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MEDICALLY IMPORTANT FUNGI and ANTIFUNGAL THERAPY

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Title: MEDICALLY IMPORTANT FUNGI Author: BOYLEB Last modified by: Paul Smyth Created Date: 11/9/2001 10:11:09 AM Document presentation format: On-screen Show – PowerPoint PPT presentation

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Title: MEDICALLY IMPORTANT FUNGI and ANTIFUNGAL THERAPY


1
MEDICALLY IMPORTANT FUNGI and ANTIFUNGAL THERAPY
  • DR. BREIDA BOYLE

2
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

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6
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

7
PATHOGENIC FUNGI
TRUE PATHOGENS
OPPORTUNISTIC PATHOGENS
8
TRUE PATHOGENS
Cutaneous infective agents
Subcutaneous infective agents
Actinomadura madurae Cladosporium Madurella
grisea Phialophora Sporothrix schenckii
Epidermophyton species Microsporum
species Trichophyton species
Systemic infective agents
Blastomyces dermatitidis Coccidioides
immitis Histoplasma capsulatum Paracoccidioides
brasiliensis
9
OPPORTUNISTIC PATHOGENS
Absidia corymbifera Aspergillus fumigatus Candida
albicans Crytococcus neoformans Pneumocystis
carinii Rhizomucor pusillus Rhizopus oryzae
(R.arrhizus)
10
PATHOGENIC FUNGI
TRUE PATHOGENS
OPPORTUNISTIC PATHOGENS
11
CLASSIFICATION OF FUNGI
  • Depends on
  • Characteristic Structures
  • Habitats
  • Modes of Growth
  • Modes of Reproduction
  • Clinical Setting
  • DNA Homology

12
Cell Wall and Membrane
  • Composed mainly of chitin rather than
    peptidoglycan (bacteria)-so unaffected by
    antibiotics
  • Cell Wall also has glucans and Mannans
  • 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

13
Cell Membrane
  • The imidazole antifungal drugs
    ( clotrimazole, ketoconazole, miconazole) and the
    triazole antifungal agents (fluconazole ,
    itraconazole, voriconazole) interact with the
    C-14 a-demethylase to block demethylation of
    lansterol to ergosterol, vital component of cell
    membrane and disruption of its synthesis results
    in death

14
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

15
MODES OF FUNGAL GROWTH
UNICELLULAR YEASTS
FILAMENTOUS MOLDS
However there are some dimorphic fungi ( they
switch between these Two forms depending on
their environment)
16
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

17
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

18
REPRODUCTION
19
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

20
ASEXUAL SPORULATION
(MITOSIS)
Colour of a particular fungus seen on bread,
culture plate is due to the Conidia, easly
airborne and disseminated
21
SEXUAL SPORULATION
meiosis
Relatively rare compared to asexual sporulation,
and spore shape often Used as a method of
identification
22
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

23
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

24
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

25
Tinea pedis(Athletes 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

26
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

27
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 , Woods lamp
  • More common in children due to medium chain fatty
    acids(C8-120 in sebum

28
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

29
Tinea vesicolor
  • Pityrasis vesicolor
  • Due to Malassezia furfur or Pityosporium
    orbiculare
  • Treatment , ketoconazole, fluconazole ,
    itraconazole

30
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

31
Fungal elements/hyphae
32
T.mentagrophytes
33
T.mentagrophytes
34
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

35
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

36
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
    species

37
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

38
SYSTEMIC MYCOSES
Systemic infective agents
  • Blastomyces dermatitidis
  • Coccidioides immitis
  • Histoplasma capsulatum
  • Paracoccidioides brasiliensis

Absidia corymbifera Aspergillus fumigatus Candida
albicans Crytococcus neoformans Pneumocystis
carinii Rhizomucor pusillus Rhizopus oryzae
(R.arrhizus)
Opportunistic fungal Pathogens
39
Eastern US
Males
Diagram of Systemic mycoses(dimorphic, yeast in
infective tissue)
40
Clinical significance
  • Simliar to Tuberculosis in that asymptomatic
    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

41
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

42
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
  • DX Culture or Exoantigen (immunodiffusion assay)

AIDS patients at particular risk Treatment
Amphotericin or Itraconazole
43
OPPORTUNISTIC PATHOGENS
Absidia corymbifera Aspergillus fumigatus Candida
albicans Crytococcus neoformans Pneumocystis
carinii Rhizomucor pusillus Rhizopus oryzae
(R.arrhizus)
44
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

45
CANDIDIASIS(candidiosis)
  • Candida albicans and other candida species which
    are normal flora in the mouth, skin , vagina and
    intestines
  • 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 ABs, systemic corticosteroids

46
Risk Factors for Candida Infection
  • Cellular Immunodeficiency
  • Antibiotic Use
  • Moisture area
  • Age
  • Hormonal Influence
  • General debility
  • Interference with Normal flora
  • Mechanical factors
  • Pregnancy
  • Oral Contraceptives
  • Diabetes mellitus
  • Administration of corticosteroids

