MEDICALLY IMPORTANT FUNGI

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					 MEDICALLY IMPORTANT
 FUNGI and ANTIFUNGAL
       THERAPY



DR. BREIDA BOYLE
             INTRODUCTION
   Fungi are a diverse group of sacrophytic and
    parasitic eukaryotic organisms
   Kingdom: Mycota
   Of 100,000 fungal species only 100 have
    pathogenic potential for humans, only a few
    account for clinically important infections
   Mycoses : Human Fungal Diseases
   Fungal spores may be important as human
    allergenic agents
          INTRODUCTION
                MYCOSES
 MUCOSAL: limited to mucosae
 CUTANEOUS: limited to the dermis
 SUBCUTANEOUS : when infection
  penetrates significantly beneath the skin
 SYSTEMIC : when the infection is deep
  within the body or disseminated to internal
  organs
   PATHOGENIC FUNGI




   TRUE     OPPORTUNISTIC
PATHOGENS    PATHOGENS
           TRUE PATHOGENS
Cutaneous infective agents        Subcutaneous infective agents
                                       Actinomadura madurae
                                           Cladosporium
 Epidermophyton species
                                          Madurella grisea
  Microsporum species
                                            Phialophora
  Trichophyton species
                                        Sporothrix schenckii

                Systemic infective agents

               Blastomyces dermatitidis
                 Coccidioides immitis
                Histoplasma capsulatum
              Paracoccidioides brasiliensis
OPPORTUNISTIC
 PATHOGENS

     Absidia corymbifera
    Aspergillus fumigatus
      Candida albicans
  Crytococcus neoformans
    Pneumocystis carinii
     Rhizomucor pusillus
 Rhizopus oryzae (R.arrhizus)
CLASSIFICATION OF FUNGI
                Depends on :
 Characteristic Structures
 Habitats
 Modes of Growth
 Modes of Reproduction
    Cell Wall and Membrane
 Composed mainly of chitin rather than
  peptidoglycan (bacteria)-so unaffected by
  antibiotics
 Chitin: consists of a polymer of N-
  acetylglucosamine
 Fungal Membrane contains ergosterol rather than
  cholesterol found in mammalian cells, use in
  antifungal agents such as amphotericin which
  binds to ergosterolpores that disrupts membrane
  function cell death
             Cell Membrane
   The imidazole antifungal drugs
    ( clotrimazole, ketoconazole, miconazole)
    and the triazole antifungal agents
    (fluconazole , itraconazole) interact with the
    C-14 α-demethylase to block demethylation
    of lansterol to ergosterol, vital component
    of cell membrane and disruption of it`s
    synthesis results in death
                  HABITAT
 All fungi are heterotrophs ( their require some
  form of organic carbon for growth)
 They depend on transport of soluble nutrients
  across their cell membrane
 To do this they secrete degradative enzymes (
  proteases etc) into their immediate environment,
  therefore they live on dead organic material
 So Natural Habitat : is soil or water containing
  decaying organic matter
          MODES OF FUNGAL
             GROWTH



                                        UNICELLULAR
     FILAMENTOUS
                                          YEASTS
        MOLDS



However there are some dimorphic fungi ( they switch between these
Two forms depending on their environment)
Filamentous (mold-like) Fungi
                  Thallus (vegetitive body)
                   –mass of threads with
                   many branches resembling
                   cotton ball
                  Mass: mycelium
                  Threads: hyphae, tubular
                   cells that in some fungi
                   are divided into segments
                   –septate whereas in other
                   fungi the hyphae are
                   uninterrupted by
                   crosswalls-nonseptate
                  Grow by branching and tip
                   elongation
             YEAST like FUNGI
   These fungi exist as
    populations of single ,
    unconnected , spheroid
    cells, not unlike many
    bacteria, although they are
    sometimes 10 times larger
    than a typical bacterial cell
   Yeasts reproduce by
    budding
   Some fungal species
    particularly those that
    cause systemic infection
    exist as dimorphic fungi
REPRODUCTION
            SPORULATION
 The principle way in which fungi reproduce and
  spread within the environment
 Fungal spores are metabolically dormant,
  protected cells, released by the mycelium in
  enormous numbers
 Borne by the air or water to new sites , where they
  germinate and establish new colonies
 Spores can be generate sexually or asexually
         ASEXUAL SPORULATION
                                                    (MITOSIS)




Colour of a particular fungus seen on bread, culture plate is due to the
Conidia, easly airborne and disseminated
        SEXUAL SPORULATION
                                                        meiosis




