Fungal Pathogens & Anti-Fungals Flashcards
Why have fungal infections become more prominent in the last several years?
1) Patients are living longer (more older people)
2) Immunosuppression therapies for other illnesses make patients more prone to opportunistic fungal infections
Who are susceptible to fungal infections?
Primary immunodeficiencies (CGD, other immune defects)
Acquired immunodeficiencies (HIV/AIDs, Cancer, transplant, immune modulating drugs)
Mech. Ventilation
Catheters
Organ dysfunction
ICU-acquired sepsis
Cells involved in immunity against fungal infections
Innate: neutrophils and band cells (immature)
Adaptive: CD4+ Th1 cells
Why are fungal infections so evenly spread across in HIV patients with low CD4+ T lymphocyte counts?
The lower the # of CD4+ cells, the more likely to get fungal infections since there is no adaptive cells to fight the fungal pathogens.
Examples of opportunistic fungi
1;. Yeast (Candida, cryptococcus, pneumocystis)
- Molds (aspergillus, mucor & rhizopus)
Examples of yeasts (3 total)
Candida
Cryptococcus
Pneumocystis
Examples of molds (3 total)
Aspergillus
Mucor & Rhizopus (zygomycetes)
Examples of dimorphic (systemic or endemic mycoses) fungi (4 total)
Histoplasma
Blastomyces
Coccidioides
Paracoccidioides
Examples of branching bacteria (2 total)
Actinomyces
Nocardia
How is mold transmitted?
through inhalation of airborne CONIDIA
What happens to conidia in absence of sufficient pulmonary defenses?
conidial germination occurs
What are the two possible outcomes of conidial germination if it successfully occurs?
- If Neutropenia: excessive hyphal growth and dissemination
2. In corticosteroid-induced immunosuppression: PMN recruitment and tissue damage
Mold that exists as septate hyphae in tissue with V-shaped branching
Aspergillus fumigatus
What are examples of respiratory tract infections caused by Aspergillus?
- sinusitis
- ABPA
- Aspergilloma
- Chronic necrotizing aspergillosis,
- invasive aspergillosis
What is the exaggerated response of the immune system that is caused by Aspergillosis and associated with asthma and CF? What is the treatment?
Allergic Bronchopulmondary Aspergillosis (ABPA)
Itraconazole; maybe corticosteroids
What is the fungus ball that grows inside lung cavities, often from TB? What is the treatment?
Aspergilloma (aka mycetoma)
surgery + antifungal
Treatment for invasive Aspergillus
azoles (Voriconazole)
Amphotericin B
Echinocandins
Imaging, microscopy/histopathology, culture, and fungal antigen tests, and NAAT are diagnostic tests for
Apergillus
Fungal antigen detection test targets what in Aspergillus?
Galactomannan or B-D-glucan in the cell wall
What Aspergillus structure will be identified in lab-grown cultures but not in tissues (infected cells)?
Conidia structure
What type of mold is becoming increasingly resistant to azole?
pan-resistant Aspergillus
Aseptate mold with wide angle branching; causes Rhinocerebral (sinus infection spreading to brain), GI, and cutaneous infections
Mucor & Rhizopus species
aka. Zygomycetes
Hallmark of mucor & Rhizopus species
Necrosis following angioinvasion (hemoptysis)
How is Mucor & Rhizopus diagnosed?
Direct observation in tissue
Treatment for Mucor & Rhizopus species (Zygomycetes)
Amphotericin B
“dimorphic” fungi means what?
Fungi is in the mold form in the environment (25 celcius) and in the yeast form in the body (37 celcius)
Oval yeast cells INSIDE macrophages; fungal homolog of MTB and can cause pneumonia with cavitary lesions
Histoplasma capsulatum
Possible dissemination to liver, spleen, bone marrow can occur with
Histoplasma capsulatum
How is Histoplasma capsulatum diagnosed?
