Fungal infections2012

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  • Inanimate: A non-living thing is one that lacks or has stopped displaying the characteristics of life. Thus, they lack or no longer displaying the capability for growth, reproduction, respiration, metabolism, and movement. They also are not capable of responding to stimuli or evolve and adapt to their environment. They also do not require energy to continue existing. Examples of non-living things are rock, water, and sun.Organisms are any contiguous living system (such as animal, fungus, micro-organism, or plant). In at least some form, all organisms are capable of respond to stimuli, reproduction, growth and development, and maintain homeostasis as a stable whole. Based on cell type, organisms may be divided into the prokaryotic and eukaryotic groups. Each may be uni or multi cellular.Prokaryotesorganisms are a group of organism that lack nucleus, mitochondria, or any other membrane-bound organelles. The prokaryotes represent two separate domains, the Bacteria and Archaea. In the past both had been classed together archaebacteria but this classification is regarded as outdated.Eukaryotic organisms are a group of organism that have a membrane-bounded cell nucleus, also contain organelles, namely mitochondria and (in plants) plastids. Fungi, animals, and plants are examples of species that are eukaryotes.Archaea and bacteria are quite similar in size and shape. Despite this visual similarity to bacteria, archaea possess genes and several metabolic pathways that are more closely related to those of eukaryotes. Initially, archaea were seen as extremophiles that lived in harsh environments, such as hot springs and salt lakes, but they have since been found in a broad range of habitats, including soil, oceans, and the human colon. No clear examples of archaealpathogenes or parasites are known. Life: الحياه Domain: نطاق-حقيقيات النوى Kingdom: مملكه –الحيوانات Phylum- cordate/ subphylum- vertebrate: شعبه- الحبليات تحت شعبة- الفقاريات Class- mammals/ subclass- Placentalia : طائفه أو صف- الثدييات تحت طائفة- المشيماوات Order-primate:-الرئيسات رتبه Family- Hominidae: فصيله(عائلة)-قردة عليا Genus-Homo: جنس- الإنسان- Species- H. sapiens: نوع- الإنسان العاقل
  • Inanimate: A non-living thing is one that lacks or has stopped displaying the characteristics of life. Thus, they lack or no longer displaying the capability for growth, reproduction, respiration, metabolism, and movement. They also are not capable of responding to stimuli or evolve and adapt to their environment. They also do not require energy to continue existing. Examples of non-living things are rock, water, and sun.Organisms are any contiguous living system (such as animal, fungus, micro-organism, or plant). In at least some form, all organisms are capable of respond to stimuli, reproduction, growth and development, and maintain homeostasis as a stable whole. Based on cell type, organisms may be divided into the prokaryotic and eukaryotic groups. Each may be uni or multi cellular.Prokaryotesorganisms are a group of organism that lack nucleus, mitochondria, or any other membrane-bound organelles. The prokaryotes represent two separate domains, the Bacteria and Archaea. In the past both had been classed together archaebacteria but this classification is regarded as outdated.Eukaryotic organisms are a group of organism that have a membrane-bounded cell nucleus, also contain organelles, namely mitochondria and (in plants) plastids. Fungi, animals, and plants are examples of species that are eukaryotes.Archaea and bacteria are quite similar in size and shape. Despite this visual similarity to bacteria, archaea possess genes and several metabolic pathways that are more closely related to those of eukaryotes. Initially, archaea were seen as extremophiles that lived in harsh environments, such as hot springs and salt lakes, but they have since been found in a broad range of habitats, including soil, oceans, and the human colon. No clear examples of archaealpathogenes or parasites are known. Life: الحياه Domain: نطاق-حقيقيات النوى Kingdom: مملكه –الحيوانات Phylum- cordate/ subphylum- vertebrate: شعبه- الحبليات تحت شعبة- الفقاريات Class- mammals/ subclass- Placentalia : طائفه أو صف- الثدييات تحت طائفة- المشيماوات Order-primate:-الرئيسات رتبه Family- Hominidae: فصيله(عائلة)-قردة عليا Genus-Homo: جنس- الإنسان- Species- H. sapiens: نوع- الإنسان العاقل
  • Inanimate: A non-living thing is one that lacks or has stopped displaying the characteristics of life. Thus, they lack or no longer displaying the capability for growth, reproduction, respiration, metabolism, and movement. They also are not capable of responding to stimuli or evolve and adapt to their environment. They also do not require energy to continue existing. Examples of non-living things are rock, water, and sun.Organisms are any contiguous living system (such as animal, fungus, micro-organism, or plant). In at least some form, all organisms are capable of respond to stimuli, reproduction, growth and development, and maintain homeostasis as a stable whole. Based on cell type, organisms may be divided into the prokaryotic and eukaryotic groups. Each may be uni or multi cellular.Prokaryotesorganisms are a group of organism that lack nucleus, mitochondria, or any other membrane-bound organelles. The prokaryotes represent two separate domains, the Bacteria and Archaea. In the past both had been classed together archaebacteria but this classification is regarded as outdated.Eukaryotic organisms are a group of organism that have a membrane-bounded cell nucleus, also contain organelles, namely mitochondria and (in plants) plastids. Fungi, animals, and plants are examples of species that are eukaryotes.Archaea and bacteria are quite similar in size and shape. Despite this visual similarity to bacteria, archaea possess genes and several metabolic pathways that are more closely related to those of eukaryotes. Initially, archaea were seen as extremophiles that lived in harsh environments, such as hot springs and salt lakes, but they have since been found in a broad range of habitats, including soil, oceans, and the human colon. No clear examples of archaealpathogenes or parasites are known. Life: الحياه Domain: نطاق-حقيقيات النوى Kingdom: مملكه –الحيوانات Phylum- cordate/ subphylum- vertebrate: شعبه- الحبليات تحت شعبة- الفقاريات Class- mammals/ subclass- Placentalia : طائفه أو صف- الثدييات تحت طائفة- المشيماوات Order-primate:-الرئيسات رتبه Family- Hominidae: فصيله(عائلة)-قردة عليا Genus-Homo: جنس- الإنسان- Species- H. sapiens: نوع- الإنسان العاقل
  • The most overt distinction between fungal cells in onw hand and plant or mammalian cells in the other hand is the cell wall of fungi. The uniqueness of this structure makes it a premier target of antifungal drugs.The fungal cell wall is composed of glucans and chitin; while the former compounds are also found in plants (plants have cellulose instead of chitin) and the latter in the exoskeleton of arthropods,[23][24] fungi are the only organisms that combine these two structural molecules in their cell wall. Fungi differ from higher plants in that they do not contain chlorophyll and thus cannot manufacture their own carbohydrates. They must use preformed carbon and nitrogen compounds made by other organisms and are therefore either saprophytic (living on dead or decaying organic matter) or parasitic (living on or within other living organisms). The group includes mushrooms, yeast, rusts, smuts, molds, and mildews, but only yeast and molds typically cause disease in humans.
  • The basic structural unit of a fungus is either a single yeast cell, or multicellular filamentous hyphae, which are the tubular projections of molds.Yeast primarily reproduce by budding, which is the out-pouching and eventual pinching off of part of the cell. A chain of budding yeast cells adhering together may appear to be like hyphae and are called pseudohyphae.Molds grow by elongation and branching of hyphae during the vegetative (feeding) stage and produce spores during the reproductive stage. Spores are small reproductive bodies that are capable of sprouting new hyphae.Clinically relevant fungi include yeasts, filamentous fungi and dimorphic fungi. Yeasts are unicellular organisms and include the relatively common Candida spp., Cryptococcus spp., and less common pathogens such as Trichosporon spp.The filamentous fungi (molds) are characterized by branching hyphae, which are either 1) Septate(with septa) as in aspergillus and many other species have septatehyphae.2) Aseptate or coenocytic (without septa) as in mucor, some zygomycetes, and other fungi.N.B. "Pseudohyphae" are distinguished from true hyphae by their method of growth, relative frailty and lack of cytoplasmic connection between the cells. Yeast can form pseudohyphae.[5] They are the result of a sort of incomplete budding where the cells remain attached after division.They are further subdivided into 1) Hyalinized groups and 2) Dematiaceous (darkly pigmented) groups. These classes include the more common Aspergillus spp. and the zygomycetes, including Rhizopus, Rhizomucor and Mucor. Less common pigmented molds that infect the central nervous system (CNS) include Pseudallescheria and Fusarium species.
