Professor:SAMIA HAWAS

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Professor:SAMIA HAWASProfessor of Medical Microbiology andImmunology.Founder of Medical Immunology Unit.Information and Public RelationsConsultant of Mansoura Universitypresident (F).Head of Medical Microbiology andImmunology Department (F).Dean of Faculty of Nursing (F).E-mail: samiahawas@hotmail.comMob:0104681230

Medical Mycology

Medical Mycology Fungi were discovered earlier than bacteriaand viruses. In the past, most fungi cause skin infectionsor cosmetic infections, where bacteria andviruses cause serious fatal diseases, so therewas no interest of studying fungi. In 1980, when HIV infection was discovered,increasing number of immunocompromizingconditions, they found that fungi producefatal diseases; from that time, fungi returnto be in focus again.

Medical Mycology It is the science thatdeals with the study ofpathogenic fungi thatproduce diseases.

Structure Fungi are eukaryoticorganisms have true nucleiwith definite nuclearmembrane, nucleolus,cytoplasmic organelles.

Structure Cell membrane offungi has sterols,which is the target ofaction of antifungalagents. Ergosteroldominates in contrastto cholesterol inmammalianmembrane.

Structure Cell wall of fungi lacks:– Peptidoglycan– Glycerol & ribitol teichoicacid– Lipopolysaccharide Cell wall composed of:– Chitin.– Glucan (important for newantifungal agent).– Mannan.

Fungal metabolism: All fungi are heterotrophic organism need toparasite or saprophyte (on plant, animal orhuman) to obtain organic source of carbon ornitrogen. All fungi are aerobic. Some are facultative anaerobes. None are strict anaerobes.

Fungal metabolism: Optimum temperature of growth 25 – 30 ºC(because most are saprophyte live in theenvironment). Some are thermophilic, and can grow athigher temperature. Fungi can tolerate a wide range of pH (2 – 9),but generally they prefer acidic media.

Reproduction

Sexual reproduction: Involve the union of 2nuclei or 2 sex cells or2 sex organs.

Asexual reproduction: It is the main method ofreproduction. It includes:– Fragmentation of hyphae & eachfragment grows into a newindividual fungus.– Fission of cell into 2 daughter cells(similar to binary fission inbacteria).– Budding of cells, each bud producenew individual (e.g. Candida).– Formation of asexual spores.

A single fungus may contain both modes ofreproduction (sexual and/or asexual).

Fungal Spores It is the method ofreproduction infungi unlikebacteria. Two types:1-Sexual2-Asexual

1) Sexual

Sexualreproduction

Sexual:–ZygosporeTwo identical cellsform a zygote.zygospore is a special type of chlamydospore arisingfrom sexual conjugation between two fungi.

Basidiospore

Ascospore.

Oosporefemale cellfertilized by malecell.

2)Asexual

2) Asexual: Thallospore:– Blastospores (bybudding from thallus).

Thallospore:– Arthrospores(forming within thelumen of hyphae, can becubical or round. Its sizeless than the size ofhyphal cell.

Chlamydospores spores that arisefrom the thallus bypulling or swellingof myceliumfilaments.

2) Asexual:Sporangiospore:– Some fungi during growthform sac filled with sporescalled sporangium.– Spores inside sporangiumcalled porangiospores.– Hyphae that carry thissporangium are calledsporangiophore.– This sporangium when getsripping, its wall will bebroken and the sporesdisseminate.

Exogenous asexual spores:o Conidia: These are sporesformed at theterminal part of afertile hypha. Conidophore:fertile hyphabearing conidia .PenicillumAsperigillus

Microconidia Unicellular,asexual externalspores.

Macroconidia: Multicellular,asexual externalspores, which havedifferent shapes.

Source of infection: Endogenous: Normal flora and it isthe main source innosocomial infection(because those peoplein hospitals areimmunocompromized).

Source of infection (cont.): Exogenous: This is the main source of fungal infectionmainly from the environment. Few fungal infections are communicablebetween human or between animals.

Mode of transmission:– Respiratory tract (air borne infection).– GIT (food & water borne infection).– Blood stream injection.– Skin contact.– Most fungal diseases are notcommunicable between human oranimals.

