Viruses and Fungi Flashcards
Fungi that cause disease are found where?
What is the associated factor of the occurrence of specific fungal diseases?
Are the fungi life cycles uni/di/pleio -morphic?
How is transmission accomplished of fungi and what is a challenge in treating fungal infections?
Most of the fungi that cause disease are naturally found in the soil and are saprobes.
Accordingly, the occurrence of specific fungal diseases is often strongly influenced by the geography of the natural habitat of the infecting fungus.
Many fungi have dimorphic or pleiomorphic life cycles; producing yeast, molds and a variety of spores.
Transmission is by contact with infected material, often in the form airborne spores. Because they are eukaryotes they cannot be treated with most common antibacterial antibiotics, but often can be treated with antifungal drugs.
GENERAL CHARACTERISTICS OF FUNGI
Fungi are eukaryotes
List the characteristics fungi may have (2)
In mold state hyphae can differentiate into NONsexual spores classified by (4) and provide 5 examples of spores.
A. Nucleus
B. Molds, yeast and mushrooms
- Yeast, single cell divide asymmetrically by budding off a daughter cell
- Molds form a mycelium normally comprised of hyphae and spores. Hyphae can either be septate or nonseptate
–Pseudomycelium is made up of elongated yeast cells
In mold state hyphae can differentiate into nonsexual spores classified by shape, size, cell wall thickness, and other morphogenetic characteristics.
- Conidia
- Arthrospores
- Blastospores
- Chlamydospores
- Aleurospores
Cell biology of bud and hyphen growth
Comment on cell wall, vesicles, microtubules, transcriptional and translational machinery, the clinical implication of a feature to the fungi cell membrane.
A. Nucleus with nucleolus, polysaccharide cell wall-usually inner glucan and outer mannan layers, mitochondria, vacuoles, vesicles, cytoskeleton of microtubules and actin microfilaments.
B. Fungi usually have two layered cell wall – glucose polymer – glucan decorated with a outer mannose polymers – manna
C. Secretory vesicles moved to growing tip by motors on the cytoskeleton
D. Microtubule comprised mitotic spindle required for cell division
E. RNA polymerase and ribosomes that are mammalian-like (not inhibited by many antibacterial antibiotics)
F. Fungi synthesize sterols (usually ergosterol) and incorporate them into membranes, important basis for much fungal chemotherapy
Sexual cycles of fungi
Describe the characterization of the sexual cycles of classified fungi. What determines different sexes genetically?
Define heterokaryon
Discuss Neurospora in terms of the development of spore production.
A. Classified fungi have sexual cycles characterized by haploid cells of different sexes that are capable of fusing to produce diploid cells that undergo meiosis to regenerate haploid cells.
Frequently vegetative growth is found for both haploid and diploid stages.
Different sexes are often due to single genetic locus, not a whole chromosome.
Hyphae of different mating types can fuse to induce heterokaryon formation and/or a sexual cycle
B. Neurospora - produces heterokaryons, two nuclei in the same cell, then like Saccharomyces haploid nuclei fuse and diploid nuclei undergo meiosis to produce haploid ascospores.
- Neurospora is a genus of Ascomycete fungi.
Classification of fungi (4)
- Ascomycetes - produce sexual haploid spores encased in a sac
- Basidiomycetes - produce sexual spores that are not in a sac, mushrooms
- Zygomycetes (Phycomycetes) - large nonseptate hyphae
- Deuteromycetes - Fungi imperfecti, sexual sates are not known yet or nonexistent
Fungi Nutrition
What is their process of alimentation, almost all and many fungi are cultural on what two types of medium?
A. Fungi are saprobic, polymeric organic material are degraded to mono and oligomers using secreted enzymes. Fungi take up small metabolites for growth.
B. Almost all fungi are culturable on Sabouraud’s medium (yeast extract plus glucose) where they show characteristic colonial morphologies. Growth on this medium sometimes can be too slow for use in diagnosis.
C. Many fungi are culturable on minimal medium (glucose, salts, NH3 and trace elements)
Many fungi show dimorphic life cycles (classic temperature dimorphism). Discuss that of yeast and mold.
A. Yeast stage 37 degrees Cel (very rich medium), budding
B. Mold stage 25 degrees Cel hyphal growth – enables organism to be disemminate and change its environment
Diagnosis of mycotic infections:
Discuss Direct microscopic observation of infected tissue (4)
Discuss two other methods for Fungal viewing/identification.
A. Direct microscopic observation of infected tissue
- 10% KOH dissolves animal tissue so fungi in skin and nails are visible. Kills the fungi as well but leave behind the cell wall.
- Calcofluor - fluorescent dye stains chitin in some fungal cell walls
- Methaneamine silver (Ag) stain fungi
- Candida and other yeasts stain purple with Gram stain
B. Several fungi that cause superficial infections fluoresce under UV light (Wood’s lamp)
C. Culturing on Sabouraud’s agar to identify specific species; often by spore morphology
Fungal Drug therapy
How does resistance arise and what is the fundamental target when synthesizing final drugs?
Discuss Polyene antibiotics. Give the two examples and MOA. What is a requirement for the antibiotics to work and what is a disadvantage to them?
- Resistance is often due to nonpermeability, long term therapy often required
- Much of it based on the presence of ergosterol rather than cholesterol in fungal membranes.
A. Polyene antibiotics –
- Amphotericin B
- Nystatin®
- Both are incorporated into sterol containing membranes and cause cells to become leaky
a. Drugs require membrane synthesis (cell growth)
b. Somewhat toxic to host since mammalian membranes also contain sterols
Fungal Drug therapy
Azoles MOA. Why are there side effects?
List examples of Azoles (4) and what’s special about one?
B. Azoles
- Inhibit mainly ergosterol biosynthesis via interfering with cyt P-450
- Side effects due to inhibition of adrenal steroid and testosterone synthesis
Ketoconazole
Itraconazole
Thiobendazole
Fluconazole
a. Fewer side effects
b. Enters cerebrospinal fluid more rapidly
Fungal Drug therapy
Discuss Terbinafine-Lamisil® MOA. What class of drug is it?
Discuss Echinocandins- give a specific example and MOA
Discuss MOA of antimitotics and give example.
Discuss other 3 classes of drugs.
- Squaline epoxidase inhibitor, Terbinafine-Lamisil®, -inhibits ergosterol biosynthesis and causes toxic buildup of squalene.
- Echinocandins
- Caspofungin (Candidas®): Inhibits 1-3 glucan synthesis by interfering with synthase. Prevents cell wall formation - Antimitotics - probably bind to tubulin and interfere with mitotic apparatus and cytoskeleton-Griseofulvin
F. Other drugs
- Sulfonamides
- Fluorocytosine
- Topical ointments and powders for superficial infections (detergents)
ASEXUAL SPORES FORMED BY CERTAIN FUNGI:
Conidia: discuss the term and spores
(Gr. konis. dust)
This term is sometimes used generally for all asexual spores. Sometimes more specifically for spores born singly or at tips of specialized hyphal branches (conidiopores). Highly diversified in shape, size, color and separation.
ASEXUAL SPORES FORMED BY CERTAIN FUNGI:
Aleuriospores: discuss the term and spores
(Gr. aleuron, wheaten flour)
Spores that resemble conidia but develop on short lateral branches or directly on the hyphae, rather than on specialized condiopores.
ASEXUAL SPORES FORMED BY CERTAIN FUNGI:
Arthrospores: discuss the term and spores
(Gr. arthron, joint)
Cylindrical cells formed by double septation of hyphae. Individual spores are released by fragmentation of hyphae, i.e., by disjunction.
ASEXUAL SPORES FORMED BY CERTAIN FUNGI:
Blastospores: discuss the term
(Gr. blastos. bud. shoot)
Buds that arise from yeast like cells.
ASEXUAL SPORES FORMED BY CERTAIN FUNGI:
Chlamydospores: discuss the term and spores
(Gr. chlamy, mantle)
Thick-walled, round spores formed from terminal or intercalated hyphal cells.
ASEXUAL SPORES FORMED BY CERTAIN FUNGI:
Sporangiospores: discuss the term and spores
(Gr. angeion.vessel)
Spores within saclike structures (sporangia) at ends of hyphae or of special hyphal branches (sporangiophores). Characteristically formed by species of Phycomyces.
CONTRAST BETWEEN FUNGI (F) AND BACTERIA (B)
Fungi to Bacteria
- Cell volume (μ3)
- Nucleus
- Cytoplasm
- Cytoplasmic membrane
- Cell Wall
- Metabolism
- Sensitivity to chemotherapeutic agents
- Dimorphism
- (F) Yeast 20-50 μ3; Molds: Not definable because of indefinite size and shape: but much greater than yeast.
(B) 1 to 5 μ3 - (F) Eukaryotic (well-defined membrane)
(B) Prokaryotic (no nucleus) - (F) Mitochondria, endoplasmic reticulum
(B) No mitochondria or ER - (F) Sterols present-ergosterol
(B) Sterols absent (except Mycoplasma) - (F) Glucans: mannans: chitin. protein complexes
(B) No chitin, glucans or mannans - (F) Heterotrophic, aerobic, facultative anaerobes: not autotrophics or obligate anaerobic
(B) Obligate and facultative aerobes and anaerobes: heterotrophic; autotrophic - (F) Sensitive to polyenes and griseofulvin (dermatophytes): not sensitive to penicillins, tetracyclines, chloramphenol, streptomycin
(B) Often sensitive to penicillins, tetracyclines, chloramphenicol, streptomycin: not sensitive to polyenes, imadazoles.
- (F) Distinguishing feature to many
(B) Very rare
CLASSES OF FUNGI
CLASS: Ascomycetes
ASEXUAL SPORES
SEXUAL SPORES
MYCELIA
REPRESENTATIVE GENERA OR GROUP
ASEXUAL SPORES- Exogenous (at ends of sides of hyphae)
SEXUAL SPORES- Ascospores w/in sacs or asci
MYCELIA- Septate
REPRESENTATIVE GENERA OR GROUP- Neurospora. Penicillium. Aspergillus. true yeasts
CLASSES OF FUNGI
CLASS: Basidiomycetes
ASEXUAL SPORES
SEXUAL SPORES
MYCELIA
REPRESENTATIVE GENERA OR GROUP
ASEXUAL SPORES- Exogenous (at ends or sides of hyphae)
SEXUAL SPORES- Basidiospores on surface of basidium
MYCELIA- Septate
REPRESENTATIVE GENERA OR GROUP- Mushrooms, rusts, smuts, Cryptococcus
CLASSES OF FUNGI
CLASS: Phycomycetes
ASEXUAL SPORES
SEXUAL SPORES
MYCELIA
REPRESENTATIVE GENERA OR GROUP
ASEXUAL SPORES- Endogenous (in sacs)
SEXUAL SPORES- Anatomy variable
MYCELIA- Non-septate
REPRESENTATIVE GENERA OR GROUP- Rhizopus. Mucor watermolds (aquatic)
CLASSES OF FUNGI
CLASS: Deuteromycetes (Fungi imperfecti)
ASEXUAL SPORES
SEXUAL SPORES
MYCELIA
REPRESENTATIVE GENERA OR GROUP
ASEXUAL SPORES- Exogenous (at ends or sides of hyphae)
SEXUAL SPORES- Absent
MYCELIA- Septate
REPRESENTATIVE GENERA OR GROUP- Many human pathogens
Grouping of Most Frequently Encountered Pathogenic Fungi (for Man) in the U.S., with respect to Tissue Involved and Dimorphism.
Type of Mycotic Disease: Systemic
A. Representative Fungus (5) and MORPHOLOGY IN (Infected Tissue Room / Temperature Culture) and Life Cycle.
- Cryptococcus neoformans; Yeast (encapsulated); Yeast (encapsulated); No dimorphism (Diamond)
- Coccidioides immitis; Spherules; Mycelia; Dimorphism*
- Histoplasma capsulatum; Yeast; Mycelia; Dimorphism
- Blastomyces dermatitis; Yeast; Mycelia; Dimorphism
- Paracoccidioidis braziliensis; Yeast; Mycelia; Dimorphism
(Diamond) Except during sexual phase.
- Spherules and mold
** Different from classical temperature dimorphism
***The fungi that parasitize epidermis, nails and hair (dermatophytes) all appear alike in infected skin, but in culture may develop a variety of specialized hyphae and spore structures that differentiate diverse genera and species.
Grouping of Most Frequently Encountered Pathogenic Fungi (for Man) in the U.S., with respect to Tissue Involved and Dimorphism.
Type of Mycotic Disease: Systemic and particularly opportunistic
A. Representative Fungus (4) and MORPHOLOGY IN (Infected Tissue Room / Temperature Culture) and Life Cycle.
- Candida (especially C. albicans); Yeast and Hyphae; Yeast and Hyphae; Dimorphism**
- Aspergillus (most often A. fumigates); Mycelia; Mycelia; No Dimorphism
- Phycomycetes (Mucor and Rhizopus species); Mycelia; Mycelia; No Dimorphism
- Pneumocystis jiroveci; Yeast-like cysts; Unknown; No Dimorphism
(Diamond) Except during sexual phase.
- Spherules and mold
** Different from classical temperature dimorphism
***The fungi that parasitize epidermis, nails and hair (dermatophytes) all appear alike in infected skin, but in culture may develop a variety of specialized hyphae and spore structures that differentiate diverse genera and species.
Grouping of Most Frequently Encountered Pathogenic Fungi (for Man) in the U.S., with respect to Tissue Involved and Dimorphism.
Type of Mycotic Disease: Subcutaneous
A. Representative Fungus (1) and MORPHOLOGY IN (Infected Tissue Room / Temperature Culture) and Life Cycle.
Sporothrix schenckii; Yeast; Mycelia; Dimorphism
Grouping of Most Frequently Encountered Pathogenic Fungi (for Man) in the U.S., with respect to Tissue Involved and Dimorphism.
Type of Mycotic Disease: Cutaneous
A. Representative Fungus (3) and MORPHOLOGY IN (Infected Tissue Room / Temperature Culture) and Life Cycle.
- Microsporum species; Mycelia; Mycelia; No Dimorphism***
- Trichophyton species; Mycelia; Mycelia: No Dimorphism***
- Epidermophyton floccosum; Mycelia; Mycelia; No Dimorphism***
(Diamond) Except during sexual phase.
