Dr. Sheppard -- Basic Mycology and Antifungal Medications Flashcards by Jodeci Malixi

Definition of hyphae

Filamentous tubular structure with or without internal septae

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Define mycelium

Group of hyphae, often used interchangeably with hyphae

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Define yeast

Unicellular round fungal cells that reproduce by budding

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Define conidia

Asexual spores of ascomycetes (most pathogenic fungi)

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Define conidiophore

Specialized hyphae that produce conidia

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Define pilobolus

Zygomycete that grows in cow dung

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Describe how pilobolus fungi spread their spores (3 steps)

1) Spores pass thruogh cow dung
2) Aims by bending stalk until shadow from sporangium falls on sensor at bottom of sporangiophore
3) Hydrostatic “cannon” guided by light shoots spores into unsoiled grass

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Why is antifungal treatment more complicated than antibacterial treatment?

Antimicrobial agents exploit differences between microorganisms and humans, but fungi are eukaryotic and closely related to humans, so ribosomes and DNA replication enzyems are too similar for targeting

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Describe the cell membrane of fungi

Principally ergosterol instead of cholesterol

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3 types of antifungals that target fungal cell membrane

Azoles
Allylamines
Polyenes

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Antifungal that can be activated selectively by fungi to arrest DNA synthesis

5-flucytosine (cytosine deaminase)

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Component of outer layer of fungal cell that is lacking on mammalian cells

Cell wall

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Antifungal that inhibits glucan synthase (disrupt cell wall)

Echinocandins

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Mechanism of azoles

Inhibition of 14 alpha demethylase (key enzyme to synthesize ergosterol) –> toxic intermediates accumulate in the cell membrane

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Mechanism of allylamines

Inhibit squalene epoxidase early in the ergosterol pathway

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Mechanism of polyenes

Binds to ergosterol in membranes, forming pores to allow cell contents to leak out

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3 forms of polyenes

Nystatin
Amphotericin B desoxycholate
Lipid-based formulations of Amphotericin

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Highly toxic polyene and the only form it can be used in

Nystatin (topical only)

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3 side effects of amphotericin B desoxycholate

Bind cholesterol
Renal failure
Severe infusional toxicity

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How are lipid-based formulations of amphotericin less toxic than amphotericin B desoxycholate and nystatin?

Use of a lipid carrier intermediate in solubility between ergosterol and cholesterol

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Disadvantage of lipi-based formulation of Amphotericin

VERY expensive

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Azole with yeast only activity

Fluconazole

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Oldest azole with yeast and mold activity

Itraconazole

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2 disadvantages of itraconazole

Poor absorption

Erratic kinetics

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Newest azoles (2)

Voriconazole | Posaconazole

Advantage of using voriconazole or posaconazole

Excellent anti-mold activity, particularly Aspergillus species

2 toxic effects of azoles (specify which azoles)

``` Hepatitis (all agents) -- VORI > ITRA > POSA > FLU Visual hallucinations (VORI) ```

Allylamine antifungal

Terbinafine (lamisil)

Primary use of terbinafine (lamisil)

Superficial fungal infections (commonly topical, but oral available for extensive infections or nail infections)

Side effect of allylamines

Hepatitis

What is 5-flucytosine (5-FC)

A prodrug converted by fungal cytosine deaminase into 5-fluorouracil (a type of chemotherapeutic)

Mechanism of 5-FC

Inhibition of DNA chain synthesis | NOTE: only useful in combination therapy

Toxicity of 5-FC

Bone marrow suppression

3 echinocandins

Caspofungin Micafungin Anidulafungin

Mechanism of echinocandins

Inhibition of synthesis of cell wall beta-glucan --> cell wall fragmentation

3 fungi that echinocandins are inactive against

Fungi with low levels of beta-glucan: - Cryptococcus - Histoplasma - Zygomycetes

Only method of administration of echinocandins

Toxicity of echinocandins

None

Contents of Piptoporus betulinus

Powerful purgatives: - Toxic resins - Active compound = agaric acid Oils toxic to metazoans

Effects of Piptoporus betunlinus

Strong, though short-lived bouts of diarrhea | Antibiotic action against mycobacteria

5 effects of fungi

1) Hypersensitivity 2) Infection 3) Mycotoxocosis 4) Mycetismus 5) Sick building/toxic mold

Define mycotoxicosis

Production of toxin in vivo

Define mycetismus

Mushroom poisoning (pre-formed toxin)

Type of hypersensitivity reaction precipitated by fungi

IgE-mediated (type I)

4 symptoms of hypersensitivity due to fungi

Asthma Rhinitis Pneumonitis Sinusitis

Common example of fungal hypersensitivity

Aspergillus allergic disease (Farmer's lung)

Cause and effect of aspergillus allergic disease

Decomposing hay with very high content of thermophilic bacteria and fungi --> massive antigen inhalation --> acute hypersensitivity pneumonia

Uncomplicated asthma from hypersensitivity cause

Sensitization to condial antigens of Asperigillus

Pathogenesis of Allergic Bronchopulmonary Aspergillosis

1) Pre-existing airway disease such as CF 2) Colonization with A. fumigatus 3) High titers of IgE antibody to hyphal antigens 4) Severe reactive airway disease 5) Progressive and destructive airway disease

2 classes of fungal disease

Superficial | Invasive

2 fungal forms involved in superficial fungal disease

Yeast | Mold

3 forms of fungi involced in invasive fungal disease

Yeast Dimorphic Mold

Describe clinical picture of invasive yeast infection

Systemic | Pulmonary disease absent or subclinical

Describe the clinical picture of invasive dimorphic fungi disease

Primary pulmonary disease with prominent dissemination

Describe the clinical picture of invasive mold infection

Primary pulmonary disease with dissemination less common

2 pathogenic yeasts

Candida species | Cryptococcus neoformans

3 methods of growth for Candida albicans

Yeast Hyphae Pseudohyphae

What is required for virulence in Candida albicans