Relatively rare compared to asexual sporulation, and spore shape often
Used as a method of identification
     CUTANEOUS MYCOSES
      -DERMATOPHYTOSES
                 EPIDEMIOLOGY
   Three genera-Trichophyton, Epidermophyton,
    Microsporum
   Anthropophilic-reside on the human skin
   Zoophilic-reside on the skin of domestic and farm
    animals
   Geophilic-reside in the soil
   Transmission from humans or animals is by
    infected skin scales
            PATHOLOGY
 Dermatophytes use keratin as a source of
  nutrition
 Therefore they infect skin, hair, nails
 All 3 organisms infect /attack skin,
  Microsporum does not infect nails and
  Epidermophyton does not infect hair, they
  do not invade underlying non-keratinized
  tissues
    CLINICAL SIGNIFICANCE
 DERMATOPHYTOSES
 Characterized by itching,scaling skin
  patches that can become inflamed and
  weeping
 Infection in different sites may be due to
  different organisms but is given one name
     Tinea pedis(Athlete`s foot)
   Common organisms are
    Trichophyton rubrum ,
    Trichophyton
    mentagrophytes and
    Epidermophyton
    floccosum.
   Initially between the toes
    spreads to nails, yellow
    and brittle
   Secondary bacterial
    infection
   Id Reaction
Tinea corporis( Ringworm)
              Epidermophyton
               floccosum, Trichophyton,
               Microsporum
              Advancing annular rings
               with scaly center
              Periphery of ring area of
               active fungal growth,
               usually inflammed and
               vesiculated
              Non-Hairy areas of trunks
               mostly
Tinea capitis( scalp ringworm)
                  Trichophyton and
                   Microsporum species
                  Depends on area
                  Small scaling patches to
                   involvement of entire hair
                   with hairloss
                  Microsporum infects hair
                   shafts , Wood`s lamp
                  More common in children
                   due to medium chain fatty
                   acids(C8-120 in sebum
    TINEA CRURIS/UNGUIUM
 Epidermophyton ,
  Trichophyton rubrum,
  simliar to ringworm but
  thighs and genitalia
 Trichophyton rubrum,
  nails thickened
  discoloured and brittle ,
  Onchomycosis
Treatment for months until
  all of the infected nail
  grows out and is trimmed
  off
           Tinea vesicolor
 Pityrasis vesicolor
 Due to Malassezia furfur or Pityosporium
  orbiculare
 Treatmenole , ketoconazole, fluconazole ,
  itraconazole
     Diagnosis of Dermatophyte
             Infection
   Nail clippings, skin scrapings, Hair /follicile
   No role for swabs
   Placed in sterile container preferably or between 2
    slides
   KOH will be added in the lab to dissolve tissue
    material
   Lactophenol blue stain to see if fungal hyphae seen
   For full identification culture on selective media
    required e.g addition of cycloheximide or
    chloramphenicol, low ph 5.0
   May Require 10-14 days for growth
   Macroscopic and microscopic identification of
    colonies
Fungal elements/hyphae
T.mentagrophytes
T.mentagrophytes
                 Treatment
 Samples to be sent for fungal staining and culture
 Infected skin may be treated with topical
  application of antifungal agents
  miconazole,nystatin and clotrimazole
 Refractory lesions oral griseofulvin and
  itraconazole, terbinafine
 Infections of hair and nails usually require
  systemic ( oral) therapy
        SUBCUTANEOUS
      MYCOSES( dermis, subc
        tissues and Bone)
   Causative organisms reside in the soil and in
    decaying or live vegetation
   Almost always acquired through traumatic
    lacerations or puncture wounds
   Common among those who work with soil and
    vegetation and have little protective clothing
   Not usually transmitted humans to humans
   Usually confined to tropics and subtropics with
    exception of Sporotrichosis in USA
                   Sporotrichosis
   Sporothrix schenckii-dimorphic fungus
   Granauloma ulcer at a puncture skin usually a
    thorn prick and may produce secondary lesions
    along draining lymphatics
   In most disease is self-limiting may exist in
    chronic form
   Treatment oral itraconazole
   Chromomycosis : Phialophora or Cladosporium
                      Mycetoma
   Madurella grisea,
    Actinomadura madura
   Localized abscess usually
    on the feet, that discharge
    pus serum and blood
   Has coloured grains(
    compact hyphae) black,
    white, red or yellow
    depending on organism
        SYSTEMIC MYCOSES
       Systemic infective agents
             Blastomyces dermatitidis
               Coccidioides immitis
              Histoplasma capsulatum
            Paracoccidioides brasiliensis