- Spherules and mold
** Different from classical temperature dimorphism
***The fungi that parasitize epidermis, nails and hair (dermatophytes) all appear alike in infected skin, but in culture may develop a variety of specialized hyphae and spore structures that differentiate diverse genera and species.
SUPERFICIAL MYCOSES
Define Dermatophytoses
Organisms metabolize fatty-acids present in skin and hair, often referred to as (2)
Dermatophytoses - localized fungal infections of the keratinized tissues (hairs, skin, nails). Infecting fungi secrete proteases that can degrade this insoluble protein. Organisms are usually saprobes and keratinized tissue is not alive.
- Ringworms or Tineas.
Names of clinical syndromes - Most common infecting agent(s) for:
Athlete’s foot Ringworm of the scalp jock itch, groin onychomycosis Ringworm of the body Beard
Note: Give scientific name of the common name clinical symptoms
- Tinea pedis - Athlete’s foot - T. mentagrophytes
- Tinea capitis - Ringworm of the scalp - Microsporum audouini, T. Tonsurans
- Tinea cruris - jock itch, groin – E. floccosum, T. mentogrophytes, T. rubrum
- Tinea unguium- onychomycosis - nails - T. rubrum, T. mentogrophytes
- Tinea corporis - Ringworm of the body - Microsporum sp., Trychophyton sp.
- Tinea barbi – beard- Trychophyton sp.
Note: bearded areas of the face and neck
Most common causative agents of mycotic disease
- Trichophyton mentagrophytes, tonsurans, rubrum
- Microsporum audouini, canis, gypseum
- Epidermophyton floccosum
- All produce ______?
macrocondia called aleurospores
Ecology of fungi (3)
Severity of mycotic infections (mild (4) /increasing severity(4))
- Found in soil
- Usually transferred from man to man
- Occasionally from dogs and cats, e.g. M. canis
D. Severity
- Mildest infections, typical-redness, exudate, vesicles, scales
- Increasing severity
a. Mycotic folliculitis
b. Temporary baldness
c. Suppuration and kerion
d. Connective tissue involvement - Nail infections cause nail degradation, hyperkeratosis in seniors
Superficial mycotic infections caused by other organisms
Tinea versicolor
Tinea favosa (favor)
Piedra
Tinea nigra
Give details of presentation, characteristics, and types.
- Tinea versicolor
a. Skin discoloration – inhibits melanin synthesis
b. Malessezia globosa and furfur (old name: Pityrosporum orbiculaire)
c. Dimorphic, normal flora - Tinea favosa (favus)
a. Localized to hair and torso
b. Scales, hyperkeratosis
c. Trichophyton schoeneinii - Piedra
a. Localized to the hair
b. Piedrai hortai (black) – binds very tightly to hair (tropical)
c. Trichosporon beigelii (white) – looser association (subtropical) - Tinea nigra
a. Black palms
b. Tropical regions
c. Exophiala werneckii
Diagnosis of all superficial fungal infections (3)
- KOH prep of infected tissue shows mycelia
- Slide culture, plate culture (slow growth, only for epidemiology)
- Wood’s Lamp, UV light, some fungi fluoresce when infecting hair or skin
Immunity (3) and Epidemiology (2) to mycotic infections.
- T cell reaction
- Soluble antibodies raised but have little or no role in elimination infection
- Secondary allergic response to many dermatophytes (dermtophytid response or id response)-itchy lesions devoid of organism
Note: Id reactions (also known as “Disseminated eczema,”and “Generalized eczema”) present with a variety of infectious disorders, often occurring in response to an inflammatory tinea of the feet, resulting in an eczematous dermatitis. The pruritic rash that characterizes the id reaction, which is considered immunologic in origin, has been referred to as dermatophytic.
- 80-90% of population has an infection some time in their lifetime
- Outbreaks common in college, army barracks, kindergartens
Treatment
Skin- Topical (5), Systemic (2)
Hair (2)
Nails (3)
- Skin
a. Topical
i. Terbinafin-Lamisil®
ii. Clotrimazole-Lotrimin®
iii. Desenex , Tinactin (Tolnaftate) - detergent
iv. Whitfield’s ointment - salicylate and benzoate; old remedy
v. Use combinations
b. Systemic
i. Terbinafin – for nails, long term
ii. Ketoconazole
- Hair
a. Cut hair
b. Griseofulvin - three to four weeks - Nails - Surgical removal of nail and/or systemic drug treatment
a. Terbinafin - Lamisil® - several months
b. Thiobendazole or itraconazole - several months
c. Griseofulvin - one year
SUBCUTANEOUS MYCOSES
SPOROTRICHOSIS:
Causative Agent Ecology (5) Pathogenesis and types (4) Lab Dx (3) Tx (2)
A. Causative Agent: Sporothrix (Sporotrichum) schenkii
B. Ecology: Soil, thorns, tree bark, timber, decaying vegetables
C. Pathogenesis: infection by direct inoculation below skin
- Lymphocutaneous
- Fixed cutaneous
- Pulmonary
- Systemic
D. Laboratory Diagnosis:
- Culture shows temperature dimorphism
- Serology
- Skin test
E. Treatment:
- Potassium iodide for surface lesions; inhibits yeast, not mold
- Amphotericin B
SUBCUTANEOUS MYCOSES
MADUROMYCOSIS (mycetoma, madura foot, madura hand) skin lesions usually confined to extremities
Ecology/Causative Agent (6)
Pathogenesis (2)
Lab Dx (1)
Tx (3) - assoc. with causative agent
A. Ecology: Causative agents are soil organisms:
- Pseudoallescheria boydii, Madurella, Exophiala and Aspergillus
- Nocardia braziliensis - actinomyces, a procaryote
- Streptomyces sp. - actinomyces, a procaryote
B. Pathogenesis:
- Break in skin -> subcutaneous tissue-> fascia-> bone
- Draining sinuses
C. Laboratory diagnosis requires culture of organism.
D. Treatment is difficult
- thiabendazole or 5-fluorocytosine may be effective for Pseudoallescheria.
- Sulfa and Penicillin for treating Actinomyces
- Surgical removal of infected tissue
SUBCUTANEOUS MYCOSES
CHROMOMYCOSIS:
Causative Agent (3) Ecology (1) Pathogenesis (5) Lab Dx (1) Tx (2)
A. Causative Agents: Highly pigmented molds
- Phialophora
- Cladosporium
- Fonsecea
B. Ecology: soil organisms
C. Pathogenesis:
- Break in skin
- Infection usually involves skin and subcutaneous tissue
- Occasionally obstructs lymph channels
- Dissemination is very rare
- Can be complicated by more serious secondary infections
D. Diagnosed by observing fungal materials in biopsy samples, sclerotic bodies. Laboratory diagnosis requires culture of organism to distinguish prokaryotic vs eukaryotic etiology
E. Treatment:
- Surgical removal of infected tissue
- Topical administration with Amphotericin B, Thiabendazole or Terbinafine
SYSTEMIC MYCOSES
HISTOPLASMOSIS
Causative Agent Ecology (2) Pathogenesis (4) In vivo where do the fungal cells grow? Lab Dx (3) Tx (2)
A. Causative Agent: Histoplasma capsulatum - (a/k/a Emmonsiella capsulatum), ascomycete
B. Ecology: Found in soil
- Midwestern river valleys
- High concentration in bird’s droppings
C. Pathogenesis: Inhalation of spores:
- Mild or asymptomatic in 95% of cases (approximately 40 million people are thought to be infected in U.S.)
- Pulmonary:
a. Acute: malaise, fever, respiratory problems
b. Chronic infections can recur
c. Healed infection gives calcified and fibrotic nodules that resemble tuberculosis - Disseminated throughout body:
a. Lymph nodes
b. Liver, spleen, heart, etc. - Skin involvement, eruptions
D. Macrophages: Grows inside of macrophages. Mutants isolated that do not survive in macrophages and have an altered glucan on the cell surface.
E. Laboratory Diagnosis:
- Biopsy of infected tissue shows macrophages filled with yeast cells - Methaneamine silver stain
- Culture:
a. Dimorphic - 37 yeast, 25 slow growing mycelia
b. Tuberculate chlamydospore - Serology:
a. Latex agglutination
b. Complement fixation
c. Hypersensitivity to histoplasmin (an antigen from culture medium), Skin tests are unreliable because many people have been exposed
d. Soluble antibodies have little or no role in eliminating infections
F. Treatment:
- Amphotericin B
- Itraconazole
SYSTEMIC MYCOSES
BLASTOMYCOSIS ( “ “ American Blastomycosis)
Causative Agent Ecology (1) and geographic regions (3) Pathogenesis (3) Lab Dx (3) Tx (3)
North American Blastomycosis
A. Causative Agent: Blastomyces dermatitidis (a/k/a Ajelomyces dermatitidis), ascomycete
B. Ecology:
- Not known, may be soil organism related to particular vegetation
- Mississippi Valley and Southeastern U.S., can occasionally be found further north
C. Pathogenesis:
- Inhalation or broken skin
- Cutaneous - primary or systemic
- Pulmonary - primary then hematogenously to bones, skin, other viscera
D. Laboratory Diagnosis:
1. Direct microscopic examination of infected tissue gives thick-walled, single budded, yeast-like organisms
- Culture on Sabouraud’s medium shows temperature dimorphism
a. 37 yeast like
b. 25 mycelia
c. Growth inhibited by cycloheximide and chloramphenicol - Serology - Latex agglutination and complement fixation tests
E. Treatment:
- Amphotericin B
- Itraconazole
- Stilbamidine, antiprotozoal-less toxic
SYSTEMIC MYCOSES
PARACOCCIDIOIDOMYCOSIS ( “ “ American Blastomycosis)
Causative Agent Ecology (1) and geographic regions (1) Pathogenesis (4) Lab Dx (4) Tx (2)
South American Blastomycosis
A. Causative Agent: Paracoccidioides brazilliensis
B. Ecology: Found in soil, South Texas and below
C. Pathogenesis: Inhalation
- Pulmonary - causes a mild respiratory tract infection not unlike Histoplasmosis
- First lesions of infection are in the mucous membranes of the nose or mouth and can spread to the face
- Lymphangetic
- Disseminated to wide variety of tissues
D. Laboratory Diagnosis:
- Direct microscopic observation shows thick walled, yeast like organisms with multiple buds
- Cultures show temperature dimorphism, requires rich medium for yeast phase
- Serology - Latex agglutination and complement fixation tests
- Skin test to hypersensitivity to secreted antigen
E. Treatment:
- Amphotericin B
- Sulfonamides (not curative)
SYSTEMIC MYCOSES
COCCIDIOIDOMYCOSIS (3 other common names)
Causative Agent Life cycle peculiarity Ecology (1) and geographic regions (3) Pathogenesis (3) and symptoms Lab Dx (2) Tx (2)
Valley fever, California fever, desert rheumatism
A. Causative Agent: Coccidioides immitis
B. Exhibit different dimorphism - spherule and mold
C. Ecology: Found in desert soil
- Southwestern U.S.
- Mexico
- Central and South America
D. Pathogenesis:
- Inhalation of arthrospores
- Often asymptomatic
- Primary pulmonary infections resemble tuberculosis
- Dissemination to skin, bone and viscera is rare
E. Laboratory Diagnosis:
- Direct examination of sputum shows:
a. Spherules, thick walled cells filled with ~100 endospores
b. Sometimes hyphae are observed in infected lung tissue - Culture on medium enriched with ascites fluids gives mixture of hyphae and spherules:
a. Temperature dimorphism
b. Arthrospores on hyphae have unique morphology
c. Serology -Latex agglutination and complement fixation
d. Skin test: hypersensitivity to coccidioidin (an antigen from culture fluid)
F. Treatment:
- Amphotericin B
- Ketoconazole
SYSTEMIC MYCOSES
CRYPTOCOCCOSIS
Causative agent Discuss physical feature of agent of life cycle Ecology Pathogenesis (3) Dx (5) Tx (4)
A. Causative Agent: Cryptococcus neoformans (a/k/a Filobasidiella neoformans), basidiomycete
B. Usually a small yeast, but also has a sexual mold stage and therefore is actually dimorphic, but not classical temperature dimorphism.
C. Ecology: Found in soil and especially pigeon droppings; Cryptococcus grows poorly at 42C. Organism is resistant to drying
D. Pathogenesis:
- Inhalation of urban dust
- Causes pulmonary infections and meningitis
- Capsules thought involved in resistance to immune response
E. Diagnosis:
- India ink to centrifuged CSF
- Culture on Sabouraud’s agar
a. Urease positive
b. Other cryptococci (albidus, laurentii, terreus, etc.)
c. Mycelium only during sexual stage - Cryptococcal antigen in CSF by latex agglutination
- Cryptococcal antibody appearance-good prognosis
- Additional assimilation and fermentation reactions used to identify different species
F. Treatment:
- Amphotericin B
- Fluoconazole
- 5-Fluorocytosine
- Ketoconazole
OPPORTUNISTIC FUNGAL INFECTIONS
Predisposing factors for opportunistic infections (12)
OPPORTUNISTIC FUNGAL INFECTIONS I. Predisposing factors for opportunistic infections: A. AIDS B. Pregnancy C. Trauma D. Endocrine disorders E. Malnutrition F. Malignancy G. Anemias H. Post-operative state I. Antibacterial therapy J. Immunosuppressive drugs K. Oral contraceptives L. Heroin addiction
OPPORTUNISTIC FUNGAL INFECTIONS
CANDIDIASIS
Most frequent causative agent
Type of Life cycle
Pathogenesis
Types of infections (13)
A. Most frequent causative agent - Candida albicans
B. Pleiomorphic - yeast, pseudohypha or hypha
C. Ecology - C. albicans ubiquitous - part of the normal flora of man (mouth, GI tract, vaginal)
D. Pathogenesis - transmitted in birth canal, produces a secreted protease that is an important virulence factor
E. Types of infections:
- Thrush (oral candidiasis)
- Skin
- Nails
- Vaginitis
- Esophagitis
- Gunshot wounds
- Endocarditis
- Pulmonary
- Burns
- Eye
- Balanoposthitis
- Urinary tract
- Chronic mucocutaneous
OPPORTUNISTIC FUNGAL INFECTIONS
CANDIDIASIS
Laboratory Diagnosis (4)
What species do not give rise to diagnostic criteria (7)
- Microscopy of stained specimens show yeast and pseudo mycelium
- Sabouraud’s medium culture - Yeast cells with some pseudomycelia, some blastospores, a few chlamydospores. Ferments and assimilates specific sugars
- C. albicans yeast cells or chlamydospores incubated at 37C in serum grow a germ tube
- Other pathogenic Candida species do not give rise to germ tubes when put in serum at 37C
a. C. stellatoidea
b. C. parapsilosis
c. C. krusei
d. C. tropoicalis
e. C. guillermondii
f. C. glabrata
OPPORTUNISTIC FUNGAL INFECTIONS
CANDIDIASIS
Tx (3) and type.