``` Morphological switching (usually a normal commensal of humans) NOTE: evidence for mating during infection has been found ```

4 forms of superficial candidiasis

OPC (thrush) Esophageal candidiasis Vaginitis Skin and nail infections

Define OPC

Suerficial infection of oral mucosa, usually associated with impaired cellular immunity

Define esophageal candidiasis

Severe version of OPC that is a common complication of HIV/AIDS

Define vaginitis due to candida

Superficial infection of the vaginal mucosa that is a common consequence of antibiotic therapy

Define superficial candidiasis causing skin and nail infections

Superficial infection of keratinized squamous epithelium

Define invasive candidiasis

Bloodstream infection (sepsis) with Candidia species

Pathogenesis of invasive candidiasis (7 steps)

1) Colonization and/or overgrowth 2) Breach of integument (GI or catheter) 3) Coincident germination 4) Evasion of soluble factors and PMNs 5) Endothelial cell adherence and invasion 6) Entrance to bloodstream 7) Tissue invasion and evasion of host responses

2 major populations at risk for invasive candidiasis

ICU and surgical patients | Hematology-oncology patients

3 methods of breaching mucosal surfaces

Intestinal surgery Chemotherapy (mucositis) IV catheters

3rd most frequent nosocomial bloodstream isolate

Candida

Mortality of invasive candidiasis

40 - 50%

Where can C. krusei's incidence reach 10 - 15% of disseminated candidiasis?

Centers where fluconazole prophylaxis is used

Intrinsic resistance profile of C. albicans

Fluconazole S | Echinocandin S

Intrinsic resistance profile of C. glabrata

Fluconazole R | Echinocandin S

Intrinsic resistance profile of C. parapsilosis

Fluconazole S | Echinocandin S/I

Intrinsic resistance profile of C. tropicalis

Fluconazole S | Echinocandin S

Intrinsic resistance profile of C. krusei

Fluconazole R | Echinocandin S

Traditional diagnosis of Candidemia

Blood culture

What is β-D-glucan

Cell wall constituent of Candida and most fungi

Define speciation

Growth of colony on solid agar (24 - 48h)

2 situations where susceptibility testing is recommended

1) All isolates from sterile sites | 2) Poor response to therapy

Drug of choice for initial therapy of candidemia

Echinocandin

Drug of choice for candidemia when sensitivity is known and patient is stable

Oral azole

2 non-pharmacological points of management for candidemia

1) Source control critical (remove catheter, drain abscess) | 2) Assess for secondary sites of infection (i.e. endophthalmitis and endocarditis)

What is cryptococcus neoformans

Encapsulated yeast

2 common species of cryptococcus neoformans

Neoformans | Gatti

2 environments that harbor cryptococcus neoformans

Soil (esp. bird droppings) | Eucalyptus trees

Method of infection of cryptococcus neoformans

Inhalation of yeast cells or basidiospores

Clinical manifestation of cryptococcus neoformans infection (2)

1) Initial = asymptomatic pulmonary infection with dissemination 2) Chronic meningitis (80 - 90% associated with HIV)

3 virulence factors of cryptococcus neoformans

Capsule Thermotolerance Melanin

Thermotolerance effect as virulence factor

Permits growth in CSF

Melanin effect as virulence factor

Anti-oxidant | Resists phagocyte killing

3 diagnostic tools for cryptococcus neoformans infection

Microscopy Culture Antigen testing

How to stain cryptococcus neoformans

Negative staining with India ink as capsule excludes the dye

How is cryptococcus neoformans antigen detectible

- Cryptococcal antigen from capsule shed during growth | - Detectible in serum and CSF by latex agglutination

Induction antifungal for cryptococcus neoformans treatment

Amphotericin B

Second antibiotic for cryptococcus neoformans treatment

Fluconazole | NOTE: lifelong suppressive therapy required

Antifungal that does not work in crpytococcus neoformans infection

Echinocandins (not beta-glucan in cell wall)

Critical symptom to manage in cryptococcus neoformans infection

Increased intracranial pressure

2 main manifestations for cryptococcus gatti

Pneumonia and meningitis in immunocompetent