                                    Absidia corymbifera
Opportunistic fungal               Aspergillus fumigatus
Pathogens                            Candida albicans
                                 Crytococcus neoformans
                                   Pneumocystis carinii
                                    Rhizomucor pusillus
                                Rhizopus oryzae (R.arrhizus)
                                               Eastern US




                                           Males
Diagram of Systemic mycoses(dimorphic, yeast in infective tissue)
        Clinical significance
 Simliar to Tb in that asymtomatic primary
  infection is seen whereas chronic
  pulmonary or disseminated infection rare
 In the immunocompetent usually mild and
  self limiting
 In the immunocompromised the same
  infections can be life threatening
        Coccidiodomycosis
 Coccidioides immitis
 Most in arid areas of south-western US
 In the soil forms arthrospores
 Spores airborne , germinate in the lungs and
  produce sphercules filled with many
  endospores- new spherule
 In disseminated cases lesions in the bone or
  CNS -meningitis
             Histoplasmosis
                                      Histoplasma capsulatum
                                      In the soil conidia,
                                       germinate lungs into
                                       yeast-like cells
                                      Becomes engulfed by
                                       macrophages and XX
                                      Benign self-limiting or
                                       chronic, progressive , fatal
                                      Disseminated disease only
                                       fungus intracellular RES
                                       parasitism
                                      Area Ohio and Mississippi
                                       River area
AIDS patients at particular risk
                                      DX: Culture or
Treatment : Amphotericin               Exoantigen
or Itraconazole                        (immunodiffusion assay)
OPPORTUNISTIC
 PATHOGENS

     Absidia corymbifera
    Aspergillus fumigatus
      Candida albicans
  Crytococcus neoformans
    Pneumocystis carinii
     Rhizomucor pusillus
 Rhizopus oryzae (R.arrhizus)
OPPORTUNISTIC MYCOSES
 Those that affect the immunocompromised
  but are rare in normal individual
 Organ transplantation, post chemotherapy
  for cancer, immunodeficient due to Aids
  and congenital immunodeficiency states
 Candida species most commonly occurring
  fungal pathogen in the ICU setting
    CANDIDIASIS(candidiosis)
 Candida albicans and other candida species which
  are normal flora in the mouth, skin , vagina and
  intestines
 C.albicans is dimorphic
 May occur as a results of overgrowth as
  suppression of bacteria by antibiotics
 Manifestations depend on the site e.g. oral
  candidiasis and vaginal candidiasis and
  disseminated candidiasis in cancer patients, post
  GI surgery and AB`s, systemic corticosteroids
      Risk Factors for Candida
             Infection
   Cellular                Interference with
    Immunodeficiency         Normal flora
   Antibiotic Use          Mechanical factors
   Moisture area           Pregnancy
   Age                     Oral Contraceptives
   Hormonal Influence      Diabetes mellitus
   General debility        Administration of
                             corticosteroids
Candida wet preparation
Candida species-Gram stain
Candida culture-24 hours
       Mucosal Candidiasis
 Pain, redness and sometimes a whitish
  coating or discharge of the mucosa
 Oral candidiasis
 Nappy rash candidiasis
 Vaginal candidiasis
 Esophageal Candidiasis
 Chronic form
             Oral Candidiasis
   Occurs in infants without any predisposing factors
   Usual predisposing factors
   Seen in patients taking antibacterials
   Pain, redness and sometimes a whitish coating or
    discharge of the mucosa
   Candida present in small numbers on the mucosa
    and the problem arises when it overgrows
    Eosophageal Candidiasis
 Orophargneal candidiasis may progress to
  eosophageal candidiasis
 Manifestataion of AIDS
 Also occurs in those who have predisposing
  factors but are HIV-negative
 Treatment: fluconazole,itraconazole or
  amphotericin
          Vaginal Candidiasis
   May occur without any obvious predisposing
    factors
   May occur frequently
                  Treatment:
    Creams and ointments: Clotrimazole 1% ,
    Miconazole 2%
   Tablets/Suppostries: Clotrimazole, Miconazole,
    Terconazole, Nystatin
   Oral Therapy: Fluconazole, Itraconazole
           NAIL CANDIDIASIS
                    Paronychia