Treatment:
- Clotrimazole (Lotramin®) – topical
- Amphotericin B - systemic
- Ketoconazole - systemic
OPPORTUNISTIC FUNGAL INFECTIONS
Pneumocystis jiroveci (formerly carinii)
Identified as what Is it normal Flora? What is typical for symptoms and Ab production Epidemiology association Ecology Pathogenesis (4) Dx (2) Tx (3) and does this organism not contain? Discuss a potential target for Tx.
A. Recently identified as a fungus rather than a protozoa based on RNA homology. Not yet possible to culture in liquid media
B. Considered normal flora
C. Most people infected asymptomatically and show Ab by age 3
D. Early clinical manifestation of AIDS
E. Ecology - airborne pathogen
F. Pathogenesis
- Reaction of dormant organism
- 30 day incubation period
- Pulmonary
- Extrapulmonary infections have been found in AIDS patients
F. Diagnosis
- Identification of organism from BAL (bronchoalveolar lavage- bronchoalveolar irrigation)
- Silver, Calcofluor or Giemsa stain useful
G. Treatment and prophylaxis- organism does not contain ergosterol
- Trimethaprin - Sulfamethoxazole
- Echinocandins - experimental
- Pentamidine – rarely used
H. rRNA contains self-splicing introns - potential chemotherapeutic target
OPPORTUNISTIC FUNGAL INFECTIONS
Aspergillosis
Causative agents (3) Ecology (3) Pathogenesis (3) and special pt. population target Lab Dx (3) Tx (2)
A. Most common causative agents (not dimorphic)
- Aspergillus fumigatus
- Aspergillus niger
- Aspergillus flavus
B. Ecology - soil, dust, decaying food
C. Pathogenesis
- Immuno-compromised host
- Allergic rhinitis
- Burns
- Otitis externa
- Diabetics
- Invasive infections in immunocompromised patients - poor prognosis
D. Laboratory diagnosis
1. Septate hyphae (not dimorphic)
2. Serology - Aspergillus galactomannan antigen in blood is a good indicator of invasive infection (newly approved diagnostic)
3. Culture on Sabouraud’s agar produces a typical mold
A common lab contaminant so finding it is unreliable. In addition, culture takes too long to be an effective diagnostic.
E. Treatment
- Amphotericin B
- Echinocandins (Caspofungin-Cancidas®)
OPPORTUNISTIC FUNGAL INFECTIONS
Zygomycosis (Phycomycosis)
Causative agents (2) Ecology (2) Pathogenesis (2) and special pt. population target Lab Dx (2) Tx (2) and mortality rate
A. Causative agents - Mucor sp. and Rhizopus (not dimorphic)
B. Ecology - soil, decaying food (Rhizopus is a common black bread mold)
C. Pathogenesis
- Severely immunocompromised individuals
a. Uncontrolled diabetics, steroid treatment, leukemia, lymphoma, etc. - rhinocerebral, pulmonary, systemic
b. Burn patients - infection in wounds - Extremely fast growing
D. Laboratory Diagnosis
- Non-septate hyphae on smear
- Culture on Sabouraud’s medium
E. Treatment
- Amphotericin B
- Surgery
- Mortality rate > 50%
MYCOTOXICOSIS
Poisoning by by-products of fungi (Discuss)
Aflatoxins- what sp. produces it, found where, effect?
Other toxins (2) and their pathogenesis
Define actinomycetes
I. Poisoning by by-products of fungi – fungi produce antibiotics/poisons as a way of protecting themselves from predation.
II. Aflatoxins:
A. Produced by Aspergillis flavus
B. Found in foods, especially peanuts
C. Arcinogenic, causes liver cancer and liver necrosis
III. Other toxins: A. Ochrotoxin 1. Produced by Aspergillis sp. 2. Causes liver necrosis B. Amanita mushroom 1. Phalloidin - binds to microtubules 2. amanitin - binds to RNA polymerase and other proteins; also a neurotoxin
ACTINOMYCETES - filamentous bacteria related to mycobacter that produce colonies that resemble molds.
What two Genera of yeast rarely give rise to opportunistic infections?
Rhodotorula and Torulopsis
Mycotic Infections may be characterized how?
List 3 types of infections
Location of the infection
- Systemic mycoses caused by: Blastomyces Coccidioides Aspergillus Histoplasma Cryptococcus Candida Sporothrix Paracoccidioides
- Cutaneous Candidiasis Candida albicans
- mucocutaneous infections : nose, pharynx, vagina, areas of bowel. Easier to treat than systemic and not as bad as systemic - Dermatophytic infections Microsporum Trichophyton Epidermophyton
- E.g typical ringworm. Usually not life threatening. Athletes foot, jock itch. Enjoy areas warm, dark, and moist.
Note: Histoplasma usually associated with lungs, Cryptococcus may cause meningitis in immunocompromised patients, Candida is the most common causative agent of septicemia after bacteria.
Anti fungal Drugs
Systemic mycoses (3) Cutaneous Candidiasis (2) Dermatophytic infections (2)
- Systemic mycoses
Amphotericin B (IV)
Flu cytosine - restricted use
Azoles (oral) - Cutaneous Candidiasis
- Nystatin (topical, suppository, suspension )
- Azoles (topical/oral) - Dermatophytic infections
Azoles (topical/oral)
Griseofulvin
Polyene Antifungals
Type of agent
Chemical property
Examples (2)
- Fungicidal
- amphipathic
- Amphotericin B
- Nyastin -only for topical Tx. Never given systemically
Amphotericin B MOA
What is responsible for the selectivity (2)?
8 molecules of Amphotericin B interacts hydrophobically with 8 molecules of ergosterol in the fungal cell membrane forming a pore. Potassium leaves first, and the follow other small molecules leading to the death of the cell.
Note: Selective because the pores are transient. Half time of pores in Fungi cells is longer than in human cells. The affinity of Amphotericin B for ergosterol is a litter better for ergosterol than the predominant cholesterol in human cells.
Amphotericin B Pharmacokinetics
Route Where is it sequestered App Vd Half Life Preparation for administration?
Why the numbers for App Vd and Half life?
Very poor oral absorption - requires parenteral administration
•Sequestered in tissue membranes very low serum levels
- App. Vd ≈ 4 L/kg
- Half-life ≈ 15 days
•Administered as a freshly prepared suspension
- Liposomal preparations
Note: Vd and half life are high because the Amphotericin B is lodge in the cell membrane of fungi.
Amphotericin B Adverse Reactions (8)
Which adverse reaction is the worst?
- Chills, fever and vomiting
- Renal toxicity (decreased renal blood flow and direct toxicity to tubule cells)
- Normocytic, normochromic anemia (high doses may cause hemolysis)
- Hypokalemia
- Arrhythmias- hypokalemia can lead to arrythmias. Further complications can occur with Rx e.g. digitalis.
- Pain, headache, impaired vision and chemical meningitis when given intrathecally. E.g Ex. patient may become combative
- Thrombophlebitis
- Anaphylaxis- anaphylactoid- not allergenic in origin but will cause similar symptoms. (anaphylactoid reaction a reaction resembling generalized anaphylaxis but not caused by IgE-mediated allergic reaction but rather by a nonimmunologic mechanism.)
-Renal Toxicity is the worst issue.
Note: Chills and fever are part of the infusion reaction and thus may coadminister steroids or acetaminophen
Formulations of Amphotericin B
Currently, the drug is available in many forms. Either “conventionally” complexed with sodium deoxycholate (ABD)
OR
lipid complex (ABLC) cholesteryl sulfate complex (ABCD) liposomal formulation (LAMB).
Discuss the shapes of all 4 formulations, daily costs, infusion reactions, and renal toxicity.
ABD - Micelles, $76, yes, yes
ABLC - Ribbons, $740, - , less common than ABD
ABCD - Disks, $360, ++ , less common than ABD
LAMB - Spheres $1099, - - , less common than ABD
Note: Prescrive liposomal prep for immunocompromised patients. Otherwise prescribe Na+ deoxycholate prep ABD.
Note: Amphotericin has a very small TI and cannot be excreted rapidly and long half life.
Flucytosine
- Originally developed as a _______
- Chemically is a derivative of ______
- Used in combination with which drug?
- Cancer drug
- Pyrimidine derivative
•Narrow spectrum of activity
- For most strains of Cryptococcus neoformans
•Usually used in combination with amphotericin B
Note: Cryptococcus can cause meningitis
Flucytosine
Selectivity is achieved how?
Combination Tx MOA
Flucytosine is more highly permeable to fungi membrane compared to human membrane.
Flucytosine becomes more permeable with the addition of Amphotericin B. The Flucytosine enters via a permease within the fungal plasma membrane and intracellular converted to 5-Flurouracil —> 5-FdUMP.
5-FdUMP inhibits*
dUMP — Thymdylate synthase —> dTMP –> DNA
Decrease of dTMP leads to inhibition of DNA synthesis and cell division
Flucytosine Pharmacokinetics
Type of agent (2)
Route
Excretion
Penetration
Antifungal and anticancer drug.
- Well absorbed orally
- Dependent upon renal function for elimination
- Penetrates well into the CNS ≈ 70% of serum levels
Note: With combination Tx of Amphotericin B the major excretion method may be a problem since an adverse effect of Amphotericin B is renal toxicity.
Flucytosine Adverse Reactions (3) and %
Should be considered first or second line Tx
When should dosage modification be considered?
Induction Tx because it kills the organism without administration major toxic agents.
- 25% exhibit nausea, vomiting, severe diarrhea and enterocolitis
- 25% exhibit elevation of hepatic enzymes- Damage to liver. Above more than 3x the normal amount of enzyme consider reducing dosage.
- 15% exhibit bone marrow depression: anemia, leukopenia, thrombocytopenia
Azoles
Two types and 7 subtypes
Imidazole’s (5 membered ring with 2 N)
- KETOCONAZOLE
- CLOTRIMAZOLE
- miconazole
- econazole
Triazoles (5 membered ring with 3 N)
- FLUCONAZOLE
- ITRACONAZOLE
- terconazole
Azoles MOA
Type of agent
Discuss selective toxicity
Compare Ketoconazole and Fluconazole with their MOA and drug interactions.
What may happen with high doses of Ketoconazole?
All azoles have the same mechanism of inhibiting the cyt P-450 dependent 14-a-demethylation of sterols. This leads to decreased ergosterol synthesis and the accumulation of 14-methyl sterols in the fungal membrane.
Selective toxicity is based on the higher affinity of the triazole or imidazole group for the heme iron of cyt P-450 of fungi when compare human cyt P-450. In addition, humans can use preformed, exogenous sterols while Fungi must make there sterols.
- All azoles are FUNGISTATIC due to the DECREASE of ergosterol synthesis
- Ketoconazole is a really good inhibitor of CytP450 dependent enzymes. Has lots of drug interactions
- Fluconazole also and inhibitor of CytP450 dependent enzymes, but not as good and has lots of drug interactions a well.
- Normally steroid biosynthesis is in the mitochondria. High doses of ketoconazole affect production of sex steroids.
Comment on the environment requirement of Ketoconazole, Fluconazole, and Itraconazole.
Comment on bioavailability
Comment on distribution ratio of CSF:serum
And which drug would be given for an upper renal (above bladder) mycotic infection?
Ketoconazole and Itraconazole have to be in an acidic environment so that they will dissolve. We have to absorb the dissolutes. Thus don’t take antiacid with it.
- Once dissolved there is good bioavailability (more than 70%)
- Fluconazole is more than 70, Ketoconazole is less than 10, Itraconazole is less than 1
Fluconazole does not require acidic environment.
-Fluconazole should be given because at the point of urinary excretion there is more than 80% of the drug active. Ketoconazole and Itraconazole are greatly metabolized and thus 2-4 and less than 1%, respectively, are active at the point of urinary excretion.
Adverse Reactions
Ketoconazole vs Fluconazole
All azoles have a TERATOGENIC POTENTIAL during pregnancy.
Ketoconazole
- Gastrointestinal distress
- Rash, pruritis
- Elevated hepatic enzymes
- Decreased sex steroid synthesis- gynecomastia, change in menses, decreased libido
- Decreased cortisol synthesis
- Severe hepatotoxicity
Fluconazole
- Gastrointestinal distress
- Rash
- Elevated hepatic enzymes
- No effect on host steroid synthesis
Comment on the discontinuation of Ketoconazole vs Fluconazole
Only 1 to 2 % of patients must discontinue fluconazole because of adverse effects.
Ketoconazole - increase in dose leads to a higher % of patients discontinuing the Rx. 0.4g/day: 4% to 1.6g/day: 60%
Drug Interactions
Discuss the biochemical effect azoles have on metabolism.
List the drug interactions (6)
Which two drugs have an effect on the levels of azoles?
Azoles inhibit hepatic microsomal drug metabolizing enzymes to varying extents. The following interactions have been reported.
Note: caused by the inhibition of CytP450 dependent enzymes.
Arrhythmias with terfenadine & astemizole Increased levels of cyclosporine Increased bleeding time with warfarin Hypoglycemia with oral hypoglycemics Increased serum levels of phenytoin Increased serum levels of digoxin
The following two Rx decrease blood levels of azoles because they induce CytP450 dependent metabolizing enzymes, thus increases the metabolism of azoles.
- Rifampin decreases blood levels of azoles
- Phenytoin decreases INTRACONAZOLE blood levels by > 10x
Primary indications for Azole Rx (9)
Candidiasis Coccidioidomycosis Cryptococcus chronic suppression Blastomycosis Histoplasmosis Sporotrichosis Pseudallescheriasis Aspergillosis
Candidiasis
Define Causative agent Tx (route-3) Route, never administer how and why, not absorbed how? Local or systemic administration?
Infections of the mucosa of the oropharynx, esophagus, bowel or vagina caused by Candida albicans
May be treated with nystatin suspensions or creams. Topical azoles are also efficacious.