  • The basic structural unit of a fungus is either a single yeast cell, or multicellular filamentous hyphae, which are the tubular projections of molds.Yeast primarily reproduce by budding, which is the out-pouching and eventual pinching off of part of the cell. A chain of budding yeast cells adhering together may appear to be like hyphae and are called pseudohyphae.Molds grow by elongation and branching of hyphae during the vegetative (feeding) stage and produce spores during the reproductive stage. Spores are small reproductive bodies that are capable of sprouting new hyphae.Clinically relevant fungi include yeasts, filamentous fungi and dimorphic fungi. Yeasts are unicellular organisms and include the relatively common Candida spp., Cryptococcus spp., and less common pathogens such as Trichosporon spp.The filamentous fungi (molds) are characterized by branching hyphae, which are either 1) Septate(with septa) as in aspergillus and many other species have septatehyphae.2) Aseptate or coenocytic (without septa) as in mucor, some zygomycetes, and other fungi.N.B. "Pseudohyphae" are distinguished from true hyphae by their method of growth, relative frailty and lack of cytoplasmic connection between the cells. Yeast can form pseudohyphae.[5] They are the result of a sort of incomplete budding where the cells remain attached after division.They are further subdivided into 1) Hyalinized groups and 2) Dematiaceous (darkly pigmented) groups. These classes include the more common Aspergillus spp. and the zygomycetes, including Rhizopus, Rhizomucor and Mucor. Less common pigmented molds that infect the central nervous system (CNS) include Pseudallescheria and Fusarium species.
  • Finally, the dimorphic, or so-called ‘endemic’, fungi are filamentous at 25 C and yeasts or spherules in host tissue or when incubated at 35 C, and include Blastomyces (south-eastern and south-central North America), Histoplasma (United States and Africa), Coccidioides (American southwest), Paracoccidioides (Brazil, Venezuela, Colombia) and Penicilliummarneffei (south-east Asia)
  • Some fungi are commensal (mucosal flora of mouth, gut, vagina etc.)Usually growth balanced by microorganisms (lactobacilli)Only a problem in situations of compromised immune responses (AIDS, antibiotics, chemotherapy, radiation, alcoholism, etc.)
  • Mycotic infections of the central nervous system are usually secondary to hematogenous dissemination from primary pulmonary infections and less often from other sites as Candida species for example are normally found in the intestinal, genital, and cutaneous flora and a wide variety of conditions promote invasion and hematogenous dissemination of this organism. Occasionally they result from direct extension from infections of the sinuses or bone. The fungal diseases, or mycoses, have been categorized as superficial or cutaneous, subcutaneous, and systemic, depending on the tissue or organs involved. The superficial or cutaneous mycoses involve the keratinized tissues of hair, skin, and nails without invasion of deeper tissue. The cutaneous mycoses are sometimes referred to as the dermatomycoses, as they are caused by a group of fungi called dermatophytes. The subcutaneous mycoses include a diverse group of infections that are characterized by the formation of a lesion at the inoculation site, often the result of injury. Generally, the fungus grows slowly in the subcutaneous tissues at the site, causing gradual spreading of the lesion, but does not disseminate to distant parts of the body.The systemic mycoses are those fungal diseases involving the internal organs, often spreading from an initial lung infection. They may become widely disseminated and involve any organ system where they can produce abscesses and granulomas (inflammatory nodules). It is mostly caused by virulent dimorphic fungi. Infections are rare (high natural immunity). Usually requires large inoculum and it is often endemic to specific areas. It starts with flu-like symptoms, meningitis then skin and/or lung manifestations. It mostly associated with four fungi:Coccidioidesimmitis -> CoccidioidomycosisHistoplasmacapsulatum -> Histoplasmosis (“Cave disease”)Blastomycesdermatitides -> BlastomycosisParacoccidioidesbrasiliensisOpportunistic mycosis: In immunocompromisedonditions (AIDS; altered mucosal flora due to antibiotics): mostly Candidiasis and Aspergillosis (often cause of epidemic death in birds)Allergic mycosis: Affect lungs or sinuses Patients may have chronic asthma, cystic fibrosis or sinusitis
  • Incidence increase because of increase in the immunocompromise personsThe most common CNS mycoses are, in order of frequency, Candidiasis, Aspergillosis, and Cryptococcosis. frequent in the neonatal period. More common in young and older individualsWith the exception of the endemic fungi and trauma induced inoculation, invasive fungal infections are largely confined to immunocompromised patients, Risk factors for fungal brain infections are 1) HIV/AIDS, 2) hematopoietic stem cell transplant (HSCT), 3) lymphoid malignancies, 4) neutropenia (Classically, neutropenia is associated with infection with Aspergillus and other molds, highlighting the importance of circulating phagocytes in controlling these pathogens. 5) hereditary immune defects, 6) immunosuppressive medications, 7) diabetesmellitus, 8) intravenousdrug abuse and 9) mechanical break downof the blood brain barrier via surgery or trauma. 10) Indwelling catheters are a risk factor for developing candidemia [4], which in turn increases the risk of CNS seeding.
  • Meningitis multiple microabscesses that may be accompanied by microgranulomas foci of hemorrhagic cerebritis
  • Meningitis multiple microabscesses that may be accompanied by microgranulomas foci of hemorrhagic cerebritis
  • Meningitis multiple microabscesses that may be accompanied by microgranulomas foci of hemorrhagic cerebritis
  • Meningitis multiple microabscesses that may be accompanied by microgranulomas foci of hemorrhagic cerebritis
  • Meningitis multiple microabscesses that may be accompanied by microgranulomas foci of hemorrhagic cerebritis
  • Meningitis multiple microabscesses that may be accompanied by microgranulomas foci of hemorrhagic cerebritis
  • Because of their size and morphologic diversity, many fungi can be seen in tissue sections by conventional light microscopic examination of Hematoxylin and Eosin (H&E) stained sections. Advantages of H & E stain is Hematoxylin & Eosin is a versatile stain that enables the pathologist to evaluate the host response Disadvantages: It is often difficult to distinguish poorly stained fungi from tissue components, even at higher magnifications. When sparse, fungi are easily overlooked in H&E stained sections.GomoriMethenamine Silver (GMS) and Periodic acid-Schiff (PAS) are the two most common stains used to look for fungi in tissues and in cytology specimens in the daily practice of pathology In the tissues, fungi usually occur either as hyphae, budding yeast, endosporulating spherules, or a combination of these forms Characters of Candida:Both yeast forms and pseudohyphae are encountered in the lesions. They may be faintly basophilic when stained with hematoxylin and eosin Intensely stained by the periodic acid–Schiff reaction. They are also easily demonstrated with the methenamine silver reaction Characters of Aspergillus:Aspergillusand the related soil fungus mucor (rhizopus) are branching hyphae.Aspergillus can be identified quickly by its septatedhyphae and the 45 degree angle branching of its hyphae Characters of Cryptococcus:Cryptococcus is an oval yeast about the size of a red cell, surrounded by a gelatinous capsule.
  • Because of their size and morphologic diversity, many fungi can be seen in tissue sections by conventional light microscopic examination of Hematoxylin and Eosin (H&E) stained sections. Advantages of H & E stain is Hematoxylin & Eosin is a versatile stain that enables the pathologist to evaluate the host response Disadvantages: It is often difficult to distinguish poorly stained fungi from tissue components, even at higher magnifications. When sparse, fungi are easily overlooked in H&E stained sections.GomoriMethenamine Silver (GMS) and Periodic acid-Schiff (PAS) are the two most common stains used to look for fungi in tissues and in cytology specimens in the daily practice of pathology In the tissues, fungi usually occur either as hyphae, budding yeast, endosporulating spherules, or a combination of these forms Characters of Candida:Both yeast forms and pseudohyphae are encountered in the lesions. They may be faintly basophilic when stained with hematoxylin and eosin Intensely stained by the periodic acid–Schiff reaction. They are also easily demonstrated with the methenamine silver reaction Characters of Aspergillus:Aspergillusand the related soil fungus mucor (rhizopus) are branching hyphae.Aspergillus can be identified quickly by its septatedhyphae and the 45 degree angle branching of its hyphae Characters of Cryptococcus:Cryptococcus is an oval yeast about the size of a red cell, surrounded by a gelatinous capsule.