47
Vulvovaginal candidiasis
Treatment miconazole, clotrimazole topically or
oral fluconazole Or itraconazole
48
Candida wet preparation
49
Candida species-Gram stain
50
Candida culture-24 hours
51
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

52
MUCOCUTANEOUS CANDIDIASIS
Cellular deficiency results in chronic
mucocutaneous candidasis
53
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

54
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, voriconazole
    or amphotericin

55
Vaginal Candidiasis
  • May occur without any obvious predisposing
    factors
  • May occur frequently
  • Treatment
  • Creams and ointments Clotrimazole 1 ,
    Miconazole 2
  • Tablets/Pessaries Clotrimazole, Miconazole,
    Terconazole, Nystatin
  • Oral Therapy Fluconazole, Itraconazole

56
NAIL CANDIDIASIS
Paronychia
Oral therapy-fluconazole etc
57
DISSEMINATED CANDIDIASIS

Treatment amphotericin or fluconazole
58
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
59
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

60
CRYTOCOCCUS NEOFORMANS
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 AIDS Subsequent
suppression with fluconazole
61
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

62
Disease caused by Aspergillus
  • Allergic Bronchopulmonary Aspergillosis
  • Farmers lung
  • Invasive Aspergillosis
  • Aspergilloma

63
Aspergillus fumigatus
64
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 antigensgt impairment
    of lung function. Associated abnormal findings on
    X-ray and asthma like symptoms

65
Farmers 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

66
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

67
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

68
ASPERGILLOMA
Diagnosis in the lab by staining and culture
characterisitic V-shaped Hyphae, Septated and
spore forming structures
Treatment Surgical removal of mass and
amphotericin Risk of massive haemoptysis
69
INVASIVE ASPERGILLOSIS INFECTION
Often treated empirically, using risk assessment
and CT(spiral) to assist in diagnosis
Treatment Amphotericin( or voriconazole) and
supportive therapy NEJMED 2002 Aug
8347(6)408-15
70
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
    abunance 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

71
MUCOR MYCOSIS/RHIZOPUS
72
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
73
RHIZOPUS from Skin Scrapings
74
PNEUMOCYSTIS CARINII PNEUMONIA (PCP)Now known as
PNEUMOCYSTIS JIROVECI Frenkel 1999
  • 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 is extremely
    difficult to culture (requires )cultured

75
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

76
Pneumocystis carinii in Alveoli
Treatment Combination sulfamethoxazole and
trimethoprim, Pentamine and additional agents
may also be used Can be used prophylaxically to
prevent infection
77
Pneumocystis carinii (jiroveci) pneumonia
78
LABORATORY IDENTIFICATION
  • Standard media Sabourauds 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

79
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

80
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

81
LABORATORY DIAGNOSIS FUNGAL INFECTIONS
  • Types of tests carried out
  • Fungal Staining Lactophenol blue staining or
    wet prep using KOH to dissolve tissue material or
    Calcofluor (fluorescence stain)
  • 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
  • Molecular Methods not used on a routine basis on
    samples(as yet)

82
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,
    voriconazole

83
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

84
Antifungal Agents Families
  • Azoles
  • Allylamines
  • Benzofurans
  • Polyenes Macrolides
  • Pyrimidines
  • Lipopeptides

Imidazoles Triazoles
Ref Antifungal Drug Resistance. Clinical
Infectious Diseases. 200336 (Suppl 1) s31-41.
85
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86
Azoles
  • Azoles
  • Causes Inhibition of C-lansterol 14 a
    demethylase, (an enzyme required for the
    synthesis of ergosterol) by binding to cytochrome
    P450
  • Resistance may be intrinsic or acquired

Imidazoles Triazoles
Voriconazole
87
Allyamines
  • Inhibits squalene epoxidase, an enzyme essential
    for synthesis of ergosterol
  • Drug acculmulates in nails, skin and fat
  • Very useful for nail infections

88
Polyene Macrolides
  • Amphotericin, nystatin
  • Antifungal activity by binding to membrane
    sterols such as ergosterol and they increase
    membrane permeability and leads to cell death
  • Higher concentrations inhibits Chitin synthase
  • Active against Aspergillus spp, Candida species
    ,Crytococccus neoformans , Zygomycetes etc

89
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

90
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

91
Benzofurans
  • Griseofulvin
  • Inhibits nucleic acid synthesis, macrotubule
    formation and chitin formation
  • Active against ringworm, not candidia or tinea
    versicolor

92
Lipopeptides
  • Echinocandins, derivatives of pneumocandin BO
  • Inhibition of 1,3-ß- glucans in the fungal wall,
    that is glucan synthase inhibitor
  • Active candida, aspergillosis and pneumocystis
    carinii in vitro
  • Licensed for refractory candida( esophageal)
    infections and invasive Aspergilllosis
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