Not absorbed orally
Systemic administration may also be employed for when there is an extensive area of tissue infection.
Note: Never parenterally. Swallow a little not a big deal because does not get absorbed in GI tract. If given parenterally more toxic properties than amphotericin.
Note: Clotrimazole - suppository for Candida vagina infections
Terbinafine
Type of agent MOA Selectivity Effective Tx for \_\_\_\_\_. Discuss routes. Adverse Effects (Common-2, Rare-2)
Fungicidal synthetic allylamine
Inhibits squalene epoxidase leading to the accumulation of toxic levels of squalene in the organism. Normally Squalene is converted to Ergosterol by Squalene epoxidase. No Ergosterol also leads to death.
Mammalian enzyme is 4,000 times less sensitive.
Effective in the treatment of dermatophytic infections:
- Topical
- Oral for onychomycosis; once a day therapy for 12 weeks is 90% effective (better than griseofulvin or itraconazole)
Adverse Effects:
Headache and GI symptoms (diarrhea, abdominal pain, nausea) are most common.
Rarely, hepatotoxicity & severe skin allergy
Note: Headache occurs usually when route is ORAL
NEW TARGETS
List the new targets for and their Rx (3). Why would these be used in substitution for other antifungal Rx?
- Chitin synthesis – nikkomycins
- Glucan synthase – Caspofungin (echinocandins)
- Mannoproteins – pradimicin
- Used for more severe issues and for substitution of Rx that not as sensitive to the infection.
- These potentially useful drugs are derived from naturally occurring substances
Parasites are eukaryotic organisms that include both single cell organisms (Protozoa) and multicellular organisms (Helminths).
Parasites have developed multiple ways of living inside human hosts. These include residing in different organs of the body, evading the host immune response and reproducing and shedding their offspring in numerous ways.
Why do we need direct observation of parasite using microscopy to confirm a prediction of a causative agent?
Most parasitic infections cause non-specific and non-identifying symptoms, predictions of infectious agent must be confirmed by direct observation of the parasite using light microscopy.
Biology of parasites.
Comment what type of organisms are they, life cycles, and geographically where are they found?
- They are eukaryotes.
- Many have complex life cycles that cannot be completed without transmission to several hosts.
- They are widely dispersed throughout the world and do not occur solely in “tropical” areas.
Compare bacterial, viral, parasitic infections.
Infectious parasites fall into two main groups (2).
- Parasites are:
a. Eukaryotes, and can be single cells (protozoa), or multicellular organisms (helminths)
b. Larger than bacteria and viruses
c. In some cases, able to change their antigenic surface proteins
d. Able to use a variety of mechanism to avoid mammalian host defenses - Infectious parasites fall into two main groups:
a. Protozoans: for example: plasmodium (malaria), trypanosomes
b. Helminths: for example: Cestodes, Trematodes, Nematodes
Note differences in mode of infection: malaria requires an insect vector. Some viral agents, such as yellow fever and dengue may also be spread by arthropod vectors. However, the insect vector in malaria plays a specific role in the life cycle of Plasmodium.
Informational
Parasite control is complex/simple?
E.g. with malaria.
Parasite control is complex. For example, malaria control relies heavily on vector elimination and prevention of mosquito bites, as well as drug prophylaxis.
Differences in the Lab Dx of bacteria, viruses, and e.g. malaria.
Bacteria and viruses may be cultured, and antibodies against them may be measured.
Diagnosis of malaria currently requires direct demonstration of the organism in the blood of an infected patient.
However, ELISA tests are currently in use for some parasites.
Parasite immunity is complex/simple.
E.g malaria
Where can parasites cause disease in humans?
Parasite immunity is complex.
For example, immunity to malaria is difficult to acquire because of serological differences of the infectious agent.
Parasites cause disease at a wide variety of sites in the body. They cause disease in many organ systems.
Parasite/host interactions are complex.
Bacteria vs Parasites
Physical barriers
Innate Immunity
Antibody responses
Killing
- Physical barriers
Bacteria: Intact skin usually impenetrable. Fatty acids of skin toxic to bacteria. Vaginal flora normally produce acid pH.
Parasites: (Special modes of entry) Insect bite, Ingestion,
STD, Direct invasion
- Innate immunity
Bacteria: Recognition of bacterial LPS activates complement, TNF, IL-1. Chemotaxis, cell adhesion. NK cells activated.
Parasite: Host response varies. Parasite may coexist with host. Initial response depends on macrophages. Macrophages secrete cytokines such as TNFa, IL1; respiratory burst produces reactive O2 metabolites, NO for parasite killing.
- Antibody responses
Bacteria: Lymphocytes activated, Specific antibodies pro- duced and targeted cells attached to complement.
Parasites: TH2 response is necessary for expulsion of GI worms.
- Killing
Bacteria: Phagocyte attaches to organism, which is then ingested. Killing occurs via: NO, O2-, lysosome formation.
Parasite: Macrophage killing mechanisms activated
Define
Definitive host
Intermediate host
Definitive host- where the parasite reproduces sexually. Often where the adult stage resides.
Intermediate host-larval stage develops
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Ascaris lumbricoides:
Who carries them.
Infection causes a decrease in _______.
Disease where are the worms found?
Discuss life cycle and mode of entry into human.
What special population are usually the host?
Pathogenesis- discuss the effects and fatal cases.
Dx, symptoms, presentation
Tx and give sequential order.
Prevention and control (3)
Comment on the durability/fragility of Eggs.
ROUND WORMS-also called Nematodes
- Ascaris lumbricoides-over half of the world carries one or more of theses worms. Infection causes a decrease in allergies since the worms recruit IgE. World-wide, mainly in tropics.
a. Disease- worms in upper part of small intestine.
b. Life cycle- complex. Accidentally ingest eggs, larvae hatch in small intestine and are carried to liver. Larvae migrate to heart, then to lungs. They then break out of lungs and migrate up trachea, are swallowed and finally reside in the gut. Adults mature in the gut and lay eggs which are then passed in feces. Acquire infection by ingestion of eggs found in soil. Often an infection in children.
c. Pathogenesis-obstruction of GI tract, malabsorption of nutrients in infection children, peritonitis, Loeffler’s syndrome (type of pneumonia associated with high eosinophils). Fatal cases of Ascarisis caused by aberrant migration of adult worms to the liver.
d. Diagnosis- eggs in stool.
Adults can be vomited up when they are migrating.
Symptoms include: No symptoms, palpable abdominal mass, obstruction (biliary or intestinal), migration associated problems.
e. Treatment-mebendazole (a vermafuge), paralyzes worms that are then expelled. Surgical intervention is a last resort. Mebendazole is the treatment for most roundworms, including whipworm, hookworms, strongyloides, pinworm.
f. Prevention and control- Eggs survive well in soil under a wide variety of conditions.
ii. Eradicate reservoir hosts.
iii Sanitary disposal of feces.
iv. Avoidance of eating uncooked vegetables in epidemic areas.
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Whipworm (scientific name)
Disease determinant
Acquisition
Epidemiology
Reservoir
Life cycle, who is the definitive host?
Pathogenesis
Dx
Prevention/Control (3)
Discuss shape of eggs.
Trichuris trichiura - Whipworm
a. Disease -
i. Light worm load-usually no symptoms
ii. Heavy worm load - prolapse of rectum, diarrhea, weight loss
iii. Acquire- fecal-oral root- eating embryonated eggs from soil or vegetables contaminated with feces.
iv. Epidemiology - world wide, greatest incidence in tropics and southern United States
v. Reservoir – only humans
b. Life cycle: humans ingest eggs in soil. Larvae migrate to colon. Adult female releases eggs into human feces. Fecal-oral passage. Humans are definitive host.
c. Pathogenesis - prolapse of rectum, diarrhea, weight loss
d. Diagnosis - Eggs in stools. Football shaped eggs.
e. Prevention, control
i. Sanitary disposal of feces
ii. Avoidance of eating uncooked vegetables in epidemic area
iii. Personal cleanliness
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Hookworm (scientific names-2)
Disease determinant and causes what ailments
Acquisition and propensity in what special population?
Epidemiology
Life cycle and definitive host
Pathogenesis
-symptom determinant
Dx (2)
Prevention/control (2)
Hookworm- Necator americanus (new world) and Ancylostoma duodenale (old world)
a. Disease -
i. Depends on worm load, mainly causes anemia due to significant blood loss.
ii. Acquire - Feces in soil, infective filariform larva enter through skin (usually children)
iii. Epidemiology - Most common in tropics and subtropics
b. Life cycle: infection is via burrowing larva that develop in soil that has been contaminated with infected stool.
Definitive host – humans
c. Pathogenesis -
Symptoms - depends upon worm load
Heavy - anemia, cardiac damage, ‘pica’ (desire to eat dirt)
d. Diagnosis
i. Eggs in patient’s feces
ii. Rhabditiform larva in stool in constipated individuals or in fecal samples that have been left unexamined for hours
e. Prevention, control
i. Sanitary disposal of feces
ii. Wearing of shoes
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Strongyloides stercoralis
Disease
Definitive host
Acquisition
Epidemiology
Life cycle (discuss) - how is infection accomplished?
Pathogenesis determinant
- Symptoms
- Special population consideration
Dx (2)
Prevention/control (2)
a. Disease - diarrhea
i. Definitive host – humans
ii. Acquisition- Feces in soil, infective filariform larva enter through skin (usually children). As in Hookworm except disease can last many years due to autoinfection, even after individual has left an endemic area.
iii. Epidemiology - tropics, Southeast Asia, Appalachia
b. Life cycle- larvae migrate from bloodstream to lungs, then swallowed and live in human small intestine. Autoinfection occurs in humans. There is also a free-living soil cycle. Larvae infect humans by penetrating unbroken skin.
c. Pathogenesis
i. Many individuals asymptomatic
ii. Moderate to heavy load - diarrhea or constipation, anemia, weight loss
iii. Hyperinfection syndrome in immunocompromised hosts
d. Diagnosis
i. Rhabditiform larva in stool or duodenal aspirate
ii. Mucosol biopsy, string test, ELISA.
e. Prevention and control - same as in Hookworm
i. Sanitary disposal of feces
ii. Wearing of shoes
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Pinworm (Scientific name)
Disease
Definitive host
Epidemiology
Life cycle - mode of transmission of eggs
Pathogenesis - results in (2)
- internal progression
- Indirect result
Dx (3)
Prevention/control (1)
Property of Egg viability and effort to eradicate contaminated areas.
Enterobius vermicularis
a. Disease- itchy anal area
i. Definitive host – humans
ii. Epidemiology – world wide.
b. Life cycle: eggs expelled from gravid female pinworm in perianal area of human. Eggs are infectious to other individuals.
c. Pathogenesis
i. Pruritus ani (irritation of anus), insomnia
ii. Internal - adults may migrate to genital tract and become imbedded and result in granuloma formation.
iii. Psychic trauma to parents when their children become infected.
d. Diagnosis
i. Sticky plastic paddle pressed on perianal region on rising in the morning
ii. Three consecutive days if first and second results are negative
iii. Stools are not examined
e. Prevention and control
i. Personal cleanliness and cleanliness of living quarters
- Eggs survive on inanimate objects in the home. Entire household gets contaminated, difficult to eradicate
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Trichinosis
Causative agent
Disease Definitive host (4) w/ peculiarity
Life cycle, mode of entry, last stop where they reside
Pathogenesis
- symptom determinant (provide specific detail)
- Px
Dx- time frame, important factors (3)
Tx
Prevention/control (2)
Trichinella spiralis
a. Disease - calcified larvae in muscle
Definitive host -pigs, rats, bears, humans (dead end)
b. Life cycle: larva, infected meat is mode of entry into the human host. Adults mature in small intestine; newborn larvae carried through blood stream and enter skeletal muscle cells. Reside in muscle cell in human/animal tissue.
c. Pathogenesis – Symptoms
i. Few ingested larva - no symptoms
ii. 50 larvae/gram - diaphragm, extraocular, deltoid, gastrocnemius, etc.
iii. Fever, muscular pain, weakness, diarrhea in acute phase
iv. Periorbital edema, splinter hemorrhages
v. Prognosis - dose related
d. Diagnosis
i. Early diagnosis difficult
ii. History
iii. High eosinophilia
iv. Biopsy of striated muscle
e. Treatment-None, supportive therapy.
f. Prevention, control
i. Feed hogs cooked garbage
ii. Cook pork and pork products well
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Wuchereria bancrofti- A cause of ________ disease
Disease (2)
- discuss the location and gender roles
Life cycle
- mode of transmission
- progression subsequent to infection
- determinant to geographic source
Pathogenesis
Dx (2)
Tx (1) which is effective against ______.
Prevention (1)
A cause of parasitic tissue disease
a. Disease – elephantiasis, filariasis. The organism is a thread-like worm that locates in the lymphatic vessels and lymph nodes. There are male and female worms and the females produce sheath-covered microfilaria (~200 M long).
b. Life cycle - transmitted by the bit of a mosquito that has previously acquired microfilaria with a blood meal. The cycle is complete when infective larva in the mosquito pass into the mammalian host where they make their way into the lymph nodes and develop into adult worms in a few months.
There is a periodicity to the emergence of microfilaria in the bloodstream- the timing (nocturnal or diurnal, during the day) is indicative of the geographic source of infection.
c. Pathogenesis- adult worms live in lymphatics and cause blockages.
d. Diagnosis - periodicity of microflaria in bloodstream requires care in sampling time. Thick blood smears are also used.
e. Treatment - Diethylcarbamazine (Heteraza) is effective against the microfilaria.
f. Prevention - control of mosquitoes.
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Brugia malayi causes _____ disease.
How is infection transmitted?
another important filarial worm that causes tissue disease.
Close related to Wuchereria. There are primate reservoirs for this worm and infection to humans is zoonotic.
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Onchocerca volvulus
Mode of transmission and type of parasite
Major cause of ________ in Africa. What contributes to that cause. What helped resolve this?
Distinguishing trait
Dx
This filariae parasite is transmitted by the bite of the black fly.
a. Disease - It was the major cause of blindness in Africa before the drug Ivermectin was available.
The distinguishing trait of this filarium is that it is found in the skin and not the blood. Eye infection by microfilarial – human immune reaction contributes to blindness.
b. Diagnosis is via microfilaria in ear skin snip.
Multicellular parasites: worms.