  • Because of their size and morphologic diversity, many fungi can be seen in tissue sections by conventional light microscopic examination of Hematoxylin and Eosin (H&E) stained sections. Advantages of H & E stain is Hematoxylin & Eosin is a versatile stain that enables the pathologist to evaluate the host response Disadvantages: It is often difficult to distinguish poorly stained fungi from tissue components, even at higher magnifications. When sparse, fungi are easily overlooked in H&E stained sections.GomoriMethenamine Silver (GMS) and Periodic acid-Schiff (PAS) are the two most common stains used to look for fungi in tissues and in cytology specimens in the daily practice of pathology In the tissues, fungi usually occur either as hyphae, budding yeast, endosporulating spherules, or a combination of these forms Characters of Candida:Both yeast forms and pseudohyphae are encountered in the lesions. They may be faintly basophilic when stained with hematoxylin and eosin Intensely stained by the periodic acid–Schiff reaction. They are also easily demonstrated with the methenamine silver reaction Characters of Aspergillus:Aspergillusand the related soil fungus mucor (rhizopus) are branching hyphae.Aspergillus can be identified quickly by its septatedhyphae and the 45 degree angle branching of its hyphae Characters of Cryptococcus:Cryptococcus is an oval yeast about the size of a red cell, surrounded by a gelatinous capsule.
  • CT Findings NECT Areas of low density ~ lacunar infarctions (infarcts may be larger) Diffuse brainedema, herniations Hemorrhages Hydrocephalus Vertebral body destruction (sclerotic lesions are rare = coccidioidomycosis) CECT Multiple foci of non-specific enhancement Some are ring-likeCritical Steps for Diagnosing Brain Infections: Slideshow. http://reference.medscape.com/features/slideshow/brain-infections. WebMD LLC.Reviewed 03/26/12MR Findings T1WI: Ill-defined areas of I signal intensity T2WI Focal or diffuse areas of 1 signal Spine: 1 Signal in vertebrae, disc and spinal cord PD/Intermediate: Same as T2WI FLAIR: Same as T2WIT2* GRE: May accentuate Ca++ or presence of blood products DWI: Slightly bright on trace images but no restricted diffusion on ADC mapTl C+Meningeal enhancement Thick meningeal enhancement ...•thick acute exudates or meningeal fibrosis Areas of non-specific appearing enhancement, may be ring-like, solitary-to-miliary May be seen in spinal cord Enhancement of disc, vertebrae and epidural space ...•discitis/osteomyelitis MRA: Vesselirregularities (vasculitis), occlusions, mycotic aneurysms MRV: Sinus thrombosis MRS: Mildly t Cho, j NAA, t lactate
  • CT Findings NECT Areas of low density ~ lacunar infarctions (infarcts may be larger) Diffuse brainedema, herniations Hemorrhages Hydrocephalus Vertebral body destruction (sclerotic lesions are rare = coccidioidomycosis) CECT Multiple foci of non-specific enhancement Some are ring-likeMR Findings T1WI: Ill-defined areas of I signal intensity T2WI Focal or diffuse areas of 1 signal Spine: 1 Signal in vertebrae, disc and spinal cord PD/Intermediate: Same as T2WI FLAIR: Same as T2WIT2* GRE: May accentuate Ca++ or presence of blood products DWI: Slightly bright on trace images but no restricted diffusion on ADC mapTl C+Meningeal enhancement Thick meningeal enhancement ...•thick acute exudates or meningeal fibrosis Areas of non-specific appearing enhancement, may be ring-like, solitary-to-miliary May be seen in spinal cord Enhancement of disc, vertebrae and epidural space ...•discitis/osteomyelitis MRA: Vesselirregularities (vasculitis), occlusions, mycotic aneurysms MRV: Sinus thrombosis MRS: Mildly t Cho, j NAA, t lactate
  • Meningitis: Fungus that primarily causes meningitis is coccidioidesimmitis, typically widespread, basal meninges being maximally involved. The basic lesion is a combination of suppurative and granulomatous inflammation. This chronic inflammatory response leads to thickening of meninges, hydrocephalus, arteritis, cranial nerve palsies and infarction. Other fungi (Blastomyces, histoplasma) may also cause meningitis.Meningo encephalitis: Cryptococcus neoformans and the candida are prone to cause meningoencephalitis. In cryptococcosis, clusters of fungi are spread throughout the brain, with little or no surrounding inflammatory responses; predominantly involve basal ganglia and cortical grey matter. The cystic lesion contains gelatinous poly saccharide which may be detected in CSF and forms the basis for latex agglutination tests which is 90% sensitive and highly specific for cryptococcosis.Rhino cerebral syndrome presents with orbital pain, nasal discharge and facial edema. There may be proptosis and visual loss. Involvement of carotids may cause hemi paresis. Subsequently trigeminal nerve and adjacent brain may be involved. This is classically found in mucormycosis where blackish necrotic areas are seen in the palate and nasal turbinates.Stroke lijke presentation (infarction/He): Asperigillus, zygomycetes, blastomyces, candidiasis cause these lesions as also nocardia, actinomyces and coccidioidomycoses. Disseminated candidiasis produce microabcesses. Vasculitis predispose to infarction and he. Aspergillosis or mucormycosis may produce sudden onset of deficit due to vasculitis. Rarely there is SAH due to mycotic aneurismal bleed. Unlike bacterial aneurysms, fungus affects the larger arteries.
  • Candidiasis: Central nervous system infection can be caused by several species, but most are due to Candida albicans Candida species are normally found in the intestinal, genital, and cutaneous flora.A wide variety of conditions promote invasion and hematogenous dissemination of this organism. These include long-term antibiotic and corticosteroid therapy, indwelling catheters, hyperalimentation lines, abdominal surgery, diabetes, burns, malignancies, neutropenia, and intravenous drug abuse, neutropenia being particularly important. Involvement of the nervous system is usually in the form of multiple microabscesses that may be accompanied by microgranulomas. Meningitis is rare except in premature infants and neonates It is a common neonatal CNS fungal infection
  • Cryptococcosis: Commonest cause of fungal meningitis. The meningitis may be subacute or chronic and may lead to hydrocephalus. Less commonly, cryptococcosis produces multiple intraparenchymalpseudocysts (perivascular spaces) that grossly look like small (2–3 mm) soap bubbles or Swiss cheese, especially in the superficial and deep gray matter. In rare cases the disease produces large or small granulomas (cryptococcomas or torulomas) in the meninges, parenchyma, ependymal surfaces, or choroid plexuses. The patients who have cryptococcomas are rarely in an immunocompromised stateThe primary human infection is in the lung. More than 50% of the patients in whom disseminated disease develops are immunocompromised. The causative agent, Cryptococcus neoformans(formerly Torulahistolytica), is found in soil that has been contaminated with bird excreta. Predisposing conditions include corticosteroid therapy, organ transplantation, collagen vascular diseases, reticuloendothelial neoplasms, and in recent years AIDS. The organisms appear as singly budding yeast forms with a narrow neck or very rarely with short pseudohyphae. They stain faintly with hematoxylin and eosin. The cell walls stain strongly with the periodic acid–Schiff, mucicarmine, and methenamine silver stains (Lazcano et al., 1993). Thick mucopolysaccharide capsules that stain with Alcian blue and colloidal iron surround these yeast forms. Tissue processing for paraffin-embedded sections often causes the capsular material to shrink onto the cell wall, leaving an emptyappearing halo around the stained organisms
  • Aspergillosis:Aspergillosis is the second or third most common mycotic infection of the nervous system Several species can cause central nervous system infection, but most cases are due to Aspergillusfumigatus or Aspergillusflavus. These mold organisms are found in soil, water, and decaying vegetation. Primary infections usually involve the lungs. Central nervous system involvement is usually the result of hematogenous dissemination (Sepkowitz and Armstrong, 1997) although some cases are due to direct extension from the sinuses and ears or the result of head trauma. Conditions that predispose to hematogenous dissemination include corticosteroid and immunosuppressive therapy …….Hematogenous dissemination generally leads to multiple lesions, whereas direct extension may produce only one or a few lesions. The fungus is highly angioinvasive, and the early lesions are often recognized radiographically as foci of hemorrhagic cerebritis that resemble hemorrhagic infarcts (McCormick et al., 1975). Much less frequently the fungus produces intraparenchymalgranulomas or even meningitis In tissue the organisms form dichotomously branching septatehyphae of uniform (4–8 m) diameter (Chandler and Watts, 1987). They are only faintly visible with hematoxylin and eosin stain and are often weakly stained with the periodic acid–Schiff technique. They are most readily demonstrated with methenamine silver stains.