Direct observation is tissue, culture, URINE antigen test
Treatment for Histoplasma capsulatum
- No txt if asymptomatic/mild
2. Itraconazole or Amphotericin if serious
Thick-walled extracellular yeast with broad-based budding (looks like a dumbbell); commonly infects skin, bones and joints
Blastomyces dermatitidis
How does Blastomyces dermatitidis act in acute or chronic pneumonia setting?
- Acute pneumonia: looks like bacterial, but doesn’t respond to antibacterial therapy; may progress to ARDS
- Chronic Pneumonia: looks like TB and Histo
How is Blastomyces dermatitidis diagnosed?
Direct observation in tissue and culture
Treatment for Blastomyces dermatitidis
Itraconazole or Amphotericin B (even for asymptomatic)
Difference between Histoplasma and Blastomyces mold (conidia) forms
Histoplasma: bumpy cones
Blastomyces: smooth cones
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…
Amphotericin B (it’s toxic though, so be careful in the real world)
fungal infection with spherules (w/ endospores inside) in tissue and barrels in environment; often disseminates to skin, lymph nodes, bones, and joints
Coccidioides immitis (Valley Fever)
Causes erythema nodosum (desert bumps)
Coccidioides immitis (Valley Fever)
How is Coccidioides immitis diagnosed?
Direct observation in biopsy, culture (BAL or tissue) or skin test
Fungal infections that can be observed with lavage (BAL)
Pneumocystis jirovecii
Coccidioides immitis
Treatment for Coccidioides immitis
Fluconazole
Amphotericin B
- if persistent or disseminating
Fungal infection that can be diagnosed with urine antigen test
Histoplasma
fungal infection that is endemic to Central and South America (Brazil); associted with outdoor work in rural areas
Paracoccidioides braziliensis
Budding yeasts of Paracocciodioides are often described as __________ and may resemble the conidia of Histo
Ship’s Wheels
Treatment for Paracoccidioides
azoles, Amphotericin B, or TMP-SMX
- Long-term (1 year) needed
Budding yeasts and/or pseudohyphae in tissues
Candida species (C. albicans)
How is Candida diagnosed?
requires culture on Sabrouraud agar and germ-tube formation @37 degrees
Candida pneumonia is rare except in
neutropenic patients
Extrapulmonary infections (Chronic mucocutaneous candidiasis, candidemia) caused by Candida are
common
Treatment for invasive candida infections
Echinocandins
Amphotericin B
*if invasive
If a question stem involves “Sabouraud agar”, that implies that the infective agent is probably…
fungal
heavily encapsulated yeast; meningitis is most common manifestation; usually with non-specific pulmonary symptoms (cough, fever, malaise)
Cryptococcus neoformans
How is Cryptococcus diagnosed?
diagnose with direct visualization (india ink) with halo, culture or antigen detection
With a cryptococcus neoformans infection with suspected meningitis, you also want to evaluate for…
pneumonia (and vice versa)
Treatment for cryptococcus neoformans
Amphotericin B + Flucytosine
Disc-shaped (cyst-like) yeast in lung tissue
Pneumocystis jirovecii
Extrapulmonary infections are rare in Pneumocystis except in
AIDS
What can be seen on CXR of Pneumocystis jirovecii?
diffuse interstitial pneumonia with “ground glass” infiltrates
How is Pneumocystis diagnosed?
direct visualization in lung tissue, lavage (BAL), or sputum to diagnose
Stain used to diagnose Pneumocystis
Silver Stain
Treatment for Pneumocystis jirovecii
TMP-SMX
Pneumocystis jirovecii is resistant to
most antifungals
branching bacteria with “beaded” filaments; gram + aerobe that is weakly acid fast; pulmonary disease is typical, along with brain abscesses
Nocardia asteroides
What pulmonary disease is typically caused by Nocardia?
pneumonia or lung abscess w/ cavity formation
What other serious condition can be caused by Nocardia in immunocompromised patients?
Brain abscess
How is Nocardia diagnosed?
