Fungal Pathogens & Anti-Fungals

Question 1

Why have fungal infections become more prominent in the last several years?

Answer 1

1) Patients are living longer (more older people)

2) Immunosuppression therapies for other illnesses make patients more prone to opportunistic fungal infections

Question 2

Who are susceptible to fungal infections?

Answer 2

Primary immunodeficiencies (CGD, other immune defects)
Acquired immunodeficiencies (HIV/AIDs, Cancer, transplant, immune modulating drugs)
Mech. Ventilation
Catheters
Organ dysfunction
ICU-acquired sepsis

Question 3

Cells involved in immunity against fungal infections

Answer 3

Innate: neutrophils and band cells (immature)
Adaptive: CD4+ Th1 cells

Question 4

Why are fungal infections so evenly spread across in HIV patients with low CD4+ T lymphocyte counts?

Answer 4

The lower the # of CD4+ cells, the more likely to get fungal infections since there is no adaptive cells to fight the fungal pathogens.

Question 5

Examples of opportunistic fungi

Answer 5

1;. Yeast (Candida, cryptococcus, pneumocystis)

2. Molds (aspergillus, mucor & rhizopus)

Question 6

Examples of yeasts (3 total)

Answer 6

Candida
Cryptococcus
Pneumocystis

Question 7

Examples of molds (3 total)

Answer 7

Aspergillus

Mucor & Rhizopus (zygomycetes)

Question 8

Examples of dimorphic (systemic or endemic mycoses) fungi (4 total)

Answer 8

Histoplasma
Blastomyces
Coccidioides
Paracoccidioides

Question 9

Examples of branching bacteria (2 total)

Answer 9

Actinomyces

Nocardia

Question 10

How is mold transmitted?

Answer 10

through inhalation of airborne CONIDIA

Question 11

What happens to conidia in absence of sufficient pulmonary defenses?

Answer 11

conidial germination occurs

Question 12

What are the two possible outcomes of conidial germination if it successfully occurs?

Answer 12

1. If Neutropenia: excessive hyphal growth and dissemination

2. In corticosteroid-induced immunosuppression: PMN recruitment and tissue damage

Question 13

Mold that exists as septate hyphae in tissue with V-shaped branching

Answer 13

Aspergillus fumigatus

Question 14

What are examples of respiratory tract infections caused by Aspergillus?

Answer 14

• sinusitis
• ABPA
• Aspergilloma
• Chronic necrotizing aspergillosis,
• invasive aspergillosis

Question 15

What is the exaggerated response of the immune system that is caused by Aspergillosis and associated with asthma and CF? What is the treatment?

Answer 15

Allergic Bronchopulmondary Aspergillosis (ABPA)

Itraconazole; maybe corticosteroids

Question 16

What is the fungus ball that grows inside lung cavities, often from TB? What is the treatment?

Answer 16

Aspergilloma (aka mycetoma)

surgery + antifungal

Question 17

Treatment for invasive Aspergillus

Answer 17

azoles (Voriconazole)
Amphotericin B
Echinocandins

Question 18

Imaging, microscopy/histopathology, culture, and fungal antigen tests, and NAAT are diagnostic tests for

Answer 18

Apergillus

Question 19

Fungal antigen detection test targets what in Aspergillus?

Answer 19

Galactomannan or B-D-glucan in the cell wall

Question 20

What Aspergillus structure will be identified in lab-grown cultures but not in tissues (infected cells)?

Answer 20

Conidia structure

Question 21

What type of mold is becoming increasingly resistant to azole?

Answer 21

pan-resistant Aspergillus

Question 22

Aseptate mold with wide angle branching; causes Rhinocerebral (sinus infection spreading to brain), GI, and cutaneous infections

Answer 22

Mucor & Rhizopus species

aka. Zygomycetes

Question 23

Hallmark of mucor & Rhizopus species

Answer 23

Necrosis following angioinvasion (hemoptysis)

Question 24

How is Mucor & Rhizopus diagnosed?

Answer 24

Direct observation in tissue

Question 25

Treatment for Mucor & Rhizopus species (Zygomycetes)

Answer 25

Amphotericin B

Question 26

"dimorphic" fungi means what?

Answer 26

Fungi is in the mold form in the environment (25 celcius) and in the yeast form in the body (37 celcius)

Question 27

Oval yeast cells INSIDE macrophages; fungal homolog of MTB and can cause pneumonia with cavitary lesions

Answer 27

Histoplasma capsulatum

Question 28

Possible dissemination to liver, spleen, bone marrow can occur with

Answer 28

Histoplasma capsulatum

Question 29

How is Histoplasma capsulatum diagnosed?

Answer 29

Direct observation is tissue, culture, URINE antigen test

Question 30

Treatment for Histoplasma capsulatum

Answer 30

1. No txt if asymptomatic/mild | 2. Itraconazole or Amphotericin if serious

Question 31

Thick-walled extracellular yeast with broad-based budding (looks like a dumbbell); commonly infects skin, bones and joints

Answer 31

Blastomyces dermatitidis

Question 32

How does Blastomyces dermatitidis act in acute or chronic pneumonia setting?