  • Mucormycosis predicting the causative organism(s) The causative agents are several genera that belong to the family Mucoraceae, including Rhizopus, Mucor, and Absidia (all are mold organisms).These ubiquitous mold organisms are found in the soil and decaying vegetation Generally Mucormycosis is very angioinvasive and often produces extensive infarction of the neural parenchyma. Several patterns of disease with somewhat different predisposing conditions have been delineated (Rangel-Guerra et al., 1985; Chimelli and Mahler-Araujo, 1997). The most common form is rhinocerebral, which is encountered mainly in patients with poorly controlled diabetes and especially acidosis and dehydration. The patients usually have periorbital swelling, proptosis, and a nasal discharge. Rhinocerebral disease results from direct extension of the mycotic infection from the nose or paranasal sinuses through veins to the orbit and brain (Duplechain and White, 1989; Chimelli and Mahler-Araujo, 1997). Central nervous system involvement may also result from hematogenous dissemination from extracranial sites such as the lungs. Conditions that predispose to hematogenous dissemination also include acidosis from diarrhea and dehydration in children, organ transplantation, …… When the central nervous system involvement results from hematogenous dissemination, the lesions often produce isolated foci of hemorrhagic necrosis of deep ganglionic structures (Cuadrado et al., 1988; Stave et al., 1989; Siddiqi and Freedman, 1994). The organisms have fairly distinctive morphology and appear as irregular broad (10–20 m diameter) hyphae (Chandler and Watts, 1987). The hyphae are nonseptate and branch at right angles. Folding of these hyphae may simulate septate forms. They are relatively well shown with hematoxylin and eosin but can be demonstrated better with methenamine silver stains.
  • CSF Examination: CSF sampling is indicated in all patients with meningitis and may show a lymphocytic pleocytosis (Cryptococcus, Candida), neutrophilic predominance (Aspergillus, Blastomycosis) or eosinophilia (Coccidioides). CSF glucose is generally low and protein high. CSF antigen testing is available for Cryptococcus and Histoplasma, with sensitivity and specificity rates reported in some series above 90%. CSF assays for galactomannan are under investigation and may prove to have clinical utility [33]. The central nervous system mycoses are difficult to diagnose with certainty in living patients with the possible exception of cryptococcosis, for which the CSF cryptococcal antigen test is extremely helpful. Definitive diagnosis of cryptococcosis can be established by CSF culture in about 75% of cases, and cryptococcal antigen tests on CSF are positive in more than 90% of cases. Examination of cerebrospinal fluid with “India ink” is a time-honored method but provides the diagnosis in only about 50% of cases (Perfect and Durack, 1997).
  • Best diagnostic clue: Meningeal enhancement, multiple enhancing non-specific appearing lesions in brain and/or spinal cord in immunosuppressed patient Location: Meninges, brain, spinal cord, vertebral bodies + discs Size: Variable size of lesions Morphology: Most lesions are ring-like and 'dot-like‘ and enhanceCT features:CT Findings NECT: Areas of low density ~ lacunar infarctions (infarcts may be larger) Diffuse brainedema, herniations Hemorrhages Hydrocephalus Vertebral body destruction (sclerotic lesions are rare = coccidioidomycosis) CECT Multiple foci of non-specific enhancement some are ring-likeMRI features:T1WI: Ill-defined areas of decrease signal intensity T2WI: Focal or diffuse areas of increase signal in Spine: increase Signal in vertebrae, disc and spinal cord PD/Intermediate: Same as T2WI FLAIR: Same as T2WITl C+: Meningeal enhancement, areas of non-specific appearing enhancement, may be ring-like, solitary-to-miliary . May be seen in spinal cord. Enhancement of disc, vertebrae and epidural space (discitis/osteomyelitis) MRA: Vesselirregularities (vasculitis), occlusions, mycotic aneurysms MRV: Sinus thrombosis MRS: Mildly increase Cho, decrease NAA, increase lactate
  • Best diagnostic clue: Meningeal enhancement, multiple enhancing non-specific appearing lesions in brain and/or spinal cord in immunosuppressed patient Location: Meninges, brain, spinal cord, vertebral bodies + discs Size: Variable size of lesions Morphology: Most lesions are ring-like and 'dot-like‘ and enhanceCT features:CT Findings NECT: Areas of low density ~ lacunar infarctions (infarcts may be larger) Diffuse brainedema, herniations Hemorrhages Hydrocephalus Vertebral body destruction (sclerotic lesions are rare = coccidioidomycosis) CECT Multiple foci of non-specific enhancement some are ring-likeMRI features:T1WI: Ill-defined areas of decrease signal intensity T2WI: Focal or diffuse areas of increase signal in Spine: increase Signal in vertebrae, disc and spinal cord PD/Intermediate: Same as T2WI FLAIR: Same as T2WITl C+: Meningeal enhancement, areas of non-specific appearing enhancement, may be ring-like, solitary-to-miliary . May be seen in spinal cord. Enhancement of disc, vertebrae and epidural space (discitis/osteomyelitis) MRA: Vesselirregularities (vasculitis), occlusions, mycotic aneurysms MRV: Sinus thrombosis MRS: Mildly increase Cho, decrease NAA, increase lactate
  • Best diagnostic clue: Meningeal enhancement, multiple enhancing non-specific appearing lesions in brain and/or spinal cord in immunosuppressed patient Location: Meninges, brain, spinal cord, vertebral bodies + discs Size: Variable size of lesions Morphology: Most lesions are ring-like and 'dot-like‘ and enhanceCT features:CT Findings NECT: Areas of low density ~ lacunar infarctions (infarcts may be larger) Diffuse brainedema, herniations Hemorrhages Hydrocephalus Vertebral body destruction (sclerotic lesions are rare = coccidioidomycosis) CECT Multiple foci of non-specific enhancement some are ring-likeMRI features:T1WI: Ill-defined areas of decrease signal intensity T2WI: Focal or diffuse areas of increase signal in Spine: increase Signal in vertebrae, disc and spinal cord PD/Intermediate: Same as T2WI FLAIR: Same as T2WITl C+: Meningeal enhancement, areas of non-specific appearing enhancement, may be ring-like, solitary-to-miliary . May be seen in spinal cord. Enhancement of disc, vertebrae and epidural space (discitis/osteomyelitis) MRA: Vesselirregularities (vasculitis), occlusions, mycotic aneurysms MRV: Sinus thrombosis MRS: Mildly increase Cho, decrease NAA, increase lactate
  • The Fungitell beta-D Glucan assay is indicated for presumptive diagnosis of fungal infection through detection of elevated levels of (1,3)- beta-D-glucan in serum. It should be used in conjunction with other diagnostic procedures. Normal human serum contains low levels of (1,3)- beta-D glucan, typically 10 to 40 pg/mL, presumably from commensal yeasts present in the alimentary canal and gastrointestinal tract. However, (1,3)- beta-D-glucan is sloughed from the cell walls during the life cycle of most pathogenic fungi. Thus, monitoring serum for evidence of elevated and rising levels of (1,3)- beta-D-glucan provides a convenient surrogate marker for invasive fungal disease. It will be elevated in many different fungal species as Candida spp., Aspergillus spp., The Fungitell beta-D Glucan assay does not detect certain fungal species such as the genus Cryptococcus, which produces very low levels of (1,3)- beta-D-glucan, nor the Zygomycetes, such as Absidia, Mucor, and Rhizopus, which are not known to produce (1,3)- beta-D-glucan. There are reports in the peer reviewed literature of lowered assay specificity in patients with gram positive bacteremia. Sensitivity rates, in some series, of 64–95%, although specificity may be decreased in the presence of concurrent bacteremia. A positive serum galactomannan assay in the setting of a radiographic brain lesion should prompt empiric antifungal therapy targeted to treat invasive aspergillosis.Refrences: Beta D Glucan (Fungitell): The University of Iowa (UIHC) Department of Pathology LABORATORY SERVICES HANDBOOK http://www.medicine.uiowa.edu/path_handbook/handbook/test2384.html. Updated: 02/25/2009. viewed 21/17/2010
  • Specimen collectionThe laboratory should be sent fresh specimens.All specimens for fungus culture should be transported to the microbiology laboratory and processed as soon as possible. Since many pathogenic fungi grow slowly, any delay in processing increases the possibility of overgrowth by rapidly growing contaminants and decreases the probability of isolating the causative agent.Direct examination of specimens: Since fungi take days to weeks to grow in culture on agar media, a direct examination result provides a rapid clues for the presence of fungal elements. The term fungal elements includes any of the structures that may be seen during examination of specimens or cultures: yeast, budding yeast, hyphae, pseudohyphae, spores, and mycelia (Multiple, loosely intertwined hyphae strands called mycelia are the fluffy, colorful colonies seen as mold growing on rotting fruit).Thegram stain, which is performed on specimens sent for bacterial culture, will detect most fungi, if present. The Wright stain, which is used routinely on peripheral blood smears and bone marrow aspirates, will also detect Histoplasmacapsulatum and Cryptococcus neoformans. Common tissue stains that are excellent for the detection of fungal elements are the periodic acid-Schiff (PAS) stain, the Gomorimethenamine-silver nitrate (GMS) stain, and the Mayer mucicarmine stain.Fluorescent antibody stains can be used to detect fungi directly in tissue or fluidsKOH PREPARATION WITH CALCOFLUOR WHITE. The potassium hydroxide (KOH): It is for examination of any type of tissues or fluid. A 10% to 20% solution of KOH is mixed with the specimen on a slide, a cover slip is placed on top of the preparation and the slide is gently heated. The preparation is then viewed under the 10x (low power) objective of a light microscope with fairly low illumination. KOH dissolves keratin and other cellular material but leaves the fungal structures intact and refractile. Hyphae, pseudohyphae, yeast, and spores can be seen. Calcofluor white, a fluorescent dye, may be added to the KOH preparation to aid in visualizing the fungal elements. Calcofluor white binds to polysaccharides in the cell wall of fungi, and fluoresces either apple-green or blue-white, depending on the combination of filters used in a fluorescent microscope.INDIA INK PREPARATION AND CRYPTOCOCCAL ANTIGEN TEST: it is for fluid specimen examination as CSF. A drop of India ink is mixed with a drop of sediment from a centrifuged specimen and the preparation is examined under the light microscope. Budding yeast in CSF surrounded by a large clear capsule against a black background is presumptive evidence of C. neoformansmeningitis.
