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1

Mycoses - Basic Facts

Fungi do not require a host to complete their life cycles; usually not communicable, infection from environment

1. Allergic mycoses - inhalation of spores: affects lungs or sinuses, patients may have chronic asthma or sinusitis

2. Superficial mycoses - dermatophytes: affect the skin, hair and nails - ‘ringworm’, jock itch, athlete’s foot, these are communicable

3. True fungal pathogens - can infect immunocompetent - only a few of these, can cause systemic infections in immunocompetent

4. Opportunistic pathogens - vast majority of fungi are in this category, infect immunocompromised/debilitated individuals for the most part

2

Properties of Fungi- part 1

Eukaryotic - have nuclei, the usual organelles, and are larger than bacteria

- rigid cell wall composed of chitin and glucan - not peptidoglycan like bacteria
- no chlorophyll (they are not plants)
- cell membrane that has ergosterol instead of cholesterol
- relative to bacteria, grooow slowly with doubling times of hours rather than
- mycoses = fungal infection in or on a part of the body; disease caused by a fungus

3

Fungi more basic facts

Mycoses is a fungal infection in or on part of the body, or a disease caused by fungus

Fungi have chitin and glucan instead of peptidoglycan

Fungi have ergosterol instead of cholesterol

These components are targets for anti-fungals
Yeasts: unicellular fungi
Molds: multicellular fungi, reproduce by forming spores (fruiting bodies)
Dimorphism: some fungi can grow as yeast or molds (candida) depending on conditions

4

Properties of Fungi Part 2 - eg unicellular or multicellular

Properties of yeast

Properties of molds?

Dimorphic?

Yeast
- unicellular
- oval shaped or round
- reproduce by budding or fission

Molds
- multicellular
- threadlike structures; hyphae
- make spores
- some molds have hyphae that have regular, repeated septae, or walls between adjoining cells eg aspergillus
- some molds have only a few septae

Dimorphic
- exist as a mold in nature
- exist as a yeast at 37 degrees C in animals
- mold in the cold; yeast in the heat

All fungi can reproduce asexually
- molds release spores
- yeast undergo binary fission

**presence or absence of septae is helpful for diagnosis

5

More about molds, how do they grow etc,

Types of hyphae

Molds elongate at their tips: apical extension
- this is important becuase this is where new Cell wall material is produced, and drugs that target glucan production disrupt growth at the tips and thus tend to be fungistatic (prevent growth, but dont kill the fungus)

Hyphae are either septae (walls) or coenocytic (hollow and multinucleated)

Mold reproduction: Can produce spores (conidiophores or sporangispores; also called fruiting body) that are easily born and germinate on suitable substrates producing new hyphae
- produce specialized structures eg sporangiphores or conidiophores that have at their tips spores which can easily become airbornne, or quite stable and spread wide distances and be inhaled

Mold allergies due to inhalation of spores - just a hypersensitivity reaction

FRUITING BODY = aspergillus

6

Laboratory diagnosis of Fungal Infections

Slide 6/69

SILVER STAIN IS BEST FOR VISUALIZING FUNGI

- lack of molecular tests; a few serology tests for some fungi
- culture of organism- most sensitive technique, but takes a lot of time (yeast grow in colonies but molds grow like molds, candida present as normal flora in 40% of people so culturing it by itself isnt enough
- **microscopic examination of tissue, sputum, etc. Fungi can appear as gram positive or negative depending on conditions but are not referred to in terms of gram staining, you should do silver stain (KOH prep used for silver stain)

NV cryptococcus is an unusual yeast in that it has a capsule (sort of like some forms of pneumococcus) formed of carbohydrate, and there is a good serologic test available to identify the presence of cryptococcal antigen

7

Treatment of Fungal Infections

what are the three targets for antifungal therapy?

Cell membrane: fungi use principally ergosterol instead of cholesterol (target this and bind and damage membrane or prevent its synthesis)

Cell wall
- unlike mammalian cells, fungi have a cell wall

DNA synthesis
- some comps may be selectively activated by fungi, arresting DNA synthesis - FLUCYTOSINE

DNA synthesis and cell membrane are most important

8

Class 1: Antifungals that directly damage the cell membrane

Polyene antibiotics
- bind directly to ergosterol forming channels in the cell membrane that disrupt osmotic integrity of the cell

Drugs in This class:
Amphotericin B, lipid formulations, broadly antifungal and you use it for serious infections

Nystatin (topical) *topical for athletes foot

9

Amphotericin B- polyene Abx given IV

Nystatin - polyene ABC used topically

Broad activity - effective against most of the important fungi

Fungicidal- used for most systemic infections

Some resistance due to reduced levels of ergosterol in the Fungal membrane

Poor penetration into joints, CNS

Administered IV

Very toxic: (bc it binds to ergosterol but can also bind to our own cholesterol)
- nephortoxicity***
- fever chills myalgia
- hypotension
- bronchospasm