Direct observation, culture
Treatment for Nocardia asteroides
TMP-SMX
branching bacteria, gram + anaerobe; normal oral flora that can lead to oral abscesses and PID w/ IUD
Actinomyces israelii
How is Actinomyces diagnosed?
Direct observation is tissue biospy
Treatment for Actinomyces israelii
Penicillin
What are the three antifungal agents?
- Cell wall active agents
- Polyenes (Amphotericin B)
- Azoles - B-Glucan synthesis inhibitors
- Echinocandins (-fungin) - DNA & Protein Synthesis Inhibitor
- Pyrimidine analogue (5-Flucytosine)
How does fungal antigen detection tests work?
Samples of urine, serum, BAL fluid, or CSF are used to detect fungal polysaccharides or proteins that have shed into body fluids during infection
What does fungal antigen detection test look for in cryptococcus species? What sample is used?
- Detects mannose-containing capsular polysaccharides
- serum or CSF
What does fungal antigen detection test look for in Aspergillus? What sample is used?
- Galactomannan released by growing hyphae
- Serum or BAL
What does fungal antigen detection test look for in Histoplasma? What sample is used?
- Different galactomannan polysaccharide
- URINE or Serum
What fungal pathogen can cross react with other endemic fungi?
Histoplasma
Penicillium which is the microbial source penicillin is now called
Talaromyces
What is the MoA of Amphotericin B (polyene)?
Binds ergosterol and forms holes in the fungal cell membrane
What is the molecular structure of Ampho B?
It has one hydrophilic face and one hydrophobic face
How can fungal cells become resistant against Amphotericin B?
- reduce concentration of ergosterol in the membrane
2. modification of ergosterol to inhibit AmpB binding
How is AmpB administered?
I.V. due to poor GIT absorption
- oral only for lumenal GI infections
Since AmpB is amphipathic, it is insoluble in water and must be formulated with _______ to keep it soluble in the plasma
lipids
toxicities of Amphotericin B that occurs in nearly 100% after IV administration but abate in 30-45 minutes
“Shake and Bake” (fever, chills, muscle spasms)
more severe toxicities of Amphotericin B
Nephrotoxicity (DCT damage)
- especially in immunosuppressants patients, renal toxicities could be additive if they are taking other drugs with nephrotoxicity
Amphotericin B pregnancy risk
Category B (safest anti-fungal during pregnancy)
Azole antifungals inhibit fungal
ergosterol synthesis (inhibit lanosterol demethylase enzyme)
Azole toxicity associated with heart
prolonged QT interval
Azole pregnancy risk category
Category D (positive evidence of risk, but some situations may dictate)
Azole toxicity associated with drug interaction
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
Azole toxicity associated with hormones
ketoconazole inhibits androgen synthesis and cause gynecomastia (breast enlargement in men) erectile dysfunction
fungal mechanism of resistance against azoles
mutations of lanosterol demethylase
why azoles and ampB should not be used together
azoles will cause less ergosterol in the cell membrane leading to reduced binding of ampB
Why is Pneumocystis jirovecii resistant to anti-fungals?
Most anti-fungals target ergosterol, and pneumocystis doesn’t have it (uses cholesterol from host) and the lanosterol enzyme has natural resistance mutations
SMX/TMP is used primarily for what fungal infection
Pneumocystis jirovecii
Sulfonamides and Trimethoprim are folate synthesis inhibitors that target what enzymes?
Sulfonamides: Pteroate Synthase
Trimethoprim: DHFR
Pneumocystis can become resistant against SMX/TMP by
mutations of pteroate synthase and DHFR
PABA (intermediate product of SMX) can overwhelm both SMX/TMP drugs (True or False)
True
SMX toxicities
Stevens-Johnson syndrome
TMP toxicities
Hematologic (megaloblastic anemia, leukopenia, granulocytopenia)
- due to folate deficiency
SMX/TMP pregnancy categories
SMX: Category B
TMP: Category C