  • Fungal culture:As the direct examination of the specimen is proceeding, the specimen is set up as a culture without delay. The viability of fungi decreases with time, and contaminant overgrowth may hinder the recovery of the pathogen. When delay cannot be avoided, the specimens, with the exception of blood, CSF, and dermatological (skin, hair, nail) specimens, can be refrigerated for a short time.Tissue samples are ground with a mortar and pestle in a small amount of sterile saline before being inoculated onto media.Cultures should be incubated for 30 days and examined at least three times weekly before reporting as negative. Rapid-growing fungi appear in one to three days, intermediate growers take five to nine days to colonize and slow growers take up to four weeks to appear. Susceptibility testing: Susceptibility testing of fungal isolates to antifungal agents is generally done only after treatment failure.
  • locally invasive skull base neoplasm Look for soft tissue mass in nasopharynx Fungal infection often angioinvasive with ICA occlusion (rare in SCCA)Multiple ring-enhancing parenchymal in immunocompetent patients Metastases Multiple pyogenic abscesses TB Parasites (e.g., neurocysticercosis) Fungal abscess (rare) Septic emboliMultiple ring-enhancing parenchymal lesions in immunocompromised patients Fungal abscesses (common) TB Toxoplasmosis
  • locally invasive skull base neoplasm Look for soft tissue mass in nasopharynx Fungal infection often angioinvasive with ICA occlusion (rare in SCCA)Multiple ring-enhancing parenchymal in immunocompetent patients Metastases Multiple pyogenic abscesses TB Parasites (e.g., neurocysticercosis) Fungal abscess (rare) Septic emboliMultiple ring-enhancing parenchymal lesions in immunocompromised patients Fungal abscesses (common) TB Toxoplasmosis
  • locally invasive skull base neoplasm Look for soft tissue mass in nasopharynx Fungal infection often angioinvasive with ICA occlusion (rare in SCCA)Multiple ring-enhancing parenchymal in immunocompetent patients Metastases Multiple pyogenic abscesses TB Parasites (e.g., neurocysticercosis) Fungal abscess (rare) Septic emboliMultiple ring-enhancing parenchymal lesions in immunocompromised patients Fungal abscesses (common) TB Toxoplasmosis
  • Mechanism of action: Bind to fungal membrane sterols (ergosterol) Alter selectively permeability to K+ (and Mg2+) => Fungicidal Resistance due to altered sterolsAntifungal ActivityAmphotericin B remains the antifungal agent with the broadest spectrum of action (against yeasts and molds).Indications:Owing to its broad spectrum of activity and fungicidal action, amphotericin B remains a useful agent for nearly all life-threatening mycotic infections, although newer less toxic agents have largely replaced amphotericin B for most conditions. It is often used as the initial induction regimen in order to rapidly reduce fungal burden and is then replaced by one of the newer azole drugs (described below) for chronic therapy or prevention of relapse. Rout of administration:Intravenous therapy: it is the standard route in systemic mycosisOral administration: Amphotericin B is poorly absorbed from the gastrointestinal tract. Oral amphotericin B is thus effective only on fungi within the lumen of the tract and cannot be used for treatment of systemic disease. Intrathecal therapy for fungal meningitis is poorly tolerated and fraught with difficulties related to maintaining cerebrospinal fluid access. Thus, intrathecal therapy with amphotericin B is being increasingly supplanted by other therapies but remains an option in cases of fungal central nervous system infections that have not responded to other agents. Local or topical administration of amphotericin B has been used with success as in mycotic corneal ulcers and keratitis. Formulation:Conventional formulation: It is nearly insoluble in water and is therefore prepared as a colloidal suspension of amphotericin B and sodium desoxycholate for intravenous injection. E.G. of this preparation is Fungizone drugLipid formulations: Several new formulations have been developed in which amphotericin B is packaged in a lipid-associated delivery system. Therapy with amphotericin B is often limited by toxicity, especially drug-induced renal impairment. This has led to the development of lipid drug formulations on the assumption that lipid-packaged drug binds to the mammalian membrane less readily, permitting the use of effective doses of the drug with lower toxicity. Liposomal amphotericin preparations package the active drug in lipid delivery vehicles, in contrast to the colloidal suspensions, which were previously the only available forms. Amphotericin binds to the lipids in these vehicles with an affinity between that for fungal ergosterol and that for human cholesterol. E.G. of this preparation are AmBisome, Amphotec, AbelcetAdverse Effects: The toxicity of amphotericin B can be divided into two broad categories: immediate reactions, related to the infusion of the drug, and those occurring more slowly. Infusion-related toxicity: Infusion-related reactions are nearly universal and consist of fever, chills, muscle spasms, vomiting, headache, and hypotension. They can be ameliorated by slowing the infusion rate or decreasing the daily dose. Premedication with antipyretics, antihistamines, meperidine, or corticosteroids can be helpful. When starting therapy, many clinicians administer a test dose of 1 mg intravenously to gauge the severity of the reaction. After intrathecal therapy with amphotericin, seizures and a chemical arachnoiditis may develop, often with serious neurologic sequelae.Cumulative toxicity: Renal damage is the most significant toxic reaction. Renal impairment occurs in nearly all patients treated with clinically significant doses of amphotericin. The irreversible form of amphotericinnephrotoxicity usually occurs in the setting of prolonged administration (> 4 g cumulative dose). Other side effects include: abnormalities of liver function tests, a varying degree of anemia, hypokalemia and hypomagnesemia. Available Forms: Powder for injection: 50mgLozenges: 10mgOral Suspension: 100mg/mLTablets: 100mgDose: A single intravenous test dose 1 mg in 20 mL of 5% dextrose solution administered over 20 to 30 minutes. The patient's temperature, pulse, respiration, and blood pressure should be recorded every 30 minutes for 2 to 4 hours. Then followed by infusion of the daily dose of 0.25-1.0 mg/kg/d (adult and pediatric dose) in D5W for 4 – 8 Hrs (The recommended concentration for intravenous infusion is 0.1 mg/mL (1 mg/10 mL). The daily lipid formulation dose is more than the conventional form (3-5mg/kg/d) Children: IV: Same as adults, expect dilution and infuse time differDuration of treatment:It is usually continued to a defined total dose (eg, 2-3 g), rather than a defined time span, as used with other antimicrobial drugs.
