34. Mycology π’ Flashcards
What are the two main phyla of fungi?
Ascomycota Basidiomycota
Which fungus out of the basidiomycetes causes the largest burden of disease?
Cryptococcus neoformans and Cryptococcus gatii Causes cryptococcal meningitis
What three types of illness do fungi cause?
Allergies Mycotoxicoses Mycoses
Define mycotoxicosis.
A toxic reaction to the ingestion/inhalation of toxins produced by fungi
What is known as the most carcinogenic natural compounds and what produces it?
Aflatoxin β Aspergillus flavus
Define mycosis.
Disease caused by fungi that is classified based on the level of tissue affected
What are the four types of mycosis?
Superficial Cutaneous Subcutaneous Systemic
What are superficial mycoses? Give some examples.
Mycoses that affect the skin and hair No tissue is invaded so there is no cellular response Black piedra White piedra Dandruff Tinea nigra
What are cutaneous mycoses? Give some examples.
Produce keratinases β causes inflammation Trychopyton and Microsporum are main examples Other examples: Tinea capitis Tinea corporis Tinia pedis
What are subcutaneous mycoses?
Chronic, localised infections of the skin and subcutaneous tissue following traumatic implantation of the aetiological agent.
What type of fungal infection is a big problem in transplant settings?
Aspegillosis
What are the three types of candida infection that can occur in the immunocompromised?
Mucosal Systemic Superficial
What are the three types of mucocutaneous candidiasis that occurs in people with HIV?
Oesophageal Vulvovaginal Oropharyngeal
What are the main risk factors for systemic candida infections?
Chemotherapy Gut-related surgery Catheters
What are the three main targets for antifungal therapy?
Cell membrane DNA synthesis Cell wall
How do antifungals that target the cell membrane work? Give some examples.
Fungal cell membranes contain ergosterol instead of cholesterol Some antifungals inhibits ergosterol synthesis Examples: azole (itraconazole) Polyene antibiotics (Amphotericin B and Nystatin)
How do antifungals that target DNA synthesis work? Give an example.
Pyrimidine analogues are used to interfere with DNA synthesis Example: Flucytosine (used for Cryptococcus)
How do antifungals that target the cell wall work? Give an example.
They inhibit the assembly of fungal cell wall components such as glucans and chitin Example: Caspofungin (a type of Echinocandin)
What components are found in fungal cell walls but not in mammalian cell walls?
Glucan Chitin
What are the four main phyla of fungi and which most commonly causes human fungal infection?
Ascomycota β MAIN ONE Basidiomycota Chytridiomycota Zygomycota
Give examples of how the morphogesis of fungi contributes to its ability to cause disease in the host.
Candida albicans exist as single spores but they can become hyphae, which allows tissue invasion Cryptococcus forms a capsule to evade phagocytosis Aspergillus sp. are inhaled as conidia and invade tissues as hyphae
Which pattern recognition receptors are important in detection of fungal pathogens?
TLR
Name 2 deficiencies that are associated with an increased risk ofchronic mucocutaneous candidiasis.
Dectin 1 (involved in activation of an inflammatory cytokine response) CARD 9 (downstream of Dectin 1)
Name 3 factors that are associated with increased risk of Aspergillosis in transplantation.
TLR4 S4 β loss of function Dectin 1 Plasminogen alleles
Which PRR is actively recruited to Aspergillus fumigatusphagolysosomes?
TLR9
What can plasminogen directly bind to?
Aspergillus fumigatus conidia
Which cells are the most important in defence against fungal infection?
Neutrophils
What do neutrophils release that enable them to trap Aspergillus?
NETs
Describe how fungal morphogenesis governs the dendritic cell modulation of adaptive immunity.
Hyphal forms = Th2 response Conidium = Th1 response
What cytokine therapy has been shown to enhance clearance ofinvasive fungal infection?
IFN-gamma
Describe the principles of adoptive immunotherapy for fungal infection.
If a patient is receiving a stem cell transplant, you can generate anti-fungal T cells, which can be cultured in large numbers and administered to the patient
Give an example of gene therapy for chronic granulomatous disorder.
Restoration of gp91 function This is involved in the generation of NADPH oxidase β this generates reactive oxygen species, which is required to kill microbes NOTE: another type of gene therapy = restoration of neutrophil NET formation
What types of hypersensitivity reaction are associated with fungal allergies?
Type 1, 3 and 4
What are two predisposing conditions for allergic bronchopulmonary aspergillosis (ABPA)?
Asthma Cystic fibrosis
What is the obligatory criteria for ABPA?
Total baseline serum IgE > 1000 IU/ml Positive immediate hypersensitivity skin test or Aspergillus-specific IgE
List some supportive criteria for ABPA.
Eosinophilia > 500 cells/ul Serum precipitating or IgG antibodies to Aspergillus fumigatus Consistent radiographic abnormalities
List some radiological features of ABPA.
Dilated bronchi with thick walls Proximal bronchiectasis Ring or linear opacities Upper or central region predilection Lobar collapse due to mucous impaction Fibrotic scarring
What might be seen in a CT scan of a patient with ABPA?
Hyper dense mucous sign
Describe the main treatment options for ABPA.
Corticosteroids Itraconazole may be used as a steroid-sparing agent Recombinant anti-IgE antibodies (omalizumab) may be useful
List three other examples of fungal allergies, including associated features of each.