A. ROUND WORMS-also called Nematodes
Aberrant nematode infections in humans (2)
Normal hosts for infection (2). Why is it aberrant?
Acquisition of infection
Discuss the two kinds of aberrant nematode infections.
- Pathological effects and Dx
Aberrant nematode infections in humans -Visceral and cutaneous larva migrans.
Normally infections of dogs and cats.
Numerous nematodes cause these aberrant human infections. Since these worms infect us accidentally and they cannot complete their life cycles in the human host.
Infection acquired- mainly when children eat dirt with eggs in it or when the body comes in contact with a larval form (cutaneous).
a. Visceral larval migrans (i.e. Toxocara canis) -
i. Affects liver, heart and CNS.
ii. Eosinophila - 30%
iii. Diagnosis- CSF examination, biopsy.
b. Cutanous larval migrans (i.e., Ancylostoma braziliense) -
i. Skin lesion, abscess formation
ii. Diagnosis-biopsy
FLATWORMS (Cestodes)
fish tapeworm
Pathogenesis
Diphyllobothrium latum- fish tapeworm.
a. “Jewish house wives’ disease”. Infection from eating larva in raw fish. Adult attaches to the human gut and reaches full length in 3 months.
b. Achieves 10 meters in length in the human gut! Causes anemia- B12 deficiency.
FLATWORMS (Cestodes)
Beef and Pork Tapeworms:
Lab Dx (3) Epidemiology (3)
Beef tapeworm:
Definitive host
Life cycle
Symptoms (2)
Pork tapeworm
Definitive host
Life cycle
Symptoms (2) and disease
Beef and Pork Tapeworms
a. Taenia saginata (beef tapeworm)
i. Definitive host - humans
ii. Life cycle: cystecerci (larvae) are ingested when we ingest infected beef. These larvae are released in the stomach and adults remain in the small intestines. Eggs from female adult are deposed with human feces. Cows ingest eggs which then hatch in their muscle.
iii. Symptoms
(a) Vague complaints of abdominal discomfort
(b) Awareness of movement of proglottids that emerge from anus.
Taenia solium (pork tapeworm)
i. Definitive host – humans
ii. Life cycle: as for the beef tape worm, except the eggs mature into larvae in the pig.
iii. Symptoms – same as beef tapeworm. If we ingest the tapeworm eggs, and not the larva in the meat muscle, we get aberrant parasite migration as larva develop in our brains and eyes. This disease is called cysticercosis.
c. Laboratory diagnosis for Both beef and pork tapeworms
i. Eggs in stool, identical in appearance for both species
ii. Differentiating T. solium and T. saginata by pressing proglottid between slide and counting main lateral branches
(a) T. solium - 7 to 12 pairs
(b) T. saginata - 15 to 30 pairs
iii. For Cysticercosis (pork tapeworm)-find larva/cysticercus in brain/muscle/eye by
(a) CAT scan or MRI
(b) ELISA test
d. Epidemiology
i. Incidence less than 2% in U.S.
iii. Spread by eating undercooked beef and pork
iv. Cysticercosis more common in Mexico, Central and South America
FLATWORMS (Cestodes)
Causative agent for HYDATID DISEASE
Definitive host Symptoms (2) Dx (3) Epidemiology (3) Prevention (2) Tx (2)
Echinococcus granulosus (HYDATID DISEASE) a. Definitive host – dog, wolf, sheep. Infection in humans leads to cyst development in liver, lung or brain.
b. Symptoms
i. Slowly growing tumor in liver (60%), lung (25%), other (15%)
ii. Rupture of cyst - possible anaphylactic shock - spread of daughter cysts throughout body
c. Diagnosis - History
i. X-ray, CAT scan, Serology
ii. No stool examination for ova
d. Epidemiology
i. Sheep raising areas - man obtains eggs in soil or from dog fur
ii. Very prevalent in China also native American Indians.
iii. Infected Australian sheep dogs brought the disease to California, Utah, etc.
e. Prevention
i. Do not feed dogs raw refuse from slaughter
ii. Treatment for dogs that have eggs in stools
f. Treatment
i. Careful surgical removal of cyst
ii. Multiorgan involvement – praziquantel
TREMATODES (flukes)
Which sp.s are the most medically important (3)
Definitive host
Sex characteristics
Life cycle is completed where
Immune responses
- Discuss the three immune responses and be particular with S. mansoni.
- Most medically important flukes are Schistosoma mansoni, japonicum and hematobium.
a. Definitive host - humans
b. Have separate sexes (all schistosomes have 2 sexes, other trematodes are hermaphroditic.)
c. Life cycle: cycle through both humans and snails to complete their complex life cycle.
d. Immune Reactions
i. Production of specific IgE antibodies and eosinophilia
(a) Due to stimulation of CD4+ helper T cells that secrete IL-4 and IL-5
(b) IgE antibody binds to helminths, eosinophils attach to these opsonized organisms by Fc receptors specific for IgE. The eosinophils are activated, secrete major basic proteins which lyse the parasites.
ii. Activated macrophages directly kill schistosome larva through action of nitric oxides and TNF
iii. S. mansoni eggs in liver stimulate CD4+ T cells, which activate macrophages, result in granulomas, severe fibrosis. Leads to disruption of venous blood flow, portal hypertension and cirrhosis.
TREMATODES (flukes)
Most medically important flukes are Schistosoma mansoni, japonicum and hematobium.
Symptoms of S. mansoni infection (11)
Lab Dx (4)
Epidemiology (4)
Prevention and control (3)
e. Symptoms of S. mansoni infection
i. Acute stage fever, malaise, diarrhea, weight loss
ii. Chronic
(a) Weight loss, anemia, splenomegaly, periportal fibrosis, ascites
(b) Intestinal structures and polyps
(c) Portal hypertension
f. Laboratory diagnosis and treatment
i. Eggs in feces (S. hematobium in urine) Multiple stools must be examined
ii. Rectal biopsy
iii. Cercarial slide agglutination test
iv. treat with praziquantel
g. Epidemiology
i. Defecation (S. mansoni and S. japonicum) and urination (S. hematobium) by infected persons contaminates water
ii. Untreated sewage into ditches, streams and lakes in endemic areas
iii. Not acquired in continental U.S. due to lack of correct snail vector, only certain fresh water snails are intermediate hosts
iv. Walking, swimming or washing clothes in contaminated water allows cercaria to penetrate skin
h. Prevention and control
i. Sanitary disposal of feces
ii Control snail population
iii. Education of people
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues
A. DIARRHEAL DISEASES caused by protozoan parasites- amebiasis, giardiasis and cryptosporidiosis. Flagyl is the treatment for amebiasis and giardiasis.
Amebiasis:
Causative agent Disease Epidemiology (5) Life cycle Pathogenesis Dx
Amebiasis - Entamoeba histolytica- ameba
a. Disease – can be asymptomic, diarrhea, acute rectocolitis (dysentery), If untreated, fulminant colitis with perforation, perianal ulceration liver abscess.
b. Epidemiology:
i. Institutional outbreaks
ii. Breakdown in sewer lines iii Homosexuals
iv. Migrant workers
v. Travelers and immigrants from endemic areas
vi. Communal living
c. Life cycle- cyst and trophozoite forms. Exist in gut after ingestion of cysts from soil. Divide by binary fission.
d. Pathogenesis- migration to liver preceded by ulceration of gut.
e. Diagnosis- eggs and ameba in stool.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues
A. DIARRHEAL DISEASES caused by protozoan parasites- amebiasis, giardiasis and cryptosporidiosis. Flagyl is the treatment for amebiasis and giardiasis.
Amebiasis - Entamoeba histolytica- ameba
Mark the differences of Amebic/Bacillary Dysentery
Mark the differences of E. histolytic/E. coli
Prevention (2)
Amebic Dysentery Few cells Charcot-Leyden crystals RBC in clumps or rouleaux Eosinophils (2-5%) Epithelial cells undamaged and damaged
Bacillary Dysentery Many cells (polys) Absent RBC - scattered Rare eosinophil Epithelial cells are bile-stained
E. histolytic Nuclei: 1-4 Karyosome: center Chromatin: regular Chromatoidal bar: large, thick
E. coli ( non-pathogenic) Nuclei: 1-8 Karyosome: off center Chromatin: irregular Chromatoidal bar: splinter
Prevention
i. Personal hygiene
ii. Environmental sanitation
(a) Water - 8 ppm iodine - cysticidal
(b) No human waste for fertilizer
(c) Sanitary disposal of feces
Bacillary dysentery is a type of dysentery, and is a severe form of shigellosis. Bacillary dysentery is associated with species of bacteria from the Enterobacteriaceae family.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues
A. DIARRHEAL DISEASES caused by protozoan parasites- amebiasis, giardiasis and cryptosporidiosis. Flagyl is the treatment for amebiasis and giardiasis.
Giardiasis:
Causative agent Disease/Symptoms Epidemiology (3) Pathogenesis Excitation Dx (2) Prevention
Giardiasis - Giardia lamblia – flagellate
a. Disease-can be asymptomic, diarrhea,
Epidemiology:
i. Children (especially day care nurseries)
ii. Travel
iii. High risk sexual activities
b. Pathogenesis - ingestion of cysts, Trophozoites attach to duodenal wall
c. Excystation in duodenum and the trophozoites attach to mucosa. Pathogenesis and symptoms-diarrhea, Malabsorption
d. Diagnosis
i. Direct and concentrated examination of feces
ii. Antigen detection test Entero-string test
e. Prevention - same as in amebiasis. i. Personal hygiene
ii. Environmental sanitation
(a) Water - 8 ppm iodine - cysticidal
(b) No human waste for fertilizer
(c) Sanitary disposal of feces
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues
A. DIARRHEAL DISEASES caused by protozoan parasites- amebiasis, giardiasis and cryptosporidiosis. Flagyl is the treatment for amebiasis and giardiasis.
Cryptosporidium:
Disease Epidemiology Life cycle Dx (2) Resistant to \_\_\_\_. Need \_\_\_\_\_ to kill.
Cryptosporidium
a. Disease - severe diarrhea in compromised host, self-limiting diarrhea in normal host
Epidemiology- world wide, appears in severely compromised patients-AIDS
i. Transient diarrhea in normal host in the tropics
ii. Major outbreak in Milwaukee (1993), water supply contaminated, 500,000 cases, other outbreaks reported.
iii. Found in wave pools
b. Life cycle- see slide. Is a coccidia (related to malaria). Constant host reinfection.
c. Diagnosis - intestinal biopsy, observe a minute coccidian about 2-4 microns spherical bodies on the mucosal surface or free in the crypts. Modified acid-fast stain of diarrheic feces.
d. Resistant to chlorine – need Clorox to kill it.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues
Sexually transmitted protozoan parasite- Trichomonas vaginalis
Disease
Life cycle
Dx
Tx
- Disease- vaginitas, urethritis. Considered a STD.
- Life cycle- human to human transmission. Lives in anaerobic environments.
- Diagnosis -wet prep - No cyst form occurs
- Treatment - flagyl - both sexual partners should be treated.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues
Blood borne infections- List (4) genera and/or sp.
Blood borne infections- caused by Plasmodium species (malaria), Babesia species (Babesiasis), Trypanosoma b. gambiense and rhodensiense (African sleeping sickness).
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
- Malaria:
Discuss the background and mode of infection
Cause for the recent increase of malaria
Discuss the features of the causative agent
List and discuss the four sp.
- Malaria:
a. Estimated numbers:
People infected with plasmodium: 800 million Cases annually: 300 million
Annual mortality: 2 million Countries affected: 103
Number of people at risk: 2,500 million Major risk to travelers!
i. Malaria is the most common tropical disease. Malaria means “bad air” in Italian. Thought to be caused by the marsh gas in hot, low areas with stagnant water. We now know that these are mosquito breading grounds and mosquitoes pass malaria from person to person.
ii. Increase in malaria infection recently due to rise in insecticide- resistant mosquitoes and drug-resistant parasites!
iii. Causative agent of malaria: Protozoan (unicellular) organism of the sporozoa family. Sporozoa are intracellular protozoa with alternating sexual and asexual reproduction.
The Sporozoa that cause malaria are four types of
Plasmodium:
P. falciparum, P. vivax, P. ovale, P. malariae
iv. All species cause recrudescence - which is reinfection of RBC’s by blood stage parasites for up to two years.
Only P. vivax and P. ovale cause relapse malaria- when hypnozoites develop from a persistent infection in the liver after many years.
Each species looks different enough while it is growing in the red cell to allow for its identification in blood smears. Diagnosis is via looking for parasites inside thin and thick blood smears.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
- Malaria:
Life cycle
Discuss the diagnostic shape of the parasites inside the RBCs (3)
Life cycle: very complex life cycle.
i. Mating of male and female gametes that are produced in human blood infection occurs in the mosquito. Because of this mating cycle, drug resistance among parasites is rapidly spread. In malaria, the taking up of a blood meal by a female Anopheles mosquito is where the life cycles “begins”.
ii. In the insect, the gametocytes (which are the male and female gametes taken up in the blood meal) fuse, and oocytes form in the stomach wall of the insect. The parasites emerge as sporozoites and migrate to the salivary gland. These infective forms are injected into humans when the mosquito takes a second blood meal.
iii. In the human host- the sporozoites enter the blood stream and travel to the liver where they change into schizonts when they rapidly divide. They emerge as merozoites. The merozoites infect red cells. They grow here as they did in the hepatic cells, feeding as trophozoites and dividing as schizonts until they emerge as merozoites. The merozoites can reinfect more red cells or transform into gametocytes. The gametocytes are what are taken up by the mosquito.
iv. The ‘shape’ of parasites inside the red cells is diagnostic of species. The grown stages here (erythrocytic phase) are:
(a) Ring-like, early trophozoites (feeding forms)
(b) Schizonts-eat hemoglobin,divide and produce a characteristic pigment, hemazoin.
(c) Merozoites released from RBCs and reinfect other RBCs or become gametocytes.
(d) Some merozoites differentiate into sexual forms- macrogametes and microgametes. The uptake of the gametes by the mosquito completes the life cycle.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
Malaria
Discuss the 4 main species:
Epidemiology
Fever
Location in human and the name of the life cycle form
Define relapse
Which is the only sp. that is life threatening?
Define tertian/quartan to fever.
4 main species:
Plasmodium malariae-quartan malaria; mild, worldwide. Only infection that causes fever spikes 3 days apart. (fever recurs on the fourth day)
Plasmodium ovale- like vivax, but less severe.