  • Mechanism of action: Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme. This enzyme functions to convert lanosterol to ergosterol (essential part of fungus wall).Mammalian cell demethylation is much less sensitive to fluconazole inhibition.Antifungal Activity:The spectrum of action of azole medications in general is broad, including many candida species, C neoformans, the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes, and, in the case of itraconazole and voriconazole (Vfend), even aspergillus infections. They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii.Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher (up to 90%) in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fluconazole (Diflucan) displays no activity against aspergillus or other filamentous fungiPharmacokinetics t 1/2 = ~24 hours Single dosage Protein binding < 12% Bioavailibility after oral dose > 90% unlike ketoconazole, absorption is not affected by food or intragastricpH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Reaches high CSF concentrations (90% of serum level) >90% excreted unchanged through the kidneySteady-state concentrations (20 µg/ml) are reached within 5-10 days following oral doses of 50-400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day.Indications:Owing to its broad spectrum of activity and fungicidal action, it remains a useful agent for chronic treatment of nearly all life-threatening mycotic infections.Fluconazole (Diflucan) has the widest therapeutic index of the azolesFormulation: Injection: vial of 25,50 and 100 mL contain 2 mg/ ml Powder for oral suspension contains 350 mg or 1400 mg of fluconazole reconstitution with 24 mL of distilled water cause: 50mg/5mL, 200mg/5mL Capsules: 50mg,150mg,200 mgAdverse Effects:As a group, the azoles are relatively nontoxic. The most common adverse reaction is relatively minor gastrointestinal upset. All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis. All azole drugs affect the mammalian cytochrome P450 system of enzymes to some extent, and consequently they are prone to drug interactions. CNS; headache, dizziness GI: DIFLUCAN Syrup contains glycerol. Glycerol may cause stomach upset, diarrhea, nausea,vomiting, abdominal pain, dyspepsia, and taste perversion. Cardiovascular: prolongation of the QT interval on the electrocardiogram. Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided. HEMATOLOGIC:leukopnea, thrombocytopenia SKIN: RashUncommon sever effects:Hepatotoxicity: DIFLUCAN has been associated with rare cases of serious hepatic toxicityAnaphylaxis: Exfoliative skin disordersInteraction:Phenytoin: There was a significant increase in phenytoin level with (Diflucan®) Oral hypoglycemics: There was a significant increase in oral hypoglycemics level with (Diflucan®) Cimetidine decrease level of (Diflucan®)Hydrochlorothiazide increase serum level of (Diflucan®)Rifampin reduced fluconazole levels to half (even though FLU is not a major substrate)Available Forms:Injection: vial of 25,50 and 100 mL contain 2 mg/ mlPowder for oral suspension contains 350 mg or 1400 mg of fluconazole reconstitution with 24 mL of distilled water cause: 50mg/5mL, 200mg/5mL Capsules: 50mg,150mg,200 mgRout of administration:Oral: with or without food as a single dose Intravenous: at a maximum rate of approximately 200 mg/hour, given as a continuous infusion.Dose:Loading dose in the first day: Double maintenance dose (up to 400mg)Maintenance dose (200-400mg/d) on a single dose Pediatric: 3-12 mg/kg/d (max 400mg/d) according to severity of case. As some older children may have clearances similar to that of adults, absolute doses exceeding 400 mg/day are not recommended.Duration of treatment:Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative.
  • Mechanism of action: Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme. This enzyme functions to convert lanosterol to ergosterol (essential part of fungus wall).Mammalian cell demethylation is much less sensitive to fluconazole inhibition.Antifungal Activity:Voriconazole has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections.*Aspergillusfumigatus *Aspergillusflavus * Aspergillusniger * Aspergillusterreus* Candida albicans * Candida glabrata * Candida krusei * Candida parapsilosis * Candida tropicalis * Fusarium spp. including Fusariumsolani * ScedosporiumapiospermumPharmacokineticst 1/2 = ~24 hrs. Protein binding = ~ 58%Bioavailibility > 90% and unlike ketoconazole, absorption is not affected by food or intragastricpH.It has non linear pharmacokinetics which means blood concentrations does not increase in proportion to dosageSteady state trough plasma concentrations with voriconazole are achieved after approximately 5 days of oral or intravenous dosing without a loading dose regimen. However, when an intravenous loading dose regimen is used, steady state trough plasma concentrations are achieved within 1 day.Reaches high CSF concentrations (90% of serum level) Metabolized by the human hepatic cytochrome P450 enzymes and the the major metabolite of voriconazole has minimal antifungal activity.Eiminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.Indications:Adverse Effects:Arrhythmias and QT ProlongationPatients have rarely developed serious exfoliativecutaneous reactions, Infusion Related Reactions: anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash VISUAL DISTURBANCES: The effect of VFEND on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored (see PRECAUTIONS – Information for Patients and ADVERSE REACTIONS – Visual Disturbances).HEPATIC TOXICITY: In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with VFEND (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy. It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving VFEND The pharmacokinetics of orally administered VFEND are not significantly affected by renal insufficiency. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment while In patients with moderate or severe renal insufficiency (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole.Information for Patients: Patients should be advised: That VFEND Tablets or Oral Suspension should be taken at least one hour before, or one hour following, a meal. that they should not drive at night while taking VFEND. VFEND may cause changes to vision, including blurring and/or photophobia. that they should avoid potentially hazardous tasks, such as driving or operating machinery if they perceive any change in vision. that strong, direct sunlight should be avoided during VFEND therapy. that VFEND for Oral Suspension contains sucrose and is not recommended for patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase deficiency or glucosegalactosemalabsorption. Drugs Interaction:Interaction: The systemic exposure to voriconazole is significantly reduced or is expected to be reduced by the concomitant administration of the following agents and their use is contraindicated:Rifampin (potent CYP450 inducer):Carbamazepine and long-acting barbiturates (potent CYP450 inducers):Co-administration of voriconazole with the following agents results in increased exposure or is expected to result in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:FentanylMethadoneNon-Steroidal Anti-Inflammatory Drugs Warfarin Oral Coumarin AnticoagulantsBenzodiazepinesCalcium Channel BlockersTwo-Way Interactions in the two drugs Phenytoin (300 mg once daily) decrease serum level of voriconazole (200 mg Q12h x 14 days) so if both drugs are used voriconazole dose should increases to 4200 mg Q12h.voriconazole (400 mg Q12h ) increase serum level of Phenytoin as high as 2 times so frequent serum level monitoring is indicated if both drugs are used. Both drugs are increasedOral Contraceptives: only monitor the side effects Proton pump inhibitors as Omeprazole: No dosage adjustment of voriconazole is recommended but omeprazole dose should be reduced by one-half.Available Forms:Powder for Oral Suspension: 200 mg/5ml Powder for injection: 200 mg VFENDTablets: 50 & 200 mgRout of administration:VFEND I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1-2 hours. NOT FOR IV BOLUS INJECTIONVFEND Tablets or Oral Suspension should be taken at least one hour before, or one hour following, a meal.Dose:Loading dose: therapy must be initiated with the specified loading dose regimen of intravenous VFEND to achieve plasma concentrations on Day 1 that are close to steady state. 6 mg/kg q12h for the first 24 hours Maintenance dose: Either IV or oral if patient can tolerate oral forms. 4 mg/kg q12h IV or 200 mg q12h orally If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours to 300 mg every 12 hours (100 mg to 200 mg every 12 hours in adult patients weighing less than 40 kg) Phenytoin may be coadministered with VFEND if the intravenous maintenance dose of VFEND is increased to 5 mg/kg every 12 hours, or the oral maintenance dose is increased from 200 mg to 400 mg every 12 hoursDuration of treatment:Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response.
