyphae with clamp connections & arthroconidia

23

What are several genera in the group pneumocystidiomycetes?

pneumocystis jirovecii

24

What is the morphology of pneumocystidiomycetes?

trophic forms & cyst-like structures

25

What are several genera in the group saccharomycetes?

candida
saccharomyces

26

What is the morphology of saccharomycetes?

budding yeasts & hyphae
pseudohyphae
Note: saccharomyces is baker's yeast

27

What are some genera in the group euascomycetes?

dermatophytes
blastomyces
histoplasma
aspergillus
coccidioides

28

What is the morphology of euascomycetes?

budding yeasts
septate hyphae
asexual conidia on specialized structures
arthroconidia

29

What is the gold standard for diagnosis of a fungal infection?

culture
difficult to do-takes skills!
days-weeks for result
has to be isolated from a normally sterile bodily fluid

30

What is especially awesome about a fungal culture if you can get one?

allows for sensitivity testing

31

How can direct microscopy be used for diagnosis of fungal infections?

scrapings-KOH to digest tissue, leave hyphae behind.
negative stain of CSF for encapsulated cryptococci--has 85% reliability

32

Describe how histopathology can be used to diagnose fungal infections?

cytologic prep
fine-needle aspirates
body fluids & exudates used
usu need an invasive sample.
can do routine stains or special stains

33

Why can histopathology be dangerous when diagnosing a fungal infection?

main reason is that if a person has a fungal infection-they may very well be immunocompromised. You could introduce new problems for them by taking an invasive sample, biopsy

34

How can serology be used to diagnose a fungal infection?

looks for antibody to fungal antigen!
complement fixation is one immunoassay format
could reflect old infection (IgM or IgG)--esp for endemic fungi

35

Which fungi is serology most useful in detecting?

coccidioidomycosis
histoplasmosis

36

What are some molecular methods for diagnosis of a fungal infection?

detects nucleic acids via PCR
useful for ID of cultured fungi
difficult to use for ID in blood or tissue

37

Antigen detection is another way to diagnose a fungal infection. Explain this.

look @ circulating antigen
look for beta glucans (cell wall) & galactomannan (shown in aspergillosis)

38

How could you get a false positive when doing antigen detection for beta glucan?

beta glucan is found in gauze & other medical equipment-have to watch out.

39

What is a useful antigen to look for when you suspect a cryptococcosis infection?

CrAg
cryptococcal antigen
successful antigen fungal test

40

What are some important anti fungal agents?

Azoles
Allylamines
Flucytosine
Echinocandins
Polyenes

41

What is an example of a common azole used to treat fungal infections?

fluconazole
used for a lot of fungal infections
low toxicity
used for candida albicans & cryptococcis
wasn't used until AIDS came along.
can be taken orally-good in underdeveloped countries
**candida is developing resistance against it.

42

What is the structure of imidazoles-a type of azole? Give 2 examples of this type.

2 nitrogens in a ring
**ketoconazole
**miconazole

43

What is the structure of triazoles-a type of azole? Give 3 examples of this type.

3 nitrogens in a ring
fluconazole
itraconazole
voriconazole

44

What is the mechanism for azoles?

blocks ergosterol synthesis-only found in fungal plasma membrane
**inhibits lanosterol 14-alpha-demethylase

45

Does resistance form against azoles? What types?

Yes,
target with decreased affinity for drug (enzyme less likely to bind)
efflux pump (get rid of that azole!)
over expression of target (can't overwhelm the enzyme)

46

What is the clinical use of ketoconazole?

limited b/c of toxicity & less efficacy

47

What is the clinical use of itraconazole?

broad spectrum anti fungal

48

What is the clinical use of voriconazole?

broad spectrum
invasive aspergillosis

49

What is the absorption, fate & excretion of azoles?

great oral bioavailability
low protein binding
good distribution to everything, even CNS!

50

What are some possible side effects of azoles?

inhibitor of Cyt P450-drug interactions

51

What are 2 structures of allylamines?

the structure of terbinafine & naftifine

52

What is the mechanism of allylamine?

inhibition of squalene epoxidase

53

What is the clinical use of allylamines?

systemic & topical treatment of dermatophyte infection

54

What is the pharmacology of allylamines?

absorbed well & cleared by liver quickly
high conc'n in fatty tissue, skin, hair & nails
can be given orally

55

What is the structure of flucytosine?

it is a prodrug
activated when it is deaminated & becomes 5-fluorouracil in yeast cell

56

What is the mechanism of flucytosine?

antimetabolite-competes with uracil & inhibits DNA & RNA synthesis

57

What are the mechanisms of resistance against flucytosine? Is this common?

common
decreased uptake of drug
failure to convert the prodrug into the active form

58

What is the clinical use of flucytosine?

used in combo with amphotericin B in treatment of cryptococcal meningitis

59

Can flucytosine be used in underdeveloped countries?

no, b/c it is expensive

60

What is the absorption, fate & excretion of flucytosine?

taken orally-rapidly absorbed in GI
distributed in the body-good CNS penetration
excreted in urine

61

What is the toxicity of flucytosine?