Plasmodium vivax-benign tertian malaria, through tropical regions and in some temperate zones.
Ovale and vivax can lie dormant for years in liver, as hypnozoites. Their maturation and reinfection of RBCs is called relapse. The liver forms that lie dormant are called hypnozoites.
Plasmodium falciparum- malignant tertian; in Africa, Asia & Latin America. Life threatening! Only one that causes mortality.
The names tertian/quartan refer to the periodicity of fever cycles- tertian malaria is when the fever spikes are 48 hrs apart, thus fever occurs on the third day.
Periodicity of fever, when synchronous after a few weeks, is characteristic of each plasmodium type.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
Malaria
Give the time span of fever spikes in all 4 sp. except P. ovale.
fever spike day 1 day 2 day 3 day 4
P. vivax + +
P. falciparum + +
P. malariae + +
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
Malaria
Dx: Symptoms Hallmark of Disease (3) Lab techniques (2) Observe (3) characteristics of the sp. Clinical sign (2)
Pathogenesis: invasion, alteration and destruction of RBCs. Rupture of RBCs and release of pyrogens are accompanied by fever, chills and sweating.
d. Diagnosis:
Symptoms are such that malaria is called “The Great Masquerader” – difficult to identify.
All types have chills, fever, headache, muscle pain, splenomegaly and anemia.
Hallmark of disease is malaria paroxysm:
i. Severe chill (20-60 min in duration)-cold stage
ii. Fever 104-107F (3-6 hrs)-hot stage
iii. Exhaustion but no other symptoms. Drop in polys and rise in monos
Thick and thin smear- Wright or giemsa stain. Perform smear 4 consecutive days; always before a fever spike (before cells lyse).
Observe rings, gametocytes, Schuffner’s dots. Each species has different characteristics in infected red cells.
Polymerase chain reaction-based assay to identify each of the 4 species.
Also useful (using PCR) to identify drug-resistant parasites.
Hepatomegaly, jaundice and edema often observed.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
Malaria
Five important outcomes that can occur after a bite from an infected mosquito.
i. Asymptomic- infection causes immune response that can
limit multiplication and lead to partial immunity.
ii. Recrudescence- periodic rise in parasitemia. Parasites stay in RBCs.
Periodic rise may be due to antigenic variation. Can occur after one year (P. falciparum) or 50 years (P. malariae).
iii. Relapse - hypnozoites forms stay in liver- remerge several years later.
iv. Blackwater fever- brown-black urine due to hemolysis of RBC that is greater that just lysis of infected cells (unknown reasons). Kidney affected and accumulate hemoglobin. Can also occur if you treat disease too aggressively.
v. Death- usually from falciparum’s resulting cerebral malaria. Falciparum malaria can lead to cerebral malaria- infected RBCs stick to cerebral capillaries.
(If initial infection is not cured, recrudescence and relapse (after a long latency time) can occur.)
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
Malaria
Discuss Plasmodium falciparum and antigenic variation
Immunity (4)
Plasmodium falciparum and antigenic variation:
- Infected RBCs stick to lumen of capillaries because the intracellular parasites places ‘docking’ proteins on the infected cell surface. These ‘docking’ proteins are antigenic and the host mounts an immune response.
The parasite has an arsenal of ‘docking’ proteins (called ‘var’ genes) and changes them to avoid the host immune response.
Immunity:
i. T and B-cell mediated. Need constant exposure to maintain resistance. Vaccines are under study.
ii. Individuals with sickle cell trait or glucose-6-phosphate deficiency are more resistant to malaria than individuals without these traits.
iii. Individuals without duffy antigens on their RBCs are protected.
iv. Thalessemia and hemoglobin C- difficult for parasites to use these hemoglobins.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
Malaria
Tx:
Prophylaxis
Tx for relapse from P. vivax or ovale (type of Rx agent)
Tx for Chloroquine-resistant infection and why?
Original treatment was _____, derived from what?
Prevention and control
Mode of acquisition (5) Controlling malaria (3)
Treatment:
i. Prophylaxis- chloroquine; there is a major resistance problem currently and thus mefloquine is the recommended drug for travelers to P. falciparium areas. If origin of infection is from a chloroquine sensitive area, then chloroquine is given. If unknown origin, assume resistance and use pyrimethamine- sulfadoxine – for 3 days.
ii. Relapse from P. vivax or ovale is preventable by a course of primaquine. This is a gametocidal drug.
iii. Chloroquine-resistant infection - pyrimethamine (folic acid antagonist works because the parasites synthesize folates de novo), mefloquine ( starting to see resistance to this, too)
iv. Note- original treatment was quinine- from the bark of the cinchoa tree. Gin and tonics!
Prevention and Control:
i. Malaria can be acquired via bite of mosquito, congenital malaria-placenta, injury, blood transfusion, hypodermic injection.
ii. Malaria can potentially be controlled by:
(a) Eradication of mosquito- resistance problem
(b) Elimination of parasites by mass prophylaxis not practical).
(c) Vaccines are being developed; vaccines against parasites are difficult since parasites are very clever!
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
Babesiosis:
Pathogenesis, special population consideration
Life cycle
Dx (6)
a. Disease- similar to malaria. Caused by intracellular blood parasite, Babesia sp., that infect RBCs. Very severe in humans without spleens.
b. Life cycle- Transmitted by the same deer ticks that transmit Lyme disease in Northeastern US. Found in travelers to Nantucket and Block Island.
c. Pathogenesis- Unlike Plasmodium, Babesia does not produce pigment (hemozoin) within RBCs.
d. Diagnosis -blood smear (see “Maltese cross” in infected RBCs). Mimics malaria in appearance but absence of pigment is characteristic. Characterized by fever, chills, lethargy; also splenomegaly and hepatomegaly.
e. Treatment- clindamycin and quinine.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
African trypanosomiasis:
(2) sp. and geographic regions Life cycle Mode of Acquisition Pathogenesis Transmission
African trypanosomiasis- Trypanosoma brucei gambiense (Western Africa) and T. b.rhodesianse (East Africa)
a. Diseases: African sleeping sickness
b. Life cycle: African trypanosomes-A human or domestic animal (cattle) acquires the parasite via the bite of an infected Tsetse fly. These flies are found only in sub-Saharan Africa and the disease is limited to this area.
The parasites reside in the blood stream and tissue spaces, eventually migrating to the brain to cause “sleeping” symptoms and eventual coma and death. The parasites are transmitted to uninfected Tsetse when the fly takes a blood meal from an infected mammal.
Protozoan parasites – single celled Eukaryotic organisms that live in a variety of human organs and tissues.
African trypanosomiasis:
Dx
Diagnosis:
African trypanosomes-blood or CNS smear. Only trypomastigote form is present.
South American trypanosomes- Blood smear or biopsy- see both trypomastigote and amastigote forms. Xenodiagnosis- feed bug on infected individual and look for parasites in insect feces. PCR methods are being developed.
e. Treatment:
African trypanosomes- Diamidines, arsenicals; DFMO at later stages.
f. Prevention and control—insect vector control, identification of biochemical targets for chemotherapy. Animal reservoirs- some animals are asymptomatical but serve as reservoirs. The animal reservoir is different for different trypanosomatids- bush buck for African trypanosomes.
Protozoan organisms that live inside human cells and infect a variety of tissues- Leishmania species (Visceral, cutaneous and mucocutaneous leishmaniasis), Trypanosoma cruzi (Chagas Disease) and Toxoplasma gondii (toxoplasmosis)
Leishmaniasis –
Leishmaniasis –
a. Diseases- different forms of Leishmaniasis.
Leishmania donovani- Kala-azar, Visceral leishmaniasis
Occurs in South and Central America, Middle east, Mediterranean areas.
Leishmania major or L. tropica- old world cutaneous (self healing) Leishmania braziliensis- mucocutaneous or cutaneous leishmaniasis (chronic and debilitating)
All leishmania transmitted by the bite of a sandfly
Most common in South and Central America, the Middle East and India. All 3 species outlined here are carried by the sand fly vector (Phlebotomus).
Note: Leishmania are close ‘cousins’ of the Trypanosoma spp
Protozoan organisms that live inside human cells and infect a variety of tissues- Leishmania species (Visceral, cutaneous and mucocutaneous leishmaniasis), Trypanosoma cruzi (Chagas Disease) and Toxoplasma gondii (toxoplasmosis)
Leishmaniasis –
b. Life cycle: The extracellular promastigote is injected into the host by the sandfly and invades the macrophages, changing into an amastigote (‘a’= without flagella).The amastigotes multiply in the macrophages and enter the blood stream where they are taken up by a sand fly as it takes a blood meal.
c. Pathogenesis-varied, depending on species.
i. Cutaneous-self-healing lesion.
Leishmania major or L. tropica- old world cutaneous
(a) Localized to skin
(b) Permanent scarring
(c) Secondary infections are problematic
ii. Visceral-all organs affected, splenomegaly and hepatomegaly occur, bone marrow is involved and anemia ensues; if untreated it is fatal.
iii. Leishmania braziliensis- mucocutaneous or cutaneous leishmaniasis
(a) Occurs around nose- attacks cartilage-may break through to the brain
(b) Diagnosis-depending upon location in body-
i. Blood and bone marrow, only see promastigote form, lymph culture.
ii. Biopsy lesion-only find amastogote form
Protozoan organisms that live inside human cells and infect a variety of tissues- Leishmania species (Visceral, cutaneous and mucocutaneous leishmaniasis), Trypanosoma cruzi (Chagas Disease) and Toxoplasma gondii (toxoplasmosis)
Leishmaniasis –
Immunity associated with production of IFN gamma and TNF by CD4+ cells-exacerbation of lesions associated with high levels of IL-4 which inhibits activation of macrophages by TNF; blocked production of cytokines.
e. Treatment–pentavalent antimonials including Pentostam and Glucantime. Pentamidine and amphotericin B are second line of defense because these drugs are rather toxic. Strains are becoming resistant to pentavalent antimonials.
f. Prevention and control:
i. Prophylaxis - no available preventative drugs
(a) Minimize contact with sand flies, wear protective clothing, destruction of mammalian reservoirs such as dogs and rodents.
(b) Immunity by previous exposure with cutaneous leishmaniasis.
ii. Relevance to clinical medicine in US- leishmaniasis and Chagas disease can be transmitted by blood transfusions. “Desert Storm” personnel were prohibited from donating blood due to the appearance of leishmaniasis in troops.
Protozoan organisms that live inside human cells and infect a variety of tissues- Leishmania species (Visceral, cutaneous and mucocutaneous leishmaniasis), Trypanosoma cruzi (Chagas Disease) and Toxoplasma gondii (toxoplasmosis)
American trypanosomiasis
American trypanosomiasis-
a. Trypanosoma cruzi- flagellated parasitic protozoa that lose their flagella and live inside many human cell types as intracellular parasites.
b. Chagas Disease or American trypanosomiasis. Infection via the bite of a reduviid bug or ‘kissing bug’.
c. Parasites have several forms, morphologically and biochemically distinguishable:
trypomastigote - found in man and animals epimastigote - found in insect vector, is infectious
promastigote - found in insect vector and easiest to culture
amastigote - intracellular form found in man. Has no flagella. All the Leishmanias and the American trypanosomes (T. cruzi) have this form.
Protozoan organisms that live inside human cells and infect a variety of tissues- Leishmania species (Visceral, cutaneous and mucocutaneous leishmaniasis), Trypanosoma cruzi (Chagas Disease) and Toxoplasma gondii (toxoplasmosis)
South American trypanosomes
South American trypanosomes: A human is infected by the bite of the kissing bug, or Reduviid bug, which lives in the thatched roofs of huts in South and Central America. These bugs bite and defecate near the mouth and the parasites, deposited in the feces, are scratched into the wound by the soon to-be infected person. The trypomastigotes infect the cells of many organs and develop into unflagellated, intracellular amastigotes. Trypomastigotes, circulating in the blood, are taken up by a Reduviid bug when it feeds.
There is no antigenic variation in T. cruz.
e. Pathogenesis: South American trypanosomes- initial infection is acute, especially in the young. Many organs are affected. In the adult, the disease initially is less severe, but leads to chronic myocarditis and megacolon. Chagas disease is characterized by cardiomegaly, enlarged esophagus and/ or colon. Symptoms due to invasion of smooth muscle cells by parasites. Autoimmunity may play a role as well.
Protozoan organisms that live inside human cells and infect a variety of tissues- Leishmania species (Visceral, cutaneous and mucocutaneous leishmaniasis), Trypanosoma cruzi (Chagas Disease) and Toxoplasma gondii (toxoplasmosis)
South American trypanosomes
f. Diagnosis: South American trypanosomes- Blood smear or biopsy- see both trypomastigote and amastigote forms.
Xenodiagnosis- feed bug on infected individual and look for parasites in insect feces.
PCR methods are being developed.
g. Treatment: Flagyl in acute phase; gamma interferon stimulates macrophages to kill amastigotes.
h. Prevention and control-(for both types of trypanosomes) insect vector control, identification of biochemical targets for chemotherapy. Animal reservoirs- some animals are asymptomatical but serve as reservoirs. The animal reservoir is different for American trypanosomiasis is the armadillo.
Protozoan organisms that live inside human cells and infect a variety of tissues- Leishmania species (Visceral, cutaneous and mucocutaneous leishmaniasis), Trypanosoma cruzi (Chagas Disease) and Toxoplasma gondii (toxoplasmosis)
Toxoplasma gondii
Toxoplasma gondii. Cause of brain, liver and congenital eye /neurological infections.
a. This is a very common infection in US and in Europe (10-80% of population). It is a serious disease in newborns who have acquired infection in utero and in immunocompromised patients.
b. Causative agent is Toxoplasma gondii, which is an intracellular parasite. Parasites live in reticuloendothelial and parenchymal cells.
c. Morphology and life cycle: T. gondii lives in man and animals. The definitive host is the cat. Infected cats pass oocysts in feces of cattle, pig, and sheep. Cats become infected when they consume mice that received parasites from these animals. Human acquires infection when they eat uncooked infected meat or when they accidentally ingest oocysts from cat feces (i.e., when cleaning out litter boxes).
Parasites initially infect macrophages, replicating as intracellular tachyzoites. These infected cells rupture and parasites infect many types of host cells. Growth is limited by cellular immunity (T cell). Eventually, tissue cysts form, many tissue cysts reside in the brain. These remain dormant as long as host cellular defenses remain active.