Answer 32

1. Acute pneumonia: looks like bacterial, but doesn't respond to antibacterial therapy; may progress to ARDS 2. Chronic Pneumonia: looks like TB and Histo

Question 33

How is Blastomyces dermatitidis diagnosed?

Answer 33

Direct observation in tissue and culture

Question 34

Treatment for Blastomyces dermatitidis

Answer 34

Itraconazole or Amphotericin B (even for asymptomatic)

Question 35

Difference between Histoplasma and Blastomyces mold (conidia) forms

Answer 35

Histoplasma: bumpy cones Blastomyces: smooth cones

Question 36

If you have step 1 question, and it asks how you would treat a fungal infection and you don't know the answer, your best bet is...

Answer 36

Amphotericin B (it's toxic though, so be careful in the real world)

Question 37

fungal infection with spherules (w/ endospores inside) in tissue and barrels in environment; often disseminates to skin, lymph nodes, bones, and joints

Answer 37

Coccidioides immitis (Valley Fever)

Question 38

Causes erythema nodosum (desert bumps)

Answer 38

Coccidioides immitis (Valley Fever)

Question 39

How is Coccidioides immitis diagnosed?

Answer 39

Direct observation in biopsy, culture (BAL or tissue) or skin test

Question 40

Fungal infections that can be observed with lavage (BAL)

Answer 40

Pneumocystis jirovecii | Coccidioides immitis

Question 41

Treatment for Coccidioides immitis

Answer 41

Fluconazole Amphotericin B * if persistent or disseminating

Question 42

Fungal infection that can be diagnosed with urine antigen test

Answer 42

Histoplasma

Question 43

fungal infection that is endemic to Central and South America (Brazil); associted with outdoor work in rural areas

Answer 43

Paracoccidioides braziliensis

Question 44

Budding yeasts of Paracocciodioides are often described as __________ and may resemble the conidia of Histo

Answer 44

Ship's Wheels

Question 45

Treatment for Paracoccidioides

Answer 45

azoles, Amphotericin B, or TMP-SMX * Long-term (1 year) needed

Question 46

Budding yeasts and/or pseudohyphae in tissues

Answer 46

Candida species (C. albicans)

Question 47

How is Candida diagnosed?

Answer 47

requires culture on Sabrouraud agar and germ-tube formation @37 degrees

Question 48

Candida pneumonia is rare except in

Answer 48

neutropenic patients

Question 49

Extrapulmonary infections (Chronic mucocutaneous candidiasis, candidemia) caused by Candida are

Answer 49

common

Question 50

Treatment for invasive candida infections

Answer 50

Echinocandins Amphotericin B *if invasive

Question 51

If a question stem involves "Sabouraud agar", that implies that the infective agent is probably...

Answer 51

fungal

Question 52

heavily encapsulated yeast; meningitis is most common manifestation; usually with non-specific pulmonary symptoms (cough, fever, malaise)

Answer 52

Cryptococcus neoformans

Question 53

How is Cryptococcus diagnosed?

Answer 53

diagnose with direct visualization (india ink) with halo, culture or antigen detection

Question 54

With a cryptococcus neoformans infection with suspected meningitis, you also want to evaluate for...

Answer 54

pneumonia (and vice versa)

Question 55

Treatment for cryptococcus neoformans

Answer 55

Amphotericin B + Flucytosine

Question 56

Disc-shaped (cyst-like) yeast in lung tissue

Answer 56

Pneumocystis jirovecii

Question 57

Extrapulmonary infections are rare in Pneumocystis except in

Answer 57

AIDS

Question 58

What can be seen on CXR of Pneumocystis jirovecii?

Answer 58

diffuse interstitial pneumonia with "ground glass" infiltrates

Question 59

How is Pneumocystis diagnosed?

Answer 59

direct visualization in lung tissue, lavage (BAL), or sputum to diagnose

Question 60

Stain used to diagnose Pneumocystis

Answer 60

Silver Stain

Question 61

Treatment for Pneumocystis jirovecii

Answer 61

TMP-SMX

Question 62

Pneumocystis jirovecii is resistant to

Answer 62

most antifungals

Question 63

branching bacteria with "beaded" filaments; gram + aerobe that is weakly acid fast; pulmonary disease is typical, along with brain abscesses

Answer 63

Nocardia asteroides

Question 64

What pulmonary disease is typically caused by Nocardia?

Answer 64

pneumonia or lung abscess w/ cavity formation

Question 65

What other serious condition can be caused by Nocardia in immunocompromised patients?

Answer 65

Brain abscess

Question 66

How is Nocardia diagnosed?