Lipid formulations
- more expensive, reduced side effects

10

Class I continued: Antifungals that indirectly damage the the cell membrane

Azole Antifungals
- ketoconazole
- voriconazole *** primary treatment for invasive aspergillus
- itraconazole
- fluconazole *** used extensively; active against most candida cryptococcus, histoplasmosis, coccidioides. NOT active against aspergillus
- miconazole, clotrimazole (and other topicals)

Inhibit ergosterol production—> fungistatic rather than fungicidal (like polyenes)

Both can be given orally or IV, both have good absorption; fluconazole is very well tolerated

11

Azole mechanism of action

Azoles prevent ergosterol synthesis (polyenes bind directly to ergosterol) so azoles are fungistatic

Triazoles all end in ‘azole’: Fluconazole, Voriconazole, (and ketoconazole)

- fluconazole is used a lot, voriconazole is a newer drug

- both can be given orally or IV, both have good absorption; fluconazole is very well tolerated and voriconazole also has a good side effect profile

- fluconazole; used extensively, active against most Candida, Cryptococcus, Histoplasma, Coccidioides. NOT active against aspergillus
- foriconazole: primary treatment for invasive Aspergillus

Often drugs of choice for localized infections and for prophylaxis. More serious infections usually amphotericin, sometimes with an azole as well

12

Class 2: cell wall active Antifungals

Echinocandins
- caspofungin is mostly used

13

Fungal Cell wall

- complex cell wall
- major constituent is glucan (polymer of glucose and can be linked together in different ways), produced by action of enzyme beta 1,3 glucan synthase
- chitin (long chain polymer of N acetylglucosamine)

Caspofungin inhibits beta 1,3 glucan synthase —> damage to the cell wall—> osmotic fragility—> fungicidal drugs

14

Caspofungin- most important echinocandin

IV only, used for
- invasive candidiasis (as good as amphotericin, cheaper)
- invasive aspergillosis refractory to other therapies

**not used much, but sometimes instead of amphotericin for systemic infections

Side effects are infusion related: IV irritation, fever headache, flushing rash, symptoms consistent with histamine release

15

Class 3: DNA synthesis inhibitors

DNA synthesis
- pyramiding analogues
- flucytosine most used

Flucytosine
- transported into fungal cell wall where it is deaminated converting it to 5 Fluorouracil—> inhibits pyramiding synthesis (and DNA synthesis)
- resistance happens a lot so it is not used alone
- used for Cryptococcus and Candida

Side effects
- bone marrow suppression
- hepatotoxicity

16

Flucytosine

Actively transported across fungal membrane

Converted to 5 fluorouracil by cytosine deaminase
- essentially functions like a prodrug to go into cell and then get modified by enzyme unique to fungus to have an effect

Our cells lack cytosine deaminase giving it specificty

Further modified and inhibits thymidylate synthase, which is needed to produce thymidine, and hence DNA synthesis

Used with amphotericin to treat crypto and candida

Resistance arises readily

Side effects with prolonged use: bone marrow suppression, hair loss, abnormal LFTs

17

Summary - the drugs most commonly used for severe systemic fungal infections

USED THE MOST

Polyenes - amphotericin B**first choice for systemic infection
- bind ergosterol and disrupt cell membrane structure

Azoles - fluconazole, voriconazole **first choice for more localized infections, sometimes with amphotericin for more serious infections
- inhibit synthesis of ergosterol

USED LESS

Echinocandins- caspofungin
- inhibit synthesis of beta 1-3 D glucan

DNA synthesis inhibitors : Flucytosine (common resistance, dont do monotherapy)

18

Over the counter Antifungals

Azoles - inhibit ergosterol synthesis
- nystatin is topical polyene and is fungicidal (inhibit ergosterol synthesis) - topical only less effective than the azoles

19

Mycoses basic facts

Allergic

Superficial cutaneous mycoses- dermatophytes

Systemic (invasive)

Allergic- from inhalation of spores
- affect lungs or sinuses
- patients may have chronic asthma or sinusitis

Superficial/cutaneous mycoses - dermatophytes
- affect skin, hair and nails ‘ringworm’ jock itch, athletes foot (communicable)

Systemic (invasive) mycoses
- true fungal pathogens- can infect immunocompetent- only a few of these
- opportunistic pathogens- infect immunocompromised (debilitated), most are in this category

20

Fungal infections covered

Primary pathogens (all dimorphic)


Opportunistic pathogens

Cutaneous Mycoses

Primary pathogens (all dimorphic)
- histoplasma capsulatum (ohio valley fever)
- coccidiodes immitis (San juanguin valley fever, or valley fever)
- blastomyces dermatidis- can happy in healthy people

Opportunistic pathogens
- candida- mostly a yeast
- cryptococcus neoforman- yeast
- pneumocystis jiroveci- a yeast
- aspergillus- a mold (septae); mucosa is like aspergillus but without septae