Oral therapy-fluconazole etc
Severe candida Infections
   May cause candidaemia,
   opthalamitis, hepatosplenic
   candidiasis,
   Line infections, secondary
   peritonitis and urinary tract
   infections in
   Hospitalised patients
   As well as mucosal candidiasis
   Of Note: candida may contaminate
   sputum specimens
          CRYTOCOCCOSIS
   Crytococcus neoformans, found worldwide
   Especially found in soil containing bird(esp.
    pigeons) droppings
   Characteristic thick capsule that surrounds
    budding yeast cell –seen Indian Ink
   Most common form is mild subclinical lung
    infection
   In the immunocompromised often disseminates to
    the brain , meningitis often fatal
   However half those with crytococcal meningitis
    have no obvious immune deficiency
               CRYTOCOCCUS




In Aids patients it is the second most common fungal infection
 after candida , potentially the most serious
Treatment: Amphotericin and flucytosine for meningitis and if HIV
Subsequent suppression with fluconazole
            ASPERGILLOSIS
   Several species of genus Aspergillus, mostly
    Aspergillus fumigatus
   Worldwide distribution, ubiquitous
   Filamentous molds, produce large numbers of
    conidiospores
   Reside in soil, decomposing organic matter and
    dust, associated outbreaks n hospitals with
    construction work
   Disease presentation depends on immunologic
    status of patient
        Disease caused by
            Aspergillus
 Allergic Bronchopulmonary Aspergillosis
 Farmer`s lung
 Invasive Aspergillosis
 Aspergilloma
          Disease caused by
              Aspergillus
   Allergic Bronchopulmonary Aspergillosis:
    in this condition the mould colonises the
    mucosal surface of lower respiratory tract
    but does not invade the mucosa. There is
    intense hypersensitivity response to the
    Aspergillus antigens> impairment of lung
    function. Associated abnormal findings on
    X-ray and asthma like symptoms
              Farmer`s Lung
   Syndrome of shortness of breath typically
    occuring several hours after exposure to
    mouldy hay. Antibodies (IgG not IgE) form
    a precipitate with aspergillus antigen in the
    alveolar walls and an inflammatory cascade
    is initiated
       Allergic Aspergillosis
 Relatively rare, can arise from inhalation of
  spores, without subsequent extensive spore
  germination hyphal invasion
 The allergic reaction results in bronchial
  constriction
 Diagnosis by immunoelectrophoresis
         ASPERGILLOSIS
 Acute Aspergillus infections
 Most severe and often fatal form of
  aspergillosis is acute invasive infection of
  the lungdissemination to brain etc
 Less severe form gives rise to a fungus ball(
  aspergilloma) , a mass of hyphal tissue that
  forms in lung cavities derived from prior
  disease
                 ASPERGILLOMA




Diagnosis by staining and culture: characterisitic V-shaped hyphae
Septated and spore forming structures
      Treatment Surgical removal of mass and amphotericin
      Risk of massive haemoptysis
     ASPERGILLUS INFECTION




Treatment Amphotericin( or voriconazole) and supportive therapy
NEJMED 2002 Aug 8:347(6);408-15
         MUCORMYCOSIS
 Most often caused by Rhizopus oryzae and less
  often by other members of the Mucorales such as
  Absidia corymbifera, Rhizopus pus
 Ubiquitous in nature, spores found in great
  abdunance on rotting fruit and old bread
 Usually restricted to those with underlying
  conditions such as burns, leukaemia or diabetus
  mellitus
 The most common form of the disease can be fatal
  within a week-Rhino cerebral Mucormycosis
    MUCOR
MYCOSIS/RHIZOPUS
   Rhinocerebral Mucormycosis




Infection begins in the nasal mucosa or sinuses and progresses to the
Orbits, the palate and the brain
Treatment: Surgical debridement of necrotic tissue , correction of
Underlying disorder and Amphotericin
RHIZOPUS from Skin
    Scrapings
    PNEUMOCYSTIS CARINII
        PNEUMONIA
 Caused by a unicellular eukaryote, Pneumocystis
  carinii
 Before the use of immunosuppressive agents and
  the onset of the AIDS epidemic , PCP was a rare
  disease
 It is one of the most common opportunisitic
  diseases of individuals with HIV-1 and usually
  fatal if untreated
 It does not contain ergosterol and has not been
  cultured
                       PCP
   Various cellular forms encysted group of dormant
    cells and vegetitive form –trophozoite
   Ubiquitous
   Activation of preexisting dormant cells in the
    lungs in immunodeficient persons
   The encysted forms induce an inflammination of
    the alveoli-exudate which blocks gas exchange
   Diagnosis by microscopic examination , by silver
    stain or fluorescence of bronchial washings or
    biopsy
Pneumocystis carinii in Alveoli