Most fungi are opportunistic:– Produce diseases inimmunocompromizedpatients.– Little is primarypathogen (causedisease in personwith intact immunesystem).

Steps of infection: I.Adherence:– By adhesions, e.g. Candida, but filamentous fungi haveno adhesions.– Fibrinonectin of epithelial cell is the receptors.– Virulence usually associated with adherence.

Steps of infection: ii. Invasion:– Mechanical trauma to skin or mucosal surface is anessential step in fungal infection, because most of theinfective element in fungi is the spore and it is noninvasive.– Some fungi have invasive power like Candida by theformation of hyphae and pseudohyphae.

Steps of infection: iii. Phagocytic interactions:– Some fungi especially dimorphic fungishow resistance to phagocytic killing.– Some fungi are capsulated and canresist phagocytosis (Cryptococcus).

Immunity to fungalinfections Innate immunity:– Non-specific works against allmicroorganisms.

Immunity to fungalinfections(cont.) Acquired immunity:The main immunity is cellularimmunity because fungi stayinside the host cell.Antibodies have limited role insome fungal diseases.

Fungal Classificationa.According to morphology:

Moulds (Filamentous fungi): Grow with formation ofhyphae, which may beseptated or non-septated.

Moulds (Filamentous fungi):– Vegetative mycelium: Some hyphae willpenetrate the media. Some hyphae present atthe surface of the media.– Aerial mycelium: Some hyphae may bedirected upward & carrythe different types ofspores that produced bythis fungus.

Yeasts– Unicellular fungi (roundedor oval in shape).– Reproduce by budding.– The only example ofpathogenic yeasts isCryptococcus neoformans.

Yeast-like Unicellular fungi (rounded oroval in shape). Reproduce by budding. But during infection itproduces pseudohyphae. Example: Candida.

Dimorphic fungi:– Can grow as yeast duringinfection in the body &on incubating culture at37 ºC.– Can grow as moulds orfilaments wheninoculated at roomtemperature.– Example: Histoplasmacapsulatum.

Fungal ClassificationB-According to nature of their sexual spores:

Phycomycetes (Zygomycetes): Sexual spores are of 2 types:– zygospores & oospores.– Usually non-pathogenic.

Ascomycetes– Sexual ascospors.– Some are pathogenic.

Basidiospores– Sexual basidiospores.– Non-pathogens.

Fungi imperfecti– Perfect or sexual state not present or not discovered, socan't be placed within one of the above three classes.– Most of pathogenic moulds, yeasts, yeast-like anddimorphic fungi belong to this group.

Human mycosisterminology

A. Anatomical terminology(According to the site of infection):– Dermatomycosis: Fungal infectionof the skin.– Pulmonary mycosis: Fungalinfection of the lung.– Cardiovascular mycosis: Fungalinfection of the cardiovascularsystem.

B. Mycological terminology (Accordingto the etiology):– Candidiasis ( Candidiosis):Fungal infection by Candida.– Aspergillosis: Fungal infectionby Aspergillus.– Cryptococcosis: Fungalinfection by Cryptococcus.– Histoplasmosis: Fungalinfection by Histoplasma.

Types of human mycosis

Superficial mycosis Infection restricted to uppermost horny layer of skin, hairand nails e.g. Pitryasisversicolor.

2 - Cutaneous mycosis: Ringworm fungi. Candidiasis of skin, mucosalsurfaces.

3- Subcutaneous mycosis(Implantation mycosis):– Most of fungi are noninvasive.– Occurs by implantationof spores into wounds.– e.g. Mycetoma (madurafoot), thorn pricksmycosis.

4- Systemic mycosis: Multi organs affected.Mode of infection: Inhalation of spores ofsaprophytic fungi. Spread of local mycosis.Examples: Cryptococcosis. Histoplasmosis. Candidiasis.

5- Opportunistic mycosis: Fungal infection by:– Fungal flora (Candida).– Saprophytic fungi in the environment(Aspergillus). This infection occur in:– Immunocompromised host (Both innate andacquired immunity).– Opportunistic conditions like:– Diabetic patients.– Cancer patients.– Corticosteroid & otherimmunosuppressive therapy (e.g.Cytotoxic drugs).– Prolonged antibiotic therapy.