  • Mechanism of action: Flucytosine is a fluorinated pyrimidine analogue taken up by the fungal enzyme cytosine permease and incorporated, causing RNA miscoding and inhibiting DNA synthesis.Antifungal Activity: This group has activity against Candida, Cryptococcus and Saccharomyces and has been demonstrated to have synergistic action with amphotericin B in induction therapy for cryptococcal meningitisKinetics:Orally absorbedWidely distributed even in CSFExc. in urine.Converted in fungal cell to 5-FU which is antimetabolite.Mammalian cells remain unaffected except few bone marrow cellsSide effects:Resistance can develop at the level of the cytosine permease or at the cytosine deaminase and develops rapidly in the setting of monotherapy.CNS: headache, vertigo, sedation, fatigue, weakness, confusion, hallucinations, psychosis, ataxia, hearing loss, paresthesia, parkinsonism, peripheral neuropathyCV: cardiac arrest, chest painGI: nausea, vomiting, diarrhea, abdominal pain, dry mouth, duodenal ulcer, hemorrhage,ulcerative colitis, anorexiaGU:azotemia, crystalluria, renal failureHEMATOLOGICHEMATOLOGIC:anemia, leukopenia, bone marrow suppression, thrombocytopenia, eosinophilia, agranulocytosis, aplasticanemiaHEPATIC: jaundiceMETABOLIC: hypoglycaemia, hypokalemiaRESPIRATORY: respiratory arrest, dyspneaSKIN: occasional rash, pruritus, urticaria, photosensitivity Indications: Never monotherapy but in combination with amphotericin B or fluconazole (diflucan)CandidiasisSevere fungal infections caused by susceptible strains of Candida species, including septicaemia, endocarditis, urinary tract, and pulmonary infectionsCryptococcosis, including meningitis, pulmonary infections, and urinary tract infections ?Aspergillosis Available Forms:Capsules: 250mg, 500mgDoses: A: PO: 50-150mg/kg/d in four divided doses. for 3 monthsC:>50kg:PO: 50-150mg/kg/d in 4 divided doses. C: < 50kg :PO: 1.5-4.5 g/m2 /d in four divided doses. C: < 50: PO:1.5-4.5 g/m2 /d in four divided doses. Neonate: PO: 50-100mg/kg/d in 1-2 divided doses.
  • Fungal infections2012

    1. 1. CNS Fungal InfectionProf. Mohamed Wael Samir Prof. Of Neurosurgery Ain Shams University
    2. 2. ILOs Enumerate the causative organism of thecommonest mycotic infections of CNS. Describe the characteristics of those causativeagents. Discuss the epidemiology of the commonest CNSfungal infection Describe the gross & histopathological features. Describe the radiological features. Describe the possible clinical presentationDiscuss diagnosis & differential diagnosis Discuss in details treatment of CNS mycosis
    3. 3. Life Tree Living • Growth subjec t= • Reproduce • Energy… Organism Non living subject = • Nothing Inanimate
    4. 4. Life Tree
    5. 5. Human FungusLife Tree Organism Eukarya Animal Fungi Cordate-Vertebrate Mammals- Placetalia Primate Hominidae Homo H Sapiens
    6. 6. Difference between Fungi and Plants mannoproteins 1,3 1,6 glucans Cell 1,3 glucan chitin membrane synthase ergosterolAtlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
    7. 7. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    8. 8. Types of fugi• Yeasts: – Unicellular fungi, reproduce by budding – Include candida group.• Filamentous Fungi (Molds ): – Multicellular filamentous, “fluffy” colonies consisting of branching tubular structures called hyphae – Include aspergillus
    9. 9. Types of fugiCandida Yeast (GMS) Aspegillus hyphae
    10. 10. Types of fugi• Dimorphic Fungi: – Either yeast or hyphae form – At ambient environmental temperatures (e.g. 25° C) grow as molds where they form reproductive spore structures. – Inhaled spores grow as yeasts at body temperature (37° C) in the host
    11. 11. Fungal Habitats• Most clinically relevant fungi reside in – Soil, – Bird feces, – Vegetation, – Skin and mucous membranes of mammals.
    12. 12. Pathogenesis of Mycotic infections of the central nervous system• Direct spread: – Paranasal sinus• Hematogenous spread: from extrtacranial fungal infection or opportunistic infection – Superficial mycosis: skin, hair, nails, mucous membrane – Deep mycosis: Subcutaneous & deeper tissue – Systemic mycosis: pulmonary infection
    13. 13. Major Types of Opportunistic Mycosis• Candidiasis: caused by Candida albicans• Cryptococcosis: caused by Cryptococcus neoformans• Aspergillosis: caused by Aspergillus sp.• Others: Blastomycosis, coccidiomycosis, histoplasmosis,
    14. 14. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    15. 15. Epidemiology• Incidence: ↑ ↑ ↑• Sex: More common in males (1 outdoor activities)• Race: No predilection• Age: More common in young and older individuals• Risk factors: • Patients with impaired cell-mediated immunity (e.g. AIDS, organ transplant) at heightened risk for severe disease. • Blastomycosis: Agricultural workers
    16. 16. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    17. 17. Macroscopic Features• Meningitis:• Multible microabscesses:• Granulomas (Micro or macro):• Vascular invasions causing areas of: – Hemorrahge – Infarction• Extensive brain necrosis• Vertebral body or disc infection
    18. 18. Macroscopic Features• Meningitis:• Multible microabscesses:• Granulomas (Micro or macro):• Vascular invasions causing areas of: – Hemorrahge – Infarction• Extensive brain necrosis• Vertebral body or disc infection
    19. 19. Macroscopic Features• Meningitis:• Multible microabscesses:• Granulomas (Micro or macro):• Vascular invasions causing areas of: – Hemorrahge – Infarction• Extensive brain necrosis• Vertebral body or disc infection
    20. 20. Macroscopic Features• Meningitis:• Multible microabscesses:• Granulomas (Micro or macro):• Vascular invasions causing areas of: – Hemorrahge – Infarction• Extensive brain necrosis• Vertebral body or disc infection
    21. 21. Macroscopic Features• Meningitis:• Multible microabscesses:• Granulomas (Micro or macro):• Vascular invasions causing areas of: – Hemorrahge – Infarction• Extensive brain necrosis• Vertebral body or disc infection
    22. 22. Macroscopic Features• Meningitis:• Multible microabscesses:• Granulomas (Micro or macro):• Vascular invasions causing areas of: – Hemorrahge – Infarction• Extensive brain necrosis• Vertebral body or disc infection
    23. 23. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    24. 24. Microscopic Features• Hematoxylin and Eosin (H&E)• Gomori Methenamine Silver (GMS)• Periodic acid-Schiff (PAS) Hematoxylin and Eosin staining of Aspergillus.
    25. 25. Microscopic Features• Hematoxylin and Eosin (H&E)• Gomori Methenamine Silver (GMS)• Periodic acid-Schiff (PAS) GMS staining of Aspergillus
    26. 26. Microscopic Features• Hematoxylin and Eosin (H&E)• Gomori Methenamine Silver (GMS)• Periodic acid-Schiff (PAS) PAS staining of Cryptococcus
    27. 27. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    28. 28. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    29. 29. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    30. 30. Radiological Features: CT
    31. 31. Radiological Features: MRI small enhancing lesions (arrows) in the MeningealIll defined in flair erivascular spaces along lenticulostriate enhancement arteries in the basal ganglia. Ring enhancement Granuloma
    32. 32. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    33. 33. Growth pattern & Spread• Spread from paranasal sinuses to brain – Through invasion of skull base or – Through vascular invasion• Spread from contaminated scalp and skull traumatic wound to brain• Spread generally from the environment to people with limited person-to-person spread.
    34. 34. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    35. 35. 1) Cell of origin & pathogenesis2) Epidemiology3) Macroscopic features4) Microscopic features5) Immunohistochemistry6) Genetic features7) Radiological features8) Growth pattern & spread9) Grading & behavior10) Prognosis
    36. 36. Prognosis• Disease’s factors: – Localized (Abscess or granuloma) # diffuse (meningoencephalitis)• Patient’s factors: – Immunocompromised # Immunocompetent• Treatment’s factors: – Early/Specific # Late/non specific
    37. 37. Clinical syndromes of CNS fungal infection Meninges, brain, spinal cord, vertebral bodies or discs• Meningitis:• Brain abscess:• Brain Mass:• Stroke-like syndrome: – Infarcts – Intracerebral hemorrhage – Mycotic aneurysms – Subarachnoid hemorrhage,
    38. 38. Candidiasis• Candida albicans• Yeast• Opportunistic infection from skin, GIT, or genitalia• Most common mycotic parenchymal infection of CNS• Multiple microabscesses ± microgranulomas
    39. 39. Cryptococcosis• Cryptococcus neoformans• Yeast• From lung to brain.• Most common mycotic meningeal infection of CNS• Less commonly, cryptococcosis produces multiple intraparenchymal pseudocysts• Causing acute or chronic insidious meningitis• Leading to hydrocephalus, dementia, focal neurological deficits.