depresses the bone marrow & can cause hepatotoxicity

62

What is the structure of echinocandins? What is an example of this type of anti fungal?

large, cyclic lipopeptide
ex: caspofungin

63

What is the mechanism of echinocandins?

inhibits glucan synthesis
remember that glucan is a major part of the fungal cell wall

64

Is there resistance against echinocandins?

rare
lab-altered target with decreased sensitivity

65

What is the clinical use of echinocandins?

used for fungi that have 1, 3 beta glucans as dominant cell wall components
ex: candida, aspergillus
used for invasive candidiasis & aspergillosis

66

What is the pharmacology of echinocandins?

administered IV
poor oral bioavailability
extensive protein binding
can't get into the CNS well
well tolerated

67

What is the structure of polyenes? What are some major examples ?

large cyclic structure w/ a hydrophobic & hydrophilic component
Ex: amphotericin B & nystatin
often lipid formulations of amphotericin B so that you get lower toxicity & better bioavailability

68

What is the mechanism of amphotericin B?

binds ergosterol
direct membrane damage

69

Is there resistance against polyenes?

rare
when it is present, resistance by reduced ergosterol in plasma membrane of the fungus, ergosterol with reduced binding to drug, masking of ergosterol

70

What is the clinical use of polyenes?

broad spectrum b/c it targets any fungus that has ergosterol in their membrane

71

What is the pharmacology of amphotericin B?

IV b/c not absorbed GI
w/o lipid: remains in plasma & bound to protein
w/ lipid: high plasma conc'n & therapeutic doses
not really excreted in urine
**nephrotoxicity b/c of nitrogen compounds in the blood (azotemia)-in 80% of pts
lipid formulation helps this, but HAVE to monitor renal fcn

72

Can amphotericin B be used in underdeveloped countries to treat fungal infections?

not often b/c it has to be given IV & it is expensive & you need extensive patient follow up to monitor for kidney damage

73

The patient is a 70-year-old woman with uncontrolled type 2 diabetes mellitus who presented with a one-month history of non-specific headaches associated with progressive swelling of her left eye. A diagnosis of invasive mucormycosis was made from a tissue biopsy taken from the internasal septum. She was successfully treated with intranasal and systemic amphotericin B. What is the mechanism of action of this antifungal agent?
 A) Inhibits lanosterol 14-α-demethylase to block ergosterol synthesis
B) Binds to ergosterol to damage cell membranes
C) Inhibits glucan synthesis
D) Inhibitions squalene epoxidase
E) Inhibits DNA and RNA synthesis

B.

Also, this pt had rhincerebral mucormycosis

74

The government of a country in Southeast Asia instituted prophylactic treatment of all AIDS patients with fluconazole to prevent development of cryptococcal meningitis. Over time, there was no increase in fluconazole resistance by Cryptococcus neoformans, but there was a dramatic increase in the resistance of Candida albicans. What is the most likely mechanism for the increased resistance to fluconazole?
A) An alteration or decrease in the amount of ergosterol in the cell membrane
B) Production of a lanosterol 14 α-demethylase with decreased affinity for the drug
C) Alterations in fungal genes that produce a failure to convert the drug into an active form
D) Alterations in genes that encode proteins involved in glucan synthesis
E) Production of squaline epoxidase with reduced binding to the drug

B. B/c that would alter the mechanism of azole drugs.

75

What are 3 major categories of pathogenic fungi?

superficial, cutaneous, subcutaneous mycoses
endemic mycoses-found in certain regions
opportunistic mycoses

76

Give some examples of endemic mycoses.

Blastomycosis
Histoplasmosis
Coccidioidomycosis
Penicilliosis

77

Give some examples of opportunistic mycoses.

Aspergillosis
Candidiasis
Cryptococcosis
Mucormycosis
Pneumocystosis

78

What's the deal with superficial mycoses?

limited to superficial surfaces of skin & hair
only of cosmetic importance

79

What are some diseases caused by superficial mycoses?

Pityriasis versicolor – Malassezia furfur
Tinea nigra – Hortae werneckii
Black piedra – Piedraia hortae
White piedra – Trichosporon spp

80

What's the deal with cutaneous mycoses?

infections of keratinized layers of skin, hair, nails
main problem is inflammation of host

81

What are some fungi that cause cutaneous mycoses?

Microsporum spp.
Trichophyton spp.
Epidermophyton floccosum

82

What are some diseases caused by cutaneous mycoses?

Dermatophytoses – infections of skin
Tinea unguium – infections of toes
Onychomycosis – infections of nails

83

What's the deal with subcutaneous mycoses?

these are infections of deep layers of skin, cornea, muscle, CT
seen in underdeveloped countries

84

What are some examples of fungi that cause subcu mycoses?

Hyaline molds – Acremonium spp., Fusarium spp.
Pigmented fungi – Alternaria spp., Cladosporium spp, Exophila spp.

85

What are some diseases caused by subcu mycoses?

Infection via traumatic inoculation
Abscess formation, nonhealing ulcers, draining sinus tracts
Localized; rarely disseminate

86

Describe the dimorphism of endemic mycoses.

in nature: saprobic morphology-at a lower temp.
in host: parasitic phase--in higher temp.

