Fungi Flashcards
Malessezia
Pathogenesis, risk factors, clinical presentation, diagnosis, treatment
- Commensal normally found on skin
- Degradation of lipids damages melanocytes and causes hyper/hypopigmented and/or pink patches on skin
- Assocaited with humidity and warm climates
- Can cause liver spots - Pityrasis Versicolor
- Also cause of dematitis and dandruff
- Diagnose with skin scraping and KOH Prep - Spaghetti and Meatball appearance
- Treat with topical ketoconazole, selenium sulfide
Only drug class that exploits fungal cell wall
Echinocandins
Why diagnosing fungi is difficult
- Antibiotics/steroids can worsten infection
- Blood cultures for systemic infections are often negative
- Difficult to discriminate b/w colonization and disease
Vaginal Candidiasis
- Presents with itching, soreness, discomfort, white discharge, rash
- Can correlate with diabetes, contraceptive use, or antibiotics
Subcutaneous Mycoses
Chronic, localized infections of skin and subcutaneous tissue that rarely spread systemically
Result of traumatic implantation of environmental fungi (thorn or splinter)
Blastomycosis
- Endemic to Eastern and Central US
- Histology shows broad-based budding that is the same size as RBC
- Associated with farmers, hunters, and campers
- Causes inflammatory lung disease that can disseminate to skin and bone
- Skin lesions can stimulate squamous cell carcinoma
- forms granulomatous nodules
Candida virulence factors
Adherence to catheters, dentures, etc
Proteolytic Enzymes (nutrient acquisition, penetration)
Biofilm formation
Mofphogenetic transition (yeast –> hyphal)
Immunomodulatory effects
Cryptococcosis
Virulence Factors
Polysaccharide capsule (antiphagocytic)
Survives in macrophages
Melanin
Has Alpha Glucan Polymers - Resistant to B-Glucan Drugs (Echinocandins)
Fungal drug resistance (drugs and mechanisms)
Resistance to Amphotericin B and Echinocandins is rare
5-FC and Azole resistance is common
Resistance usually due to:
- efflux pumps
- upregulation of target enzyme
- point mutations
- intrinsic resistance - some species
Dermatophytes (Tinea) Infections - Cutaneous Mycoses
Tinea pedia - Athlete’s foot
Tinea cruris - inguinal area
Tinea capitis - head or scalp; associated with lymphadenopathy, alopecia, scaling
Tinea corporis - Occurs on torso; Ringworm; can be acquired from contact with infected dog or cat
Tinea unguium - occurs on nails
Aflatoxin
Mycotoxin produced by Aspergillis
Leads to hepatocellular carcinoma
Mucormycosis
Species, risk factors, disease
Species: Rhizopus or Mucor
Risk factors:
- DIABETES - diabetes defining illness (“functional neutropenia”)
- Ketoacidosis
- AIDS, steroid use, organ transplant
Disease:
- Invasive sinusitis with rhonocerebral spread
- Pulmonary infections in diabetics
- Skin infections in burn patients
Cryptococcosis
Risk factors and disease
- Caused by yeast
- Acquired via spores inhaled from pigeon droppings
- C. gatti associated with Eucalyptus trees
- Initial disease is flu-like or pneumonia, but can cause meningitis
- Cryptococcal meningitis is AIDS defining illness
Predisposing factors to Candida diseases
CD 4 T Cell Defect –> Oral Candidiasis (thrush)
Neutropenia –> Systemic Candidiasis (high morbidity)
Genetic Defect (Th17 or AIRE) –> Mucocutaneous Candidiasis
Dysregulated Inflammatory Respose (or no defect) –> Vaginitis
Mucormycosis
Pathogenesis, Diagnosis, Treatment
- Pathogenesis*: Iron utilization at acidic pH, proteinases, damages endothelial cells, invades blood vessels and causes thrombosis
- Diagnosis*: Characteristic aseptate hyphae with right-angle branching
- Treatment*: Amphotericin B
Aspergillus
Diagnosis
Diagnosis:
- Non-pigmented, septated hyphae with acute-angle branching
- Aspergilloma: proliferating hyphae from fungal balls
- Invasive Aspergillosis: Galactomannan Antigen Test (80% sensitive)
- Chronic Pulmonary Aspergillosis: Often confused with TB
Yeast
- Spheroid/oval shaped cell
- reproduce asexually
- Genera-specific bud shapes important for diagnosis
Name the 4 major fungal drug classes and their targets
- Polyenes –> egosterol
- Azoles –> egosterol
- Echinocandins –> cell wall