Aspergillus rhinosinusitis ο· May be allergic or invasive ο· Obliterated sinuses ο· Treated with oral corticosteroids Severe asthma with fungal sensitisation ο· Fungal sensitisation as a potential cause of severe asthma ο· Requires exclusion of ABPA ο· Treatment with anti-fungal unclear Hypersensitivity pneumonitis (extrinsic allergic alveolitis) ο· Allergy requires long-term exposure to allergen (often occupational)
What test is used to diagnose fungal allergies?
Skin prick testing
Which type of hypersensitivity is each of the previously mentioned fungal allergies?
ABPA β type 1 or 4 Asthma β type 1 Rhinitis β type 1 Hypersensitivity pneumonitis β type 4
Different mechanisms of antifungals?
- alter cell membrane permeability 2. block nucleic acid synthesis 3. disrupt microtubule functions
Antifungals that alter cell membrane permeability?
Azoles (ketoconazole), polyenes (Nystatin), Terbinafine
Antifungals that block nucleic acid synthesis?
Flucytosine
Antifungals that disrupt microtubule functions?
Griseofulvin
What topical drugs are used for cutaneous fungal infections?
azoles and polyenes
What are the systemic drugs used for superficial fungal infections?
Griseofulvin, Terbinafine, and Itraconazole (azole)
Systemic drugs used for systemic fungal infections? *Bad systemic infections
Amphoteracin B (Amphoterrible -> donβt use) Azoles Flucytosine (5-FC)
What are the topical azalea antifungals and their MOA?
clotrimazole, ketoconazole, miconazole - fungicidal, impairs the formation of fungal cell membranes therefore increasing permeability (so intracellular contents leak out leading to cell death)
Clinical uses of Topical azole antifungals
tinea corporis (body), tinea cruris (jock itch), tinea pedis (athletes foot), cutaneous candidiasis (yeast infection) *Tinea=condition caused by dermatophytes
CIs of topical azole antifungals (c,k,m)
pregnancy, lactation -caution w/ liver failure - donβt use ketoconazole if hx of sulfa allergy
Application of topical azole antifungals
lotion or powder -> apply 2x daily for 2-4 weeks continue for 1 week after lesions clear
MOA of topical azole antifungals
inhibit CYP450, inhibit synthesis of ergosterol (cell membrane of fungi) SE: pruritis, irritation, burning or stinging
Clotrimazole
Names: Gyne-Lotrimin, Mycelex 3&7, Trivagizole 3 Indications: - cutaneous candidiasis (topical) - vulvovaginal candidiasis (topical) -oropharyngeal candidiasis (thrush -> oral formulation) CI: hypersensitivity to clotrimazole or any other component of formula
Oropharyngeal candidiasis dosing
troche dissolved slowly 5x / day for 14 days
Clotrimazole MOA
binds to phospholipids in the fungal cell membrane altering permeability and loss of intracellular elements -very little systemic absorption from topical -oral: inhibitory concentrations in saliva for up to 3 hours post dissolution of troche
Drug interactions for clotrimazole
topical= none oral drug interactions similar to other azaleas due to inhibition of P450 enzymes
Adverse effects of Clotrimazole
Topical: vulvovaginal burning oral: abn. LFTs, pruritus, N/V monitor: periodic LFTs
Ketoconazole (topical)
formula: cream, foam, gel or shampoo indications: tinea corporis, tinea cruris, tinea pedis, cutaneous candidiasis, + seborrheic dermatitis and tinea versicolor
Topical azoles: miconazole (micatin, monistat, desenx, lotrimin AF)
formulations: aerosol, powder aerosol, intravaginal supp, cream, ointment, lotion indications: tinea corporis, tinea cruris, tinea pedis, cutaneous candidiasis, tinea versicolor + vulvovaginal candidiasis -intravaginal sups may interfere with warfarin
Topical Polyene: Nystatin (mycostatin)
Indications: cutaneous and mucocutaneous infections caused by candida -oral and intestinal candidia infections CIs: hypersensitivity reaction
Mycostatin MOA
binds to sterols in fungal cell membrane and changes the cell wall permeability leading to the leakage of intracellular contents
Mycostatin dosing
cream, ointment and powder:100,000 U/g 2-3x daily oral suspension - 400,000-600000 U QID intestinal infections: tablets- 500000-1,000,000 U po q8H
Mycostatin pharmokinetics/dynamics
onset of action -> relief of sxs: w/in 24-72 hours systemic absorption- none (why its used to tx intestinal infections) -no drug interactions
Adverse effects of mycostatin
contact dermatitis - develop blisters -SJS -oral: N/V/D
Systemic drugs for superficial fungal infections
Griseofulvin, terbinafine, itraconazole -for hair, skin and nails
Griseofulvin indications
used to tx tine infections of skin, hair and nails -most commonly used for tx of tine capitis (scalp)
Griseofulvin MOA
inhibits fungal cell division binds to himan keratin making it resistant to fungal invasion (goes down into hair follicles as hair grows out, takes a long time to work)
Duration fo Griseofulvin therapy
tinea corporis: 2-4 weeks tinea cruris: 2-6 weeks tinea capitis: 4-6 weeks tinea pedis: 4-8 weeks tinea unguium (nails): 4-6 months or longer administration: fatty meal (PB or ice cream) may increase GI absorption - with food or milk to decrease GI upset