Diagnosis of fungal infections

1. Direct Microscopic Preparation: a) Unstained preparation Important and rapid method of diagnosis of fungalinfections. Scraping of lesion or bits of exudates (e.g. sputum, pus).––––––Put on clean slide.Add drop of KOH (10 – 30%).Put cover slip.Gentle heating for 5 – 10 minutes (not direct heating).Examin by high power lens of the microscope.Find diagnostic fungal elements.

1. Direct Microscopic Preparation: b) Stained preparation:– Rapid and easy.– Cover slip preparation (KOH)Indiamayink be stained withLactophenol cotton bluestain.– India ink preparation is usedfor demonstration ofCryptococcus neoformans.– Its positivity not more than30%.Cellotape FlagPreparations.

2. Culture for isolation of fungi: Sabouraud s dextrose agar(SDA):– Composed of agar dextrose peptone.– Disadvantage: Bacteria cangrow on it.

2. Culture for isolation of fungi: SDA Chloramphenicol (0.05%):– Chloramphenicol is added to inhibit bacterial growth.

2. Culture for isolation of fungi: SDA Chloramphenicol Cyclohexamide (0.5%):– Cyclohexamide is added to inhibit the growth ofsaprophytic fungal contaminants.

2. Culture for isolation of fungi: Blood agar:– Some fungi as yeast, and yeast like(Candida and Cryptococcus) grow rapidlyas bacteria after 4 weeks fromincubation.

Growth is identified by: Macroscopiccharacters: e.g. colourfrom both sides (recto –verso examination),shape, size and textureof the colony. Microscopic stainedpreparation. Biochemical reaction:Sugar fermentation andassimilation (especiallyin yeast).

3. Microculture: Used to: See whole morphologicaldetails of fungi. Prevent disturbing fungalmorphology. It has 2 types: Direct evaluation of aculture in an open petridish under themicroscope. Slide culture technique.

4. Histopathology:Yeast cells: They may beintracellular small yeast:e.g. Histoplasmacapsulatum.– They may have alarge distinguishingcapsule: e.g.Cryptococcus.

4. Histopathology: Spherules:– Intact spherules arelarge sac-likestructure filled withsporangiospores.Left: A patient showing thedisseminated stage of disease(coccidioidomycosis).Top right: spherules.Bottom right: chains of arthrosporesinterspersed with empty cellularcompartments.

4. Histopathology: Hyphae:– They may be brown in colouror non-coloured.– They may be septated or nonseptated.

4. Histopathology: Granules:– They are tightly packed masses ofhyphae or filaments, which aresurrounded by tough outer rind.

4. Histopathology: Combination of yeast cellsand hyphae: As in Candida.

5. Woods light: Helps in clinicaldiagnosis. Long wave ultravioletrays (black rays) whichwhen come in contactwith mycotic areas ofskin and hair producefluorescent colours. Disadvantage: it occursin some mycoticinfections only.

6. Indirect method of diagnosis: Detection of circulating antibodies (Serologicaldiagnosis): It has limited role. Used in diagnosis and follow up of Cryptococcus andCandida with limits.

Tests used for detecting fungalantibodies:– Precipitation reaction.– Agglutination.– Electrophoretic tests.– Complement fixation.– Indirect fluorescent antibody.– ELISA.ELISA AGGLUTINATIONprecipitationElectrophoresis

Fungal skin tests: It has no value indiagnosis. It does not differentiatebetween active and pastinfection. Mainly used forepidemiological study. It is observed by formationof induration and swellingdue to reaction betweeninjected antigen and Tcells. e.g. Histoplasmin,Candidin, Tricophytintests.

Antifungal therapy Topical antifungals:– Polyenes e.g. nystatin, fungizone– Azoles (e.g. miconazole,Ketoconazole, econazole,clotrimazole).– Miscellaneous e.g tolanftate,allylamine, iodine.