- Nucleoside inhibitor –> uracil
Invasive Aspergillosis
INflammatory, granulomatous, necrotizing disease of lungs
Can be systemic and fatal
Associated with neutropenia, organ transplant, bone marrow transplant, and immunosuppressive therapy
Azoles
- Inhibit egosterol syntheses - 14-alpha-demethylase
- Lanosterol -X-> Egosterol
- Prevent cell from dividing
- Fungistatic - more likley to build resistance
- Toxic sterols incorporated into membrane
- Used for local or less serious infections
Cutaneous Candidiasis
- Onychomycosis (nails)
- Intertrigo (rash of body folds)
- Diaper rash
Risk factors: Diabetes, diapers, obesity, alcoholism
Treatment: Itraconazole (oral), topical antifungals
Pneumocystis jirovecii
Diagnosis and treatment
Diagnosis:
- Giemsa Stain - Trophic form; aggregates of 2-8
- GMS Stain - spores; squashed ping pong balls
Treatment:
- TMP-SMX
Superficial mycoses
- do not invade living tissue
- no cellular response from host
- Malassezia furfur is most common species
- Easy to diagnose with KOH skin scrapings
Pneumocystis jirovecii
Risk factors, disease
- Causes Pneumocystis Pneumonia in immunocompromised
- PCP causes interstitial fibrosis of lungs with pulmonary infiltrate
- Risk factors include: chronic lung disease, HIV, corticosteroids, immunosuppressents, cigarette smoking, low CD 4 Count
4 Types of Mycotic Diseases
- Superficial
- Cutaneous
- Subcutaneous
- Systemic
Fungal Microscopy methods
KOH Wet Mount
- allows you to visualize hyphae and morphology
- KOH dissolves skin, hair, and debris
- Lactophenol blue stain added
GMS - Gormori Methenamine Silver (silver stain)
Calcofluor White (immunofluorescent stain for chitin)
Explanation for rise of Opportunistic Fungal Infections
Incidence has risen dramatically in recent years due to modern medical techniques and AIDS
What characteristic allows a fungi to become a pathogen?
Ability to grow at 37°C
Disseminated Candidiasis
- Bloodstream infection
- Most originate from biofilms on IV catheters
- Acute Stage shows: fever, skin lesions, shock
- Chronic Shows: slow spread of lesions, hepato-splenic lesions, infrequent fungemia
- DIFFICULT TO DIAGNOSE
- Treat with Fluconazole and Echinocandin (First Line), or Amphocerin B as second line (toxic)
Fungi that can acheive person-to-person transmission
- Dermatophytes
- Candidiasis (hand hygeine)
- Pneumocystosis (unknown, aerosol suspected)
Histoplasmosis
- Endemic to Misissippi and Ohio River Valleys
- Associated with Caves (bat droppings) or Construction
- You will see Macrophages filled with Histoplasma
- Cause palatal/tongue ulcers, splenomegaly
Paracoccidioidomycosis
- Endemic to Latin America
- Histology shows Captain’s Wheel budding formation
- Symtoms similar to Coccidioidomycosis, more common in males
What factors determine whether a fungus will cause disease in a host?
Size of inoculum and host resistance
What are some ways drugs can exploit fungi?
- Fungi have egosterol in their membranes, mammals have cholesterol
- They have cell walls of glucans and mannans, no peptidoglycan
Allergic Bronchopulmonary Aspergillosis (ABPA)
Risk to those infected with COPD, cystic fibrosis, emphysema
Type 1 Hypersensitivity
Diagnosis of Disseminated Candidiasis
- CHROMagar on culture identifies species
- Serology only 50% sensitive in blood
- Direct tissue samples may show organism
Non-invasive Aspergillosis
Colonization of preexisting cavities in lung (TB)
Pulmonary aspergilloma (fungus balls)
Mycetismus
Ingestion of preformed fungal toxin (mushroom poisioning)
Sporotrichosis
- Caused by Sporothrixi schenckii
- Rose Grower’s Disease - entry via thorn or splinter
- Defining Characteristic: Nodular lesions that trace path of lymphatic drainage
- Gardeners and plant nursery workers at risk
- Cigar Shaped Yeast
- Treat with Itraconazole or Potassium Iodide
Important immune players against fungi
- PRR’s
- Neutrophils
- T Cells
Echinocandins
- Blocks B(1,3) glucan synthesase (Inhibits cell wall synthesis)
- Leads to dissolution of cell wall
- Only available in IV form - use for life threatening disseminated infection
How do we know if an infection is fungal?