Treatment: Combination sulfamethoxazole and trimethoprim
Can be used prophylaxically to prevent infection
Pneumocystis carinii
    pneumonia
            LABORATORY
           IDENTIFICATION
 Standard media –Sabouraud`s agar, potato
  dextrose agar, low ph 5.0 , inhibits bacterial
  growth but allows fungal colonies to form
 Cultures can be started from spores or hyphae
  fragments
 Specimens: blood, pus, CSF, sputum, tissue
  biopsies, skin scrapings , nail clippings
 Identification by the morphology of conidia
  structures and carbonhydrate assimiliation tests
 LABORATORY DIAGNOSIS
  OF FUNGAL INFECTION
                    Specimens
 Depends on site of infection
 Systemic: -Blood culture( really only useful for
  yeast-low sensitivity) or
           - antigen testing e.g.crytococcal
  and histoplamsosis antigen
 Pneumonia: Bronchoscopy washings or
  brushings for staining and fungal culture or
  bronchial biopsy
    LABORATORY DIAGNOSIS
     OF FUNGAL INFECTIONS
 Meningitis: Cerebrospinal fluid for
  Lactophenol blue staining and indian ink
  and crytococcal antigen and fungal culture
 If Skin infection require skin scrapings
 If nail infection require nail clippings
 Galactomannan antigen testing for
  aspergillus infection
    LABORATORY DIAGNOSIS
      FUNGAL INFECTIONS
           Types of tests carried out
   Fungal Staining – Lactophenol blue staining or
    wet prep using KOH to dissolve tissue material
   Fungal culture on media that encourages fungal
    growth e.g. PDA
   Antigen Testing i.e. to test for antigen present in
    the wall of fungus e.g crytococcal antigen,
    galactomannan used in serum and CSF samples
   PCR not used on a routine basis on samples
MANAGEMENT OF FUNGAL
     INFECTIONS
 Some such as superfical skin infections require
  topical therapy only with cream e.g.miconazole
  cream
 Some require local therpy e.g. pessaries for
  vaginal candidasis
 Some require oral therapy for skin and nail
  infections up to 1 year e.g. terbinafine
 In the immunocompromised systemic therapy
  required e.g. fluconazole i./v or amphotericin
MANAGEMENT OF FUNGAL
     INFECTIONS
 Important to diagnose fungal infections
  early in the immunocompromised as there is
  a high mortality associated with infection
 Empirical therapy often started in advance
  of laboratory diagnosis in these patients
    Antifungal Agents: Families
   Azoles                  Polyenes

Imidazoles   Triazoles      Pyrimidines
   Allylamines
                            Lipopeptides
   Benzofurans
Azoles
      Azoles

    Imidazoles   Triazoles

      Causes Inhibition of
       C-14 α demethylase,
       (an enzyme required
       for the synthesis of
       ergosterol) by binding
       to cytochrome P450
                 Allyamines
 Inhibits squalene
  epoxidase, an enzyme
  essential for synthesis
  of ergosterol
 Drug acculmulates in
  nails, skin and fat
 Very useful for nail
  infections
Polyenes
     Amphotericin, nystatin
     Antifungal activity by
      binding to membrane
      sterols such as
      ergosterol and they
      increase membrane
      permeability and leads
      to cell death
               Amphotericin
 Numerous forms
 Pastilles, Parenteral forms: amphotericin B,
  deoxycholate form, colloidal form, Liposomal
  form
 Toxicity: Dose dependent reduction in GFR, by
  direct vasoconstritive effect on afferent renal
  arterioles, destruction of renal tubular cells and
  basement membrane and loss of functioning units
 Also nausea .vomiting, phlebitis and ACUTE
  REACTION: fever,chills,tachyapnea
                    Pyrimidines
   Fluorine analogue of a
    normal cell constituent
    cytosine
   Demination results in 5-
    fluorouracil, to 5-
    flurodeoxyuridylic acid
    monophosphate, a non-
    competitive inhibitor of
    thymidylate synthetase
   Used particularly in
    crytococcal meningitis-
    74% of serum levels
             Benzofurans
 Griseofulvin
 Inhibits nucleic acid synthesis, macrotubule
  formation and chitin formation
 Active against ringworm, not candidia or
  tinea versicolor
              Lipopeptides
 Echinocandins, derivatives of
  pneumocandin BO
 Inhibition of ß 1 ,3 glucans in the fungal
  wall
 Active candida, aspergillosis and
  pneumocystis carinii

				
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