Immunosuppression reactivates disease with possible fatal dissemination.
Protozoan organisms that live inside human cells and infect a variety of tissues- Leishmania species (Visceral, cutaneous and mucocutaneous leishmaniasis), Trypanosoma cruzi (Chagas Disease) and Toxoplasma gondii (toxoplasmosis)
Toxoplasma gondii
d. In adults, infections are asymptomatic, or mild mononucleosis - like symptoms. Serious disease is caused by congenital infection- major CNS and respiratory problems.
e. Congenital infection:- when mother receives a primary infection when pregnant, she will transmit disease to fetus with grave consequences: mental retardation, etc. Infection of the CNS is responsible for the pathology of the disease. Congenital infection may show up many years after birth.
Protozoan organisms that live inside human cells and infect a variety of tissues- Leishmania species (Visceral, cutaneous and mucocutaneous leishmaniasis), Trypanosoma cruzi (Chagas Disease) and Toxoplasma gondii (toxoplasmosis)
Toxoplasma gondii
f. Diagnosis: Lymph node biopsy. Initially perform antibody titers. Rise in antibody titer over time– variable titers at any one time indicate past exposure or early disease, medium titers indicate recent exposure or present disease, high titers indicate active disease.
g. Therapy: Combination of pyrimethamine and sulfadiazine for newborns and immunocompromised patients. During pregnancy spiramycin is used.
h. Prevention and control:
i. Avoid uncooked or rare meat
ii. For pregnant women, do not change cat litter boxes, avoid rare/uncooked meat
iii. Indoor cats - feed can or dry food to eliminate problem.
DIAGNOSTIC METHODS FOR PARASITIC INFECTIONS
Details of Diagnostic methods:
Blood smear Dx organisms (4)
Details of Diagnostic methods:
A. Blood smear
- Malaria
- Trypanosomes
- Babesia
- Lymph Filarial worms
DIAGNOSTIC METHODS FOR PARASITIC INFECTIONS
Stool samples Dx organisms (9)
Stool samples
- Cysts of amoeba
- Giardia trophozoites or cysts
- Cryptosporidia - cysts
- Tapeworm eggs and proglottids that crawl out of anus
- Ascaris eggs
- Fluke eggs - Schistosoma eggs
- Anal area-pinworm
- Whip worm- eggs
- Hookworm eggs
DIAGNOSTIC METHODS FOR PARASITIC INFECTIONS
Tissue biopsy Dx for organisms (8)
Tissue biopsy
- Trichinella in muscle
- Hydatic cyst- dog tapeworm-Echinococcus
- Strongyloides - worms
- Adult Acaris in liver
- Free living amoeba- Naegleria
- Amebic liver abscess
- Meagcolon, cardiomyopathies- Trypanosoma cruzi - amastigotes
- Visceral Leishmaniasis – amastigoes
DIAGNOSTIC METHODS FOR PARASITIC INFECTIONS
Skin observation and biopsy Dx for organisms (2)
Immunological techniques Dx for organisms (2)
Skin observation and biopsy
- Cutanous leishmaniasis
- Dracuncules- fire worm
E. Immunological techniques
- Toxoplasma- antibody test for IgM and IgG antibodies
- Cryptosporidium- ELISA antibody test
PARASITIC INFECTIONS
Modes of infection
Direct (3)
Modes of infection
A. Direct
- Hookworm
- Schistosomes
- Strongyloides
PARASITIC INFECTIONS
Modes of infection
Arthropod borne (4)
Arthropod-borne
- Plasmodium
- Trypanosomes
- Onchocherca
- Wucheria
PARASITIC INFECTIONS
Modes of infection
Fecal-oral (2)
Fecal –oral
- Direct-feces to mouth: Amoeba Pinworm Hookworm
- Water borne- Schistosomes
PARASITIC INFECTIONS
Modes of infection
Ingestion of food (4)
Ingestion from food
- Tapeworms
- Anisekiasis
- Toxoplasma
- Trichonella
VI. Summary of prevention: A. Interrupt route of influx B. Vaccination C. Insect control D. Prophylactic use of drugs
VII. How parasites avoid host defenses
A. Entry into cell via a membrane bound vacuole.
- Lysosome fails to fuse with vacuole.
- Cell (Tox. gondii) escapes.
B. Parasites in appropriate stage of development may escape into cytoplasm of host cell and divide (trypomastigote stage of Tryp. cruz).
C. Surface protease helps cells resist digestion in phagosome (Leishmania spp.)
D. Antigenic variation.
- Variable surface glycoproteins in African trypanosomes.
- Acquisition of host surface antigens in schistosomes.
E. Encystment (Entamoeba, Trichinella).
F. Development of an extracellular cuticle (nematodes).
G. Interference with host immune response.
- Release of huge quantities of soluble antigen which diverts antibody response (P.falciparum).
- Suppression of delayed hypersensitivity.
a. Alteration of specific CD4 subsets
b. Altering balance of TH1, TH2 cells - Interference with macrophage function.
a. Deficient antigen presentation (schistosomes)
b. Overload with glycoconjugates, polysaccharides.
H. Disruption of lymphoid cells (Trichinella spiralis releases soluble lymphocytotoxic factor).
Informational
Most mycotic diseases are associated with (3).
Most diseases are associated with either poor hygiene, immunosuppression (either disease-induced or drug-induced) or diabetes mellitus.
Parasitic Diseases
- Group of unicellular (protozoa) or multicellular (metazoa or helminths) complex organisms that can infect normal and immunocompromised hosts via fecal-oral contamination, arthropod bites or direct invasion by larval forms.
- Pathology varies from minimal reactions, to chronic, possibly granulomatous, inflammation, usually with a significant eosinophilic component and fibrosis (scarring).
Eosinophilic component is classical with what type of response. What type of parasites are usually chronic and pathological in state?
Eosinophilic component is classical with hypersensitivity response. The invasive parasites are usually chronic and pathological in state.
Protozoa
Consider the different outcomes in developing countries vs USA.
List the protozoa:
Lumenal (3)
Bloodstream (2)
Tissue (5)
- Common cause of disease/death in developing countries and are widely present in U.S. but usually not fatal.
- Reproductive life cycles are more complex than bacteria or fungi.
- Lumenal: Giardia, Cryptosporidia, Entameba
- Bloodstream: Plasmodium sp, Trypanosoma sp.
- Tissue: E. histolytica, T. cruzi, Leishmania, Toxoplasma, Trichomonas
Note: Entameba has the ability to be in the lumen and be invasive to be in the tissue.
Giardia
Pathogenesis
Physical microscopy feature
causes disease by interfering with absorption
- diarrhea
- malabsorption
Surface parasite of small intestines: Two eyes looking at you
Cryptosporidia sp.
Special population consideration and symptoms
Physical microscopy feature
Pathogenesis
Immunocompromised patients presenting with diarrhea
- Diarrhea
- Malabsorption
Surface parasite: Dot like smuts on the surface of villi
- Parasite displace the microvilli –> malabsorption, diarrhea
Cecum: Amebiasis
Causative agent
Pathogenesis (3)
Entemabe histolytic
- Iliocecal bowel ulcer
- erythrophagocytosis - the protozoan ingests RBCs
- liver abscess “amebic abscess” - Organisms gain access from GI into vasculature –> get into vein –> portal vein –> liver disease
Note: Less common but after liver abscess the protozoan may travel to the brain
Trypanosome
Vector
Disease/Pathogenesis
Microscopic feature
- Tsetse fly (Glossina) “Arthropod-borne”
- Trypanosomiasis- Ultimately disease is due to the infiltration of Trypanosomes into brain tissue.
Sleeping disease is characterized by macrophage engulfed trypanosomes in the brain and inflammatory response.
- Trypanosomes in blood and not inside RBCs. Extracellular organism that will eventually invade tissue.
Trypanosomiasis
Chagas Disease:
Causative Agent
Pathogenesis
Discuss other possible routes of homage
Trypanosome cruz
Organism is intracelullar and does not cause much of an inflammatory response.
Likes to get into striated muscle - e.g. the HEART; patients will develop heart disease.
Also likes to get into the esophagus.
Leishmaniasis
Epidemiology
2 forms
Microscopic feature
Leishmaniasis, also spelled leishmaniosis, is a disease caused by protozoan parasites of the genus Leishmania and spread by the bite of certain types of sandflies.
Prevalent in the Middle East - Esp. Iran and Iraq
Cutaneous and Visceral (systemic)
Found in macrophages
Toxoplasmosis
Epidemiology
Special population consideration and reason (2)
Reservoir
Toxoplasmosis is a parasitic disease caused by Toxoplasma gondii.
Prevalent in immunocompromised patients e.g. AIDS and women cleaning cat litter box.
Toxoplasma gondii can cross placenta
Reservoir : domesticated animals; “Filet American” in Belgium
TORCH - acronym for congenital infections
TO- Toxoplasmosis
Give generalities of these worms regarding pathogenesis. Give specifics of Ascaris
Worms (Metazoa)
•Nematodes (Roundworms):
–Ascaris, hookworms, Trichuris
•Cestodes (Tapeworms):
–Taenia saginatum/solium, Echinococcus sp.
•Trematodes (Flukes):
–Schistosoma sp., Paragonimus, Clonorchis,
Opisthorchis
Some of these only cause disease because of malabsorption.
Increased severity may increase upon consumption of larva. Larva penetrates small bowel wall gets into circulation and returns into small bowel into its mature form.
Ascaris in particular the larva penetrate the small bowel and makes its ways into the lung. This causes an inflammatory response, we cough and some of the larva we swallow back up where the larva mature into adult and remain in GI not being pathological.
Toxoplasma gondii pneumonia
Describe and give microscopic characteristics
Necrotizing pneumonia with exudate within alveola spaces and inflammatory cells. In the alveolar spaces cyst are seen with Taxozoates
How is Ascaris Dx?
The bumpy shaped ova in feces.
What is the normal egg-larva cycle. What is different with S.I.: Strongyloides?
Normally :
Eggs excreted into feces and becomes larva once picked up by something else
SI is different because:
Ova changes into larva state before excreted. The larva has potential to penetrate tissue before excretion.
Larva can be seen in the small bowel mucosal wall.
Discuss Trichinella spirals
Clinical Dx.
Larva form circulates in the tissues encysts in striated muscle causing aocalized inflammatory response with increased eosinophils.
Dx: increased eosinophil count.
Trichinella spiralis is a nematode parasite, occurring in rodents, pigs, horses, bears, and humans, and is responsible for the disease trichinosis. It is sometimes referred to as the “pork worm” due to it being found commonly in undercooked pork products.
Blood: Filiariasis (Wuchereria bancrofti)
Predilection of winding up in lymphatics and clogs —-> chronic edema.
Long standing edema —> lymphaedema —> skin thickens (hyperkeratonic)
Elephantiasis (Wuchereria)
Skin: Cysticercus cyst (Tapeworm disease)
Majorly found in Middle East.
Persists as larval stage and the liver is greatly affected. Large cystic lesions may be mistaken for a cystic tumor
Absolute alcohol will first be injected into cyst
Wuchereria onchocerca
Onchocerciasis: Major cause of blindness in developing countries “River blindness” Organism can be found circulating the eye.
Tx: Ivermectin
Skin: Cysticercus cyst (Tapeworm disease)
Can also cyst in the brain particularly pork and beef tape warms
Dwarf tape worm
Cystic echinococcosis (CE) is the larval cystic stage (called echinococcal cysts) of a small taeniid-type tapeworm (Echinococcus granulosus) that may cause illness in intermediate hosts, generally herbivorous animals and people who are infected accidentally.
By eating contaminated animals. Humans become the accidental second part of the life cycle; larval stage (cyst).
Liver is greatly affected by these large space occupying cysts. Can be confused for a cystic tumor. Hydatid cyst in liver.
Tx: If Dx prior to operation as echinococcal cysts provide absolute alcohol treatment. It kills off the organism and now can be surgically removed.
If rupture a cyst then the daughter cyst will spread out and enter into peritoneal surface.
Schistosomiasis
schistosomiasis mansoni
Generally a middle east and Asian disease but has a prevalence in Puerto Rico.
Schistosomiasis is found in fresh water found in snails in larval form. Larval form Cercaria can penetrate intact skin. Depending on type of Schistosomiasis determine where they migrate.
Schistosoma mansoni (ME -Egypt and PR) - Adults live in inferior mesentric venous plexus
Schistosoma japonicum (Asia)- larva in liver migrate down portal vein and the adults develop in inferior or superior mesenteric vein
Left side of bowel (Inf) or rest of colon and most of small bowel (Sup). Adult found in small bowel or right side of colon.
Schistosoma haematobium- larva get into liver but push into the hepatic venous side and end up in circulation perivesical plexus (veins surrounding bladder)
Schistosoma mansoni
larva live in inferior mesenteric vein –> portal vein —> liver —> focal eosinophils surrounding ovum
Leads into portal fibrosis —> edema and ascites
Granulomatous reaction to present ovum with eosinophilic presence.
Granulomas heal by fibrosis. Shriveled ovum with giant nucleated cell.
Liver: Schistosome fibrosis
Portal hypertension with Ascites
Schistosoma haematobium
Schistosoma haematobium ova (calcified)
Bladder: S. haematobium-induced squamous metaplasia
Transmitted through the wall of the bladder and eventually pass through the urine after the chronic cystitis nature.
Chronic disease we get metaplasia, i.e. the change of one type of tissue type to another
Chronic cystitis —> leads change of transitional epithelium to squamous epithelium (metaplasia) –> leading to squamous cell carcinoma of bladder
Metaplasia predisposes person to cancer.
“Oncogenic” Parasites
•Schistosoma haematobium: Squamous cell
carcinoma of urinary bladder
Liver flukes
• Clonorchis sinensis: Adenocarcinoma of biliary ductal system (cholangiocarcinoma)
Superficial Mycoses
•Generally don’t cause lesions!
- Don’t cause chronic inflammatory disease
-Live only in the keratin liver. Non invasive.
Cutaneous Mycoses
- Mainly live in skin.
- Generally do not cause systemic disease.
- Scaly lesions
- In epidermis, fungi release factors that are chemotactic for PMNs; One exception to the chronic inflammation rule
- In dermis, fungi cause a chronic inflammation
Tinea pedis
- Spongiosis, neutrophils, septate hyphae.