87

What does blastomyces dermatitis look like in tissue (parasitic)? What does it look like in nature (saprobic)?

parasitic: broad-based yeast
saprobic: nondescript mycelium

88

Where is blastomyces dermatitis found?

found in decaying organic matter in the ohio & mississippi river valleys

89

Which diseases are caused by blastomyces dermatitis?

pulmonary disease
extra pulmonary disease-skin, GU, CNS
disseminated disease if a pt is immunocompromised

90

What does histoplasma capsulatum look like in tissue (parasitic)? What does it look like in nature (saprobic)?

Tissue: intracellular budding yeast (likes to grow in phagocytic cells)
Nature: tuberculate macroconidia

91

Where do you find histoplasma capsulatum?

soil with high nitrogen content – bird/bat droppings
Ohio and Mississippi river valleys, Mexico, Central and South America

92

Which diseases does histoplasma capsulatum cause?

Acute pulmonary – 90% asymptomatic
Chronic pulmonary
Progressive disseminated

93

What does coccidioides immitis aka posadasii appear like in tissue (parasitic) & in nature (saprobic)?

Parasitic: endosporulating spherule
Saprobic: arthroconidia

94

Where is coccidioides immitis found?

soil, dust-airborne when dry
Southwest US
Mexico
Central & S. America

95

Which diseases does coccidioides immitis cause?

Primary pulmonary – often asymptomatic
Progressive pulmonary
Disseminated – usually immunocompromised

96

T/F None of the endemic mycoses have man-to-man transmission.

True.

97

What does penicillium marneffei look like in tissue (parasitic) & in nature (saprobic)?

parasitic: sausage-shaped yeast
saprobic: pigmented mold

98

Where is penicillium marneffei found?

soil, bamboo rat
Southeast Asia

99

Which diseases are caused by penicillium marneffei?

Disseminated infection more common in AIDS
Resembles histoplasmosis, cryptococcosis or tuberculosis

100

How does paracoccidioides brasiliensis appear in tissue (parasitic) & in nature (saprobic)?

parasitic: large, multiply budding yeast
saprobic: nondescript mold

101

Where is paracoccidioides brasiliensis found?

soil
S & Central America

102

Which diseases is paracoccidioides brasiliensis associated with?

Self-limiting pulmonary disease
Progressive pulmonary
Disseminated
More common in children and immunocompromised patient

103

What are the highlights of aspergillus? Note: opportunistic infection.

it is everywhere in air, soil, decaying matter! You are breathing it in now!
you get infected thru inhalation of spores
it has septate, branching hyphae when it is in tissue

104

Which diseases does aspergillus cause?

Allergic reactions
Obstructive paranasal or bronchial (called fungus ball)
Invasive pulmonary and disseminated
At risk: Neutropenic or immunodeficient patient – BMT, solid organ transplant
High fatality rate

105

What are the highlights of candida? note: opportunistic

multiple species, albicans is the most common
yeast-like forms with buds, pseudohyphae & germ tubes
found in normal flora of humans

106

Which diseases does candida cause?

Oropharyngeal infection – thrush
Esophagitis – AIDS
Vulvovaginal
Hematogenous disseminated

107

What are the highlights of cryptococcus? Note: opportunistic

encapsulated yeast
2 species: neoformans, gattii
ubiquitious saprophyte-found in pigeons & trees
can do an immunoassay for the capsular antigen
has a large polysaccharide capsule!

108

What's special about this assay that can be done for cryptococcus?

1 drop of blood
noninvasive
done in Africa for AIDS patients

109

Where does cryptococcus gattii occur?

the northwest

110

Which diseases can be caused by cryptococcus?

pulmonary cryptococcosis-not common
cryptococcal meningitis-opportunistic
opportunistic with AIDS or immunosuppression
seen in AIDS patients in underdeveloped countries

111

What are the highlights of mucormycosis? Note: opportunistic

aseptate coenocytic hyphae
found in soil, decaying vegetation
acquired via inhalation of spores

112

Which diseases can be acquired by mucormycosis?

Rhinocerebral – unique to diabetic ketoacidosis
Pulmonary
Disseminated, angioinvasive
Patients with metabolic acidosis and hematologic malignancy

113

What are the highlights of pneumocystis jirovecii? Note: opportunistic

can be asexual or sexual in its life cycle
tropic, sporocyst & cyst forms
cysts appear as empty, collapsed balls
main réservoir: humans!
Most people are infected with it! But it is opportunistic.

114

Which diseases are caused by pneumocystis jirovecii?

AIDS, immunosuppression, infants
Interstitial plasma cell pneumonitis
High mortality if untreated

115

The patient is a homeless 24-year-old male who presents with shortness of breath, fever and a non-productive cough. The patient was diagnosed with AIDS on the basis of CD4 counts and viral load. Examination of induced sputum showed cysts suggestive of Pneumocystis infection. What is the initial source of infection by Pneumocystis jirovecii?
A) An infected animal
B) An infected human
C) Contamination in the domestic water system
D) Water in an air-conditioning cooling tower
E) Contaminated soil

B. Most likely reservoir