    40. 40. Aspergillosis• Aspergillus fumigatus or Aspergillus flavus• Septated mold• From soil to lung then to brain• 2nd-3rd common mycotic infection of CNS• Foci of hemorrhagic cerebritis
    41. 41. Mucormycosis (Phycomycosis)• Belong to the family Mucoraceae, including Rhizopus, Mucor, and Absidia• Aseptated molds• From soil to sinus and lung then to brain• Increasing mycotic infection of CNS• Sinus mass
    42. 42. Diagnosis• Imaging:• Testing for serum beta glucan:• fungal culture: – Blood – CSF obtained by lumbar puncture – Tissue obtained by biopsy.• CSF analysis:• Specific fungal antibody tests:
    43. 43. Imaging: Meningitis
    44. 44. Imaging: Fungal abscess
    45. 45. Imaging: Granulomas
    46. 46. Beta D Glucan Essay
    47. 47. Direct examination of specimens• Gram stain:• Common tissue stains as – Periodic acid-Schiff (PAS) stain. – Gomori methenamine-silver nitrate (GMS) stain.• KOH preparation with calcofluor white:• INDIA INK PREPARATION
    48. 48. Fungal culture• Rapid-growing fungi appear in one to three days:• Intermediate growers take five to nine days:• Slow growers take up to four weeks to appear:
    49. 49. Differential Diagnosis• locally invasive skull base neoplasm:• Multiple ring-enhancing parenchymal lesions in immunocompetent patients: – Metastases - Multiple pyogenic abscesses – TB - Parasites (e.g., neurocysticercosis) – Fungal abscess (rare) - Septic emboli• Multiple ring-enhancing parenchymal lesions in immunocompromised patients – Fungal abscesses (common) – TB - Toxoplasmosis - PCNSL
    50. 50. Differential Diagnosis• locally invasive skull base neoplasm:• Multiple ring-enhancing parenchymal lesions in immunocompetent patients: – Metastases - Multiple pyogenic abscesses – TB - Parasites (e.g., neurocysticercosis) – Fungal abscess (rare) - Septic emboli• Multiple ring-enhancing parenchymal lesions in immunocompromised patients – Fungal abscesses (common) – TB - Toxoplasmosis - PCNSL
    51. 51. Differential Diagnosis• locally invasive skull base neoplasm:• Multiple ring-enhancing parenchymal lesions in immunocompetent patients: – Metastases - Multiple pyogenic abscesses – TB - Parasites (e.g., neurocysticercosis) – Fungal abscess (rare) - Septic emboli• Multiple ring-enhancing parenchymal lesions in immunocompromised patients – Fungal abscesses (common) – TB - Toxoplasmosis - PCNSL
    52. 52. Chemotherapeutic Agents• Antibiotics• Antifungals• Antivirals• Antihelmintics• Antiprotozoal• Anticancer drugs
    53. 53. What are the targets for antifungal therapy? Cell Wall Unlike mammalian cells, fungi have a cell wall Cell membrane Fungi use principally ergosterol instead of cholesterol DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis.
    54. 54. Cell Membrane Active Antifungal • Cell WALL • Echinocandins • Inhibit B (1,3) glucan synthesis • No drug in CSF or urine • Used i.v.
    55. 55. Cell Membrane Active Antifungal Cell membrane 1. Polyene antifungals - Amphotericin B 2. Azole antifungals - Imidazoles (mostly topical) : Ketoconazole -Triazoles: 1) Fluconazole (Diflucan®) 2) Itraconazole (Sporanox ®) 3) Voriconazole (Vfend ®) 4) Posaconazole (Noxafil ®) 3. Allylamines class
    56. 56. Polyenes: Amphotericin B (Fungizone ®)• Mechanism of action:• Antifungal Activity: Broad spectrum for both yeast & Molds• Indications: imperial treatment in serious illness• Rout of administration: – IV (not well tolerated- chills, headaches, nausea) or – Intra-thecal for fungal meningitis• Adverse effects: – Infusion-related toxicity:: – Cumulative toxicity: Renal impairment• Dose: – Test dose: 1 mg + 20 mL of D5% over 20 - 30 minutes – Then: 0.25-1.0 mg/kg/d• Duration: 2-3 gm
    57. 57. Fluconazole (Diflucan®)• Mechanism of action:• Antifungal Activity: Broad spectrum for yeast only• Rout of administration: – Oral cap: 50 & 150 or syrup 50mg/5mL – Intravenous: 50 ml (2mg/ml)• Adverse effects: – The most common adverse reaction is relatively minor gastrointestinal upset – Drug interaction: • (Diflucan®) ↑ serum level of phenytoin, oral hypoglycemic • (Diflucan®) serum level ↓ by cimetidin and Rifampin• Dose: – Loading dose for one day: Double maintenance dose (up to 400mg) – Maintenance dose: 200-400mg/d on a single dose [Pediatric: 3-12 mg/kg/d (max 400mg/d) ]• Duration: until infection resolved
    58. 58. Voriconazole (Vfend ®)• Mechanism of action:• Antifungal Activity: Broad spectrum for both yeast & Molds esp Aspergillus• Rout of administration: – Oral Tablets: 50 & 200 mg or Powder for Oral Suspension: 200 mg/5ml – Intravenous: Powder for injection: 200 mg• Adverse effects: – Infusion Related Reactions: – Arrhythmias and QT Prolongation – Visual disturbances: – Drug interaction: • ((Vfend ®) ↑ serum level of phenytoin, oral Anticoagulants, NSAI, fentanyl, Calcium Blockers • ((Vfend ®) serum level ↓ by phenytoin and Rifampin• Dose: – Loading dose for one day: 6 mg/kg q12h – Maintenance dose: 4 mg/kg q12h IV or 200 mg q12h orally• Duration: – until infection resolved
    59. 59. DNA & Protein Synthesis Active Antifungal DNA synthesis 1. Flucytosine 2. Griseofulvin (Grisactin®, Fulvicin®) - Mainly for skin fungus
    60. 60. 5’-Flucytosine (Ancobon ®)• Mechanism of action:• Antifungal Activity: Candida, Cryptococcus and ?Aspergillosis• Rout of administration: – Oral• Adverse effects: – Hepatic – Bone marrow• Dose: – A: PO: 50-150mg/kg/d in four divided doses. for 3 months – C:>50kg:PO: 50-150mg/kg/d in 4 divided doses. – C: < 50kg :PO: 1.5-4.5 g/m2 /d in four divided doses. – C: < 50: PO:1.5-4.5 g/m2 /d in four divided doses. – Neonate: PO: 50-100mg/kg/d in 1-2 divided doses.• Duration: – until infection resolved ( ~ 3 months)
    61. 61. disease protocal dose duration HIV neg. 1 Amphotericin 0.7MKD 2 wk +flucytosine 100MKD +fluconazole 400mg/d 10 wk 2 Amphotericin 0.7MKD 10 wk +flucytosine 100MKD HIV pos. Amphotericin 0.7MKD 2 wk induction +flucytosine 100MKD +fluconazole 400mg/d 10 wkmaintanance Fluconazole 400 mg/d
    62. 62. Refrences• Eileen P. Scully, Lindsey R. Baden and Joel T. Katz (2008): Fungal brain infections. Curr Opin Neurol 21:347–352• Anne G. Osborn et al 2004: Infection and Demyelinating Disease. In: Diagnostic imaging Brain. First Edition. Amirsys Inc, Salt Lake City, Utah. part I/section 8/ pp 4- 82• Srevenc. Bausermanandk. Gillnaul (2001). Bacterial, fungal, and parasitic diseases of the central nervous system. In: Principles and practice of neuropathology, 2nd ed (James S. Nelson, Hernando Mena, Joseph E. Parisi and Sydney S. Schochet) Oxford University Press, Inc. pp.45-77• Critical Steps for Diagnosing Brain Infections: Slideshow. http://reference.medscape.com/features/slideshow/brain-infections. WebMD LLC. Reviewed 03/26/12

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