Cutaneous Mycoses

21

True Fungal pathogens characteristics

Can infect immunocompetent

All dimorphic, live in hyphae state in the soil, yeast state at 37 C

Thermal dimorphism

Restricted to certain endemic regions of the world

Solid is the normal habitat

Infection by inhalation of spores—> pulmonary infections
- histoplasma - higher river valley and northeast - valley fever
- coccidioides - American southwest
- blastomyces

22

Histoplasmosis: Ohio Valley Fever

22/69

Histoplasma capsulatum

Most common true fungal pathogen- causes histoplasmosis

Dimorphic fungus, produces spores that are inhaled

Associated with bird and bat dropping’s (high nitrogen soil)

Only intracellular fungus

Distributed worldwide, most prevalent in Ohio river valley

Most infections are asymptomactic

23

Histoplasma pathogenesis

Inhalation of spores from disturbed soil

Spores germinate to yeast in the lung

Usually stays localized or may spread via lymphatics within monocytes (taken up by macrophages and cause granulomatous inflammation)

Intensity of exposure and immune status are determinants of pathogenesis

Reactivation in immunocompromsied

Only intracellular fungal pathogen of significance

24

Histoplasma Clinical Presentations

Pic 24/69

70-90% infections asymptomatic

If large inoculum, most have Sx

Typically acute, self limited flu like syndrome, recover in 1 - 2 weeks, doesnt require treatment

Rarely progressive pulmonary disease develops with cavitary lesions and fibrosis

Can sometimes cause a chronic disease, and like TB can remain in your lungs for a long time and be reactivated later—> forms granulomatous like TB but not caseating

Disseminated hematogenous spread can present with overwhelming shock, disseminated intravascular coagulation, respiratory distress and high mortality

25

Histoplasma lab diagnosis and treatment

Microscopic/histologic identification of intracellular yeast

Culture can take 2 - 3 weeks

Urine antigen- detects histoplasma polysaccharide antigen in the urine of infected individuals - best with disseminated form of disease

Usually self limited so dont treat

Amphotericin for significant disease (targets ergosterol)

Long term itraconazole for immunocompromised such as aids patients for prophylaxis

26

Blastomyces Dermatitidis: North American blastomycosis

Picks slide 27

Causes blastomycosis in humans and other animals, particularly dogs

Distributed in soil of a large section of the midwestern and southeastern US

Inhaled conidiophores (spores) convert to yeasts and multiply in lungs - broad-based budding

Symptoms include cough and fever

Other systemic complaints are common

Can spread to other organs, particularly to skin and bone causing chronic granulomatous lesions

Skin lesions can be chronic—> crusted lesions on exposed skin surfaces

Detected microscopically with KOH prep of sputum—> broad-based budding yeast forms

Treatment: amphotericin B

27

Coccidioidomycosis: Valley Fever

Slide 29/69

Like histoplasmosis, coccidiodomycosis is a primary pathogen - it can infect normal people - most virulent primary fungal pathogen**
- likes dry soil, distributed in the soil
Immitis - most common species

Distinctive morphology
- block like arthroconidia in the free-living stage and spherules containing endoscopes in the lungs, the spherules rupture, releasing the spores which spread and start process again

Arthrospores inhaled from dust, create spherules and nodules in the lung

Distinctive morphology = block like cells

Summary: sores inhaled—> grow and form large spherules that are full of new spores—> spheres rupture releasing spores that then go off and make new spheres

28

Coccidioidomycosis: epidemiology

Lives in alkaline soils in semarid, host climates and is endemic to southwestern US

San Joaquin valley fever

About 150,000 cases per year

60% asymptomatic

Reportable disease in California

When it causes symptoms, typically selflimited flu like like HIsto, but some people (immunosuppressed) get disseminated disease

Around 100 deaths per year, rate of infection has been increasing throughout the past decade

29

Coccidioidomycosis: Clinical

Chest film slide 32

Degree of dust exposure is important

Typical valley fever is self-limited
- 7 - 21 days after exposure-cough, fever, joint pain
- sometimes hemostasis, sometimes erythema nodosum (painful nodules on shins)
- can see eosinophilia

Chest film can show infiltrates with lymphadenopathy. Nodules if seen are a more specific finding, and sometimes peripheral, thin-walled cavities are seen

Infection confers immunity and a positive skin test

Disseminated disease (rare) can involve most any organ, especially meninges, fatal if not treated

30

Coccidioidomycosis: diagnosis and treatment

Often missed-non-specific Sxs

Sputum culture
- can take weeks
- lab hazard

Microscopic - large spherules in tissue/sputum

Self limited infection does not require treatment

Disseminated disease or patients with risk factors: amphotericin B plus an Azole, treat with azole for a year (targeting ergosterol)

**SOUTHERN CALI**