Systemic antifungals: Polyenes (e.g Amphotericin-B). 5-flucytosine. Azoles (e.g itraconazole, fluconazole). Terbinafine. Griseofulvin Iodine. New antifungal Echinocandins e.g caspofungin New triazole e.g voriconazole

Mechanism of action ofantifungalCell membraneNucleic nCell wallCuspofungin

1) Polynes– Bind to ergosterol in the fungal cellmembrane altered permeability leakage of K , Mg , Sugar Cell death– It is fungicidal, has broad Spectrum usageuntil now– Hepatotoxic and nephrotoxic– Lipid preparations (as liposomalamphotericin-B) are more tolerable and lesstoxic.

2) Azole– Inhibits ergosterol biosynthesis via bindingto cytochrome p- 450 dependent enzyme14α demethylase accumulation of 14 αsterol depletes sterols.– Hepatotxic, spermatogenesis inhibitor soits usage restricted– Fluconazole crosses blood brain barrier soused in treatment of cryptococcalmeningitis.

3) Criseofulvin– Exact mechanism is unknown– Inhibit nucleic acid synthesis– Have antimitotic activity by inhibitingmicrotubules assembly "microtubules calledcytoskeleton that support shape, transportof substrates of eukaryotic cell"– Inhibit synthesis of cell wall chitin.

4) 5- Flucytosin: Deaminatedin cell to5- fluorouracil, which replace uracil base inRNA disruption of protein synthesis.

How to select proper antifungal drug?–We can select properantifungal drug viasusceptibility testingmethod e.g– Broth dilution method– Agar diffusion method

I. Superficial fungalinfection

A. Ring worm fungi(Tinea dermatophytosis)Dermatophytosis Fungal infection bydermatophytes ofkeratinousstructures (skin, hair,nails).

A. Ring worm fungiCommon clinical types:1. Tinea Corporus: Dermatophyteinfection ofthe glabrousskin (trunk,back, dorsum ofthe hand).

A. Ring worm fungiCommon clinical types:2. Tinea Capitis: Fungal infection of the skin of thescalp and hair. This takes 3 forms of hairinvolvement: a) Endothrix:– There is abundant fungus growthinside the hair shaft. b) Ectothrix:– The spores surround the hair shaftfrom outside lead to weakness andfalling of the hair. c) Favic type:– Some fungal mycelia are present insidethe shaft with air space.

A. Ring worm fungiCommon clinical types:3. Tinea Barbae: Fungal infection ofthe beard andmoustache skinarea in male.

A. Ring worm fungiCommon clinical types:4. Tinea Pedis (Athlete's foot):– Ring worm of thefoot.– It is infection ofthe feet or toeswithdermatophytefungus– include soles, nailsand inter-digitalpeeling.

A. Ring worm fungiCommon clinical types:5. Tinea Manum:– Fungal infection ofthe palm of the handand inter-digitalareas.

– Fungalinfectionof thecrural areaandperineum.A. Ring worm fungiCommon clinical types:7. Tinea cruris

A. Ring worm fungiCommon clinical types:7. Tinea Unguim:– Fungalinfection ofthe nail ofthe hand.

EpidemiologyAccording to the source of infection

1- Anthroprophilic:–From human on

2- Zoophilic:– From animalto human.– e.g.Microsporumcanis.Microsporum canis

3- Geophilic:– Spores found insoil.– e.g.Microsporumgypseum.Microsporumgypseum

Pathogenesis:1. Infective stage is arthrospore of fungus or keratinous materialcontaining fungus element.2. Needs direct or indirect contact (indirect by the use of the sameitems of the patient).3. Need slight trauma.4. Active infection restricted to the basal keratinocytes of theepidermis.

Causative fungus:Dermatophytes include 3 genera: 1. Epidermophyton. e.g. E. flocosum. 2. Trichophyton. e.g. T. rubrum. 3. Microsporum. e.g. M. canis.

Diagnosis of dermatophyteinfection:

Diagnosis of dermatophyte infection: 1. Clinical picture. 2. Wood's light (negative result doesn't excludefungal infection). 3. Direct examination by KOH preparation:Diagnostic element in skin & nail is the septatedhyphae and arthrospores.Diagnostic element in hair is the endothrix,ectothrix or favic.