Answer 66

Direct observation, culture

Question 67

Treatment for Nocardia asteroides

Answer 67

TMP-SMX

Question 68

branching bacteria, gram + anaerobe; normal oral flora that can lead to oral abscesses and PID w/ IUD

Answer 68

Actinomyces israelii

Question 69

How is Actinomyces diagnosed?

Answer 69

Direct observation is tissue biospy

Question 70

Treatment for Actinomyces israelii

Answer 70

Penicillin

Question 71

What are the three antifungal agents?

Answer 71

1. Cell wall active agents - Polyenes (Amphotericin B) - Azoles 2. B-Glucan synthesis inhibitors - Echinocandins (-fungin) 3. DNA & Protein Synthesis Inhibitor - Pyrimidine analogue (5-Flucytosine)

Question 72

How does fungal antigen detection tests work?

Answer 72

Samples of urine, serum, BAL fluid, or CSF are used to detect fungal polysaccharides or proteins that have shed into body fluids during infection

Question 73

What does fungal antigen detection test look for in cryptococcus species? What sample is used?

Answer 73

- Detects mannose-containing capsular polysaccharides | - serum or CSF

Question 74

What does fungal antigen detection test look for in Aspergillus? What sample is used?

Answer 74

- Galactomannan released by growing hyphae | - Serum or BAL

Question 75

What does fungal antigen detection test look for in Histoplasma? What sample is used?

Answer 75

- Different galactomannan polysaccharide | - URINE or Serum

Question 76

What fungal pathogen can cross react with other endemic fungi?

Answer 76

Histoplasma

Question 77

Penicillium which is the microbial source penicillin is now called

Answer 77

Talaromyces

Question 78

What is the MoA of Amphotericin B (polyene)?

Answer 78

Binds ergosterol and forms holes in the fungal cell membrane

Question 79

What is the molecular structure of Ampho B?

Answer 79

It has one hydrophilic face and one hydrophobic face

Question 80

How can fungal cells become resistant against Amphotericin B?

Answer 80

1. reduce concentration of ergosterol in the membrane | 2. modification of ergosterol to inhibit AmpB binding

Question 81

How is AmpB administered?

Answer 81

I.V. due to poor GIT absorption * oral only for lumenal GI infections

Question 82

Since AmpB is amphipathic, it is insoluble in water and must be formulated with _______ to keep it soluble in the plasma

Answer 82

lipids

Question 83

toxicities of Amphotericin B that occurs in nearly 100% after IV administration but abate in 30-45 minutes

Answer 83

"Shake and Bake" (fever, chills, muscle spasms)

Question 84

more severe toxicities of Amphotericin B

Answer 84

Nephrotoxicity (DCT damage) * especially in immunosuppressants patients, renal toxicities could be additive if they are taking other drugs with nephrotoxicity

Question 85

Amphotericin B pregnancy risk

Answer 85

Category B (safest anti-fungal during pregnancy)

Question 86

Azole antifungals inhibit fungal

Answer 86

ergosterol synthesis (inhibit lanosterol demethylase enzyme)

Question 87

Azole toxicity associated with heart

Answer 87

prolonged QT interval

Question 88

Azole pregnancy risk category

Answer 88

Category D (positive evidence of risk, but some situations may dictate)

Question 89

Azole toxicity associated with drug interaction

Answer 89

azole Inhibits a handful of CYP enzymes, decreasing the metabolism and increasing the serum conc. of other drugs (increase their toxicities) * especially for HIV drugs

Question 90

Azole toxicity associated with hormones

Answer 90

ketoconazole inhibits androgen synthesis and cause gynecomastia (breast enlargement in men) erectile dysfunction

Question 91

fungal mechanism of resistance against azoles

Answer 91

mutations of lanosterol demethylase

Question 92

why azoles and ampB should not be used together

Answer 92

azoles will cause less ergosterol in the cell membrane leading to reduced binding of ampB

Question 93

Why is Pneumocystis jirovecii resistant to anti-fungals?

Answer 93

Most anti-fungals target ergosterol, and pneumocystis doesn't have it (uses cholesterol from host) and the lanosterol enzyme has natural resistance mutations

Question 94

SMX/TMP is used primarily for what fungal infection

Answer 94

Pneumocystis jirovecii

Question 95

Sulfonamides and Trimethoprim are folate synthesis inhibitors that target what enzymes?

Answer 95

Sulfonamides: Pteroate Synthase Trimethoprim: DHFR

Question 96

Pneumocystis can become resistant against SMX/TMP by

Answer 96

mutations of pteroate synthase and DHFR

Question 97

PABA (intermediate product of SMX) can overwhelm both SMX/TMP drugs (True or False)

Answer 97

True

Question 98

SMX toxicities

Answer 98

Stevens-Johnson syndrome

Question 99

TMP toxicities

Answer 99

Hematologic (megaloblastic anemia, leukopenia, granulocytopenia) * due to folate deficiency

Question 100

SMX/TMP pregnancy categories

Answer 100

SMX: Category B TMP: Category C