- Antibiotics don’t work
- Duration - Viral infection would have been cleared already
Amphotericin B
- Polyene drug class
- Fungicidal
- Binds to egosterol and forms holes in fungal membrane
- Used to treat systemic infections
- HIGH TOXICITY (especially nephrotoxicity)
Chronic Mucocutaneous Candidiasis
- Due to mutation in STAT or AIRE
- Defective Th17 signaling
- Severity of presentation varies
- Treat the endocrine or autoimmune manifestations
Mold
- Includes Hyphae and Mycelium (mass of hyphae)
- Filamentous, cylindrical cels
- Septae or non-septae
- sexual reproduciton
Fungal cell wall composition
Chitin, Glucan, Mannan
Chromoblastomycosis (black molds)
Transmission, risk factors, clinical presentation, treatment, diagnosis
- Common in warmer climates
- Transmitted through thorny plant or splinter
- Agrucultural laborers who work barefoot at risk
- Presents with cutaneous and subcutaneous mycosis with chronic granulomas on feet and legs
- Treat with surgery; deep lesions are treated with itraconazole
- Pigmented cells on H&E, Gray “mouse fur” mold on culture
Testing Antifungal Sensitivity
MIC - Minimum Inhibitory Concentration
MIC is the lowest concentration of antifungal that allows visible growth
80% of growth inhibition is commonly used
How do fungi disseminate and infect?
Fungi form spores, which allow them to disperse in water and air
Characteristics that separate fungi from other Domains and Kingdoms
- Eukaryotic (separates from bacteria)
- Heterophilic (separates from plants and algae)
- Rigid cell walls (separates from animals)
Opportunistic Fungal Infections (species)
- Candida albicans
- Aspergillus fumigatus
- Cryptococcus neoformans
- Mucor and Rhizopus
Coccidiomycosis
- Endemic to Southwestern US and California
- Histology shows spherule filled with endospores (much larger than RBC)
- Those at risk include retirees, archeologists, farmers, and military
- Disseminates to skin and bone
- Erythema nodusum (desert bumps) or mulitforme arthralgias (desert rheumatism)
- Can cause meningitis
General virulance factors of fungi
Similar to Bacteria:
- Adhesins –> Biofilm formation
- Capsule formation
- Evasion of host response
- Modulation of host immune response (dysregulation of cytokines)
- Aquisition of nutrients from host cells
- Mycotoxins (Aflatoxin)
Unique:
- Ability to switch cell type - dimorphism
- Cell wall barriers
Polymorphic
fungi that have multiple growth forms but these do not correlate to a distinct stage in their life cycle (hyphal, pseudohyphal, yeast)
Cryptococcosis
diagnosis and treatment
- India Ink stain - capsule excludes ink
- Mucicarmine Stain - red staining is diagnostic
- Latex agglutination test (for polysaccharide capsule)
- Grown on Niger Seed Agar
Treatment
- Amphotericin B and 5-Fluorocytesine
- Long term Fluconazole for AIDS patients
Systemic Mycoses
Characteristics, Organisms
- Involve deep viscera and disseminate widely; often fatal
- Require aggressive treatment - Azoles for local infection, Amphotericin B for systemic
- All are dimorphic - mold in cold, yeast in heat
- Usually diagnosed based on geography
- Include: Histoplasma, Blastomyces, Coccidioides, and Paracoccidioides
5-Flucytosine
- Converted to 5-fluorouracil by Cytosine Deaminase
- Interferes with fungal DNA Synthesis
- Our cells do not take up this drug
- Fungistatic - but rapid acquisition of resistance; must be used in synergy with another class of drug (usually Amphotericin to reduce its side effects)
Dimorphic
Fungi that grow as mold or yeasts during specific stages of their life cycle
Oral Candidiasis
Pharyngeal or esophageal thrush - creamy white plaques
At risk:
- HIV Patients with CD 4 < 200
- Infants (T cell immunity not developed)
Primary pathogen vs Opportunistic pathogen
Primary pathogen can cause disease in immunocompetent host
Opportunistic pathogen is restricted to an immunocompromised host
Dermatophytes
Pathogenesis, risk factors, clinical presentation, diagnosis, treatment
- Contains keratinases that break down keratin in skin, nails, and hair
- Acquired from direct contact with infected host
- Risk factors include: elementary school, contact sports, humid areas, tight shoes, sweating, public showers, and locker rooms
- Presents with itchy red circular rash (ringworm)
- Branching Septae visible on KOH prep skin scrapings
- Treat skin ringworm with non-prescription Azole
- Treat scalp ringworm with prescription oral anti-fungal
Candida morphology
Polymorphic
Yeast, pseudohypha, and true hyphae (for invasion)
Ability to form germ tubes is diagnostic feature
Dermatophytes species
Microsporum, Trichophyton, Epidermophyton
Pityriasis Versicolor
Disease caused by Malassezia
Liver spots