Diagnosis of dermatophyte infection:4. Culture: On Sabouraud'sdextrose agar withchloramphenicol &actidion (cyclohexamide). Dermatophyte testmedium that is yellow incolour (if turned red, thisindicate positive test).

Diagnosis of dermatophyte infection:Growth is examined by: Macroscopic examination. Microscopic examination: In order todifferentiate between the three genera ofdermatophytes according to the type ofmacroconidia present

Diagnosis of dermatophyte infection:Growth is examined by: Microsporum: Spindleshape, multicellular withrough surface.

Diagnosis of dermatophyte infection:Growth is examined by:Epidermophyton:Clup shape (racket)with smoothsurface.

Diagnosis of dermatophyte infection:Growth is examined by:Trichophyton: pencil shape withsmooth surface.

Treatment A. Systemic agents (oral): Griseofolvin (drug of choice). Itraconazole. Allylamine (Lamisil). Ketoconazole (not used now). B. Topical agents: White field. Clotrimazole (Canesten). Miconazole (Daktarin). Prohylaxis against Tinea pedis: Keep the feet dry. Rub between toes by dry piece of gauze & alcohol.

B. Pityriasis versicolor(Tinea versicolor)

Pityriasis versicolorDefinition:– Chronic superficial fungalinfection of the upper mosthorny layer of the epidermis.– Main area affected is the trunkbut it can appear in any site ofthe skin– Infection causes nothingexcept loss of the normal skinpigmentation may result inhypo- or hyper-pigmentation(blotchy appearance).

Etiology:– Caused by yeastflora calledPityrosporumorbicularis.

Diagnosis:– Direct microscopicexamination of skinscrapping by KOHpreparation.– Diagnostic element isshort angular hyphae& yeast cells(spaghetti & meat ballappearance).

Treatment:–Any topical azole is effective (e.g.Miconazole, Clotrimazole).–If the infection is recurrent or widelydiffused in the trunk: Selenium blueShampoo (1% selenium sulfide).

Candidal infection

Source of infection: Endogenous: (autoinfection): Present asnormal flora in oral cavity, GIT, female genitaltract and skin which is the major source ofinfection. Exogenous: By sexual intercourse.

Pathogenesis and virulence factors: Adhesin: Colonization on the mucosal surface. Pseudohyphae: inflammation and tissuedistruction. Protease enzyme: invasion. Endotoxin like: Releasing of histamine leadingto clinical reaction. Resistance to intracellular killing ofphagocytes.

Predisposing factors: Extreme of age. Pregnancy and diabetes. Prolonged use of antibiotics, steroids orimmunosuppressive drugs. Traumatic conditions such as catheter or IVlines.

Immunity: Cell mediated. Humoral immunity has a limited role.

Causative agents: Candida albicans. Non-albicansCandida: Candida tropicalis. Candida glabarata(doesn’t causepseudohyphae).

Clinical manifestations of diseases caused byCandida: Mucocutaneousinfection: Oral thrush: In themouth (cheesy coveringlayer), mouth angles:(stomatitis), at the lips(cheilitis). Vaginitis: White-milkydischarge and itching.

Clinical manifestations of diseases caused byCandida:Cutaneous infections: Skin: Napkin area inbaby, axilla, groin,submammary folds,characterized bySatellite lesions,redness, itching and redfollicles. Nail: Onychia andparonychia.

Clinical manifestations of diseases causedby Candida:systemic infections:–Urinary tract mia, fungemia.

Laboratory diagnosis ofCandidiasis:

A. Direct:1. Microscopicexamination:– Unstainedpreparation orstained preparation(KOH) lactophenolcotton blue stains.– For detection ofyeast cells andpseudohyphae.

2. Culture:– On SDA medium.– The suspected growth isidentified by: Macroscopicappearance of: thecolonies after 24 – 48hours are white,smooth, creamy andhave characteristicyeast odo

Fungi were discovered earlier than bacteria and viruses. In the past, most fungi cause skin infections or cosmetic infections, where bacteria and viruses cause serious fatal diseases, so there was no interest of studying fungi. In 1980, when HIV infectio

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