Edema separating the cell layers. Neutrophils within the epidermis
Subcutaneous Mycoses
Inoculated into the dermis and subcutis - get in through pricks in the skin and may enter the lymphatics (e.g. Sporotrichosis)
•Cause abscesses, suppurative granulomas, reactive thickening of the epidermis and ulcers, lymphangitis
- Invasive, get into subcutaneuos tissue, cause chronic inflammation and leads to secondary change to skin overlying
Sporotrichosis- Can tract the lymphatics because of the overlying inflammation
Systemic Mycoses “Geographic Fungi”
•Disseminate in the body but can also cause skin lesions
A) True pathogenic fungi:
–Associated with specific geographic locations
–Form necrotizing granulomas—mimic Tb
–Major ones are Histoplasmosis, N.A. Blastomycosis, S.A. Blastomycosis, Coccidiomycosis.
True- intrinsically pathologically causing disease in anyone. Immuno- competent/compromised.
Histoplasmosis
Histoplasmosis: Caseating granuloma + Silver stain
Necrotizing caseating granuloma in lung cannot differentiate from TB
Bat dropping spore inhalation may be a cause.
Systemic Mycoses (2)
B) Opportunistic Fungi : We are more concerned about these in this part of the country
- “only” cause disease in immunocompromised/diabetic individuals
- Candida sp.: most common. Unique in that it usually causes abscesses, not granulomas
- Aspergillus sp.: may cause hypersensitivity (without entering the body) or grow in pulmonary cavities (“fungus ball”) or pneumonia and grow into blood vessels infarction (as does Mucor); This leads into thrombosis –> MI
Note: These are very common normally causing issue for immunocompromised or DM patients.
Note: Aspergillus sp found on bread mold
Note: Mucor is an organisms seen predominately in DM patients.
Aspergillus and Mucor both cause pneumonia, gets into blood vessels –> MI (same thing with blood vessel can occur in other areas of body e.g. body and cause an infarction
Aspergillus sp.
Fungus ball
Mucor sp. in cerebral blood vessel
Systemic Mycoses (3)
- B) Opportunistic Fungi:
- Cryptococcus neoformans: both a true pathogen and an opportunistic yeast, forms granulomas or grows in sub-arachnoid space meningitis
- Pneumocystis jiroveci: mainly in immuno-suppressed patientsintra-alveolar eosinophilic exudate + interstitial chronic pneumonia (requires special stains to be seen)
Note: Cryptococcus neoformans found in pigeon droppings.
Note: Pneumocystis jiroveci- became one of the major infections diseases for AIDS patients
Prophylaxis: vactrum for AIDS/HIV/Cancer patients to prevent Pneumocystis
Cryptococcal Meningitis
mucicarnin stains. Stain mucin (mucopolysaccharide)
Has a mucoid capsule
Pneumocystis pneumonia (eosinophilic exudate)
Pneumocystis is not routinely visualized with H&E
Pneumocystis juroveci (GMS stain); Silver stain. Reclassified as fungal because of this staining. Before was considered parasitic
Stains
Two types
•Silver stain aka GMS (Grocott’s methenamine silver stain) or Grocott stain
•PAS stain (Periodic acid–Schiff stain)
(Unlike most bacteria, most fungi can usually be seen on H & E stain but special stains make them appear more prominent).
Effector Mechanisms
- Innate immunity to parasites: Macrophages participate in resistance toparasitic infections in a number of ways (6)
a. Phagocytosis (protozoa)
b. Secretion of cytotoxic substances (Helminths)
c. Produce cytokines that regulate inflammation e.g. IL- 1, TNF,
d. NO - involved in kill of Leishmania
e. Granuloma formation – wall-off parasites
f. Presentation of antigen to T cells.
However, many parasites are effective in resisting these mechanisms and persist in the host, sometimes replicating within macrophages.
Adaptive immunity to parasites – a wide variety of responses exist, which is not surprising giving the diversity of parasitic organisms.
Discuss T cells, antibody, and determinant of varied immune strategies.
a. T cells: T helper, cytotoxic, cytokine production (Th1 vs. Th2). Th1 cells deal better with intracellular parasites by activating the macrophages and parenchymal cells; Th2 deal with extracellular organisms.
b. Antibody: Eosinophils and high levels of IgE are associated with parasitic worms. Other antibody classes are associated with opsonization, complement lysis, blocking of invasion, etc.
c. Effective immune strategies can vary:
- Different stages of the parasite life cycle. For example, in malaria infection, at the liver stage, cytotoxic T cells can contribute to parasite control, but at the bloodstage, since RBC do not express MHC Class I, other mechanisms are more important (antibody, free radicals, phagocytosis).
- VECTOR also effects Immune response.
-Host Immune status: –Immunocompetence –Age –Nutrition –Coinfection
Th1 vs. Th2 immunity to parasites: Parasites have taught us a lot about therelative roles of Th1 and Th2 cytokines in disease resistance. Th1 and Th2cytokines can be mutually antagonistic, so balance of these cytokines will decide the outcome of infection.
Discuss Th2 IL involved during a response and to what specifically.
MOA of the product produced by IL4 and IL5. The product functions most efficiently when?
Discuss the role of smooth muscle contraction upon the eradication of parasites.
Th2 responses are particularly important in helminthic infections.
IL-3, IL-4, IL-5 production by activated T cells leads to increased eosinophil killing of schistosome larvae (Schistosomes “helminths”.
Eosinophils kill these parasitic worms by oxygen dependent and independent means. They can degranulate in antigen specific or non-specific manner. They function most efficiently in an antigen-dependent manner by binding the Fc portions of IgG or IgE antibody to their surfaces, while the Fab domains bind to the worm.
This results in the release of major basic protein, which is toxic to the worm. This is a form of ADCC. The eosinophils work together with the mast cells, and their killing is enhanced by mast cell products that are released following IgE-dependent degranulation.
Smooth muscle contraction, for example, helps expel the parasites from the gut. Th2 cytokines are important for these responses: IL-4 results in class switching to IgE production and IL-5 is a growth and activation factor for eosinophils. It should be noted that the protective response is mixed, with some contribution of Th1 responses as well.
Note: ADCC = Antibody‐dependent Cellular Cytotoxicity
Th1 vs. Th2 immunity to parasites: Parasites have taught us a lot about therelative roles of Th1 and Th2 cytokines in disease resistance. Th1 and Th2cytokines can be mutually antagonistic, so balance of these cytokines will decide the outcome of infection.
Discuss Th1 response and its importance to fighting parasites (specifically which ones).
What occurs if Th2 predominates during an infection of Leishmania?
Discuss the interplay of two ILs of Th1 response.
Th1 cytokines are important in resistance to protozoan parasites.
IFN-required for macrophage destruction of leishmania and Toxoplasma. Th2 cytokines predominate (IL-4, IL-10), then the macrophages are unable to eliminate the parasite.
Other Th1-inducing cytokines play a role in this resistance: IL-12 produced by macrophages will up-regulate the IFN-production by the Th1 and NK cells, but IL-10 is later expressed to prevent immunopathology.
Escape Mechanisms of Parasites (6)
Give an example of immunopathology.
- Site sequestration
- Complement resistance
- Avoidance of intra-phagocytic digestion - protozoa
- Antigenic variation - Trypanosomes
- Avoidance of recognition: schistosomes cloak themselves with hostmolecules.
- Suppression of host response - very common
- Immunopathology: over-zealous immune response can have damaging consequences for the host.
Discuss the role of transition of Th1 or Th2
Th1: Dendritic cells will be induced by small parasites e.g. protozoans to release IL-12. The IL-12 will induce NK to secrete INF-gamma. IL-12 and INF-gamma activate naive CD4 T cells to commit to differentiate into Th1. Th1 cells secrete INF-gamma, TNF, and IL-2.
Th2: Pathogens such as worms (helminths) will induce NK1.1+ T cells to secrete IL-4. Naive CD4 T cells are activated in the presence of IL-4 and commit to differentiate into Th2. Th2 cells secrete IL-4, IL-5, IL-13.
Th1 and Th2 can serve as antagonists.
List the cytokines produced by Th1, Th2, and macrophages.
Th1 produces IL-2, TNF, IFN-gamma.
IL-2 is positively feedback to Th1 to continue induction. TNF and IFN-gamma cause increased induction to express IL-12 and thus loop back to Th1.
IL-2, TNG, IFN-gamma serve to activate macrophage.
Th-2 produces IL-4 which antagonizes (inhibits) the effect of IFN-gamma on the macrophage and thus we get no macrophage activation.
Immuneregulation of Th1 by IL-10
Discuss Chronic controlled infection, Unchecked lethal infection, and controlled infection/uncontrolled inflammation.
Chronic controlled infection:
Young Th1 produces IL-2. As positive proliferation feedback occurs with IL-2 the Th1 becomes very active.
Th1 then starts to produce IL-10 and along with IFN-gamma, the two antagonize their effects. IFN-gamma on the macrophage increased the NO-mediated parasite killing. IL-10 inhibits the macrophage and its production of IL-12, which serves as positive proliferation feedback for Th1.
Unchecked lethal infection:
Necrotizing disease without IFN-gamma. The parasite proliferates. Without the activation of macrophage there is also no production of IL-12.
Controlled infection/uncontrolled inflammation:
Parasite cleared but IFN-gamma and IL-12 will continue to stimulate Th1 to make IFN-gamma. Overexpression of IFN-gamma, IL-12, and production of TNF will cause multi-organ damage due to Hyperinflammation.
Quicker self destruction than the lack of IFN-gamma (persistance of parasite)
Schistosomes
Discuss and they induce what chemokines?
Describe the immune response against the larva and any other cell types or signals involved.
- Parasitic worms
- Induce IL-4 (class switch to IgE), IL-5 (promotes generation and activation of eosinophils)
- Favors Th2 response, IgE expression
- IgE binds to high affinity Fc-EpsilonRI receptors on eosinophils
- ADCC against the Schistosome larva; release of major basic protein; mostly by IgE, but also IgA
- Other allergic mediators involved in gut hyperactivity
- CTL, macrophages also involved
Mast-cell activation and granule release
Discuss the disease associated symptoms of GI, airway, and blood vessels.
GI - increased fluid secretion, increased peristalsis –> expulsion of GI tract contents (diarrhea, vomiting)
Airway - decreased diameter, increased mucus secretion –> expulsion of airway contents (phlegm, coughing)
Blood vessels - increased blood flow, increased permeability –>Edema, inflammation, increased lymph flowing carriage of antigen to lymph nodes.
Note: In type I hypersensitivity, anaphylaxis
Host Resistance to Malaria Depends on Pathogen Stage
Map out the invasion of Sporozoites of Plasmodium falciparum via mosquito vector into blood vessel during pre-erythrocyte stage, erythrocyte stage, and sexual stage.
Sporozoites enter the capillaries an Abs are produced against it. The sporozoites enter the liver. They invade a hepatocyte, harbor a vacuole and get released as merozoite into the blood stream. The merozoite now enter RBCs or reticulocytes and undergo asexual reproduction. Then the RBCs is burst open–> hemolytic anemia –> and now their is the development of gametocytes.
Note: with the uptake of Ab by the mosquito prevention of the maturation of gametocytes into pathogen is possible thus reducing the incidence of population disease.
Note: their is also host defense with the involvement of CTL, free radicals, Abs, and cytokines.
Cytotoxic T cells Contribute to Liver-stage Immunity to Malaria
Map out the invasion of Sporozoites of Plasmodium falciparum via mosquito vector into the lymphatics and to the liver.
Sporozoites enter the lymph vessel and make their way into the lymph node. In the lymph node the dendritic cell picks up the Sporozoites and presents it a naive T cell via MHC complex.
In the liver the activated T cells both CTL and Th cells will have their role in eradicating hepatocyte infected cells and prime neighboring hepatocytes not yet infected.
CTL release perforin which poke holes in the cell. Granzymes are the excutioner; does the killing.
In a Th1 response IFN-gamma will activate JAK-STAT. Turns on the genes to serve to kill pathogen.
The IFN-gamma will spill over to the other cells and prime them even though they have not been infected yet; making them antimicrobial.
At the Erythrocyte Stage, Other Immune Mechanisms Including Ab and Innate Effectors Predominate for immunity against infected erythrocytes.
Discuss the immunity of an infected RBC within the liver.
A hepatic stage immune response is unrelated to immune response in the blood stage.
The antigens expressed are different for both in the case of antigens expressed from an infected RBC and an infected hepatocyte.
Cell mediated Response: From an infected RBC a dendritic cell primes a Naive T cell to become a Th1 cell. In the sinus of the liver the Th1 cell expressed INF-gamme to activated a macrophage in the red pulp of the liver.
With an activated macrophage can now kill the infected RBCs.
Later the response switches over to a more Ab dominated immune response.
Discuss how Schistosomiasis can lead to a granulomatous response.
Cercaria can penetrate intact skin.
Adult worm have very thick follicular tissue and able to resist immune response.
The adult worm can live for decades in the body. Female worm will lay hundreds of eggs/day and excreted in feces.
Some of the eggs will be swept up into the portal vein and cause a granulomatous response.
Chronic Infection
Discuss the time lapse of Cercariae, Schistosome, adult worm, and eggs.
Early Th1 cell but with the production of eggs there is a switch to Th2 cell response. Eggs are the cause of this switch. With the persistence of the worm we go into a Regulatory T cell phase.
Immunomodulatory or immunosuppressant cytokines IL-10 and TGF-beta.
Explain the Hygiene Hypothesis
Sudden loss of an co-evolved immunomodulating internal environment due to eradication of worm infections in populations leading to increased incidence in autoimmunity and allergy.
Our immune system was evolved under the conditions of these now non influential pathogens. Regulatory T cell helps in dampening the long term effects of Th1/Th17 and Th2 responses. Without the exposure to these pathogens we may be lacking in the T regulatory response and achieving more organ specific autoimmune diseases or allergies due to over expression of Th1/Th17 and Th2, respectively.
Viruses are the smallest infectious agents. They are found in every kingdom (bacteria, plants and animal)
As pathogens, viruses are distinct from bacteria in that they have no metabolism of their own, and are complete obligate parasites at the molecular level. Thus, much effort in clinical virology has focused on understanding how viruses utilize host functions to support their replication and dissemination.
23 families of clinically relevant human viruses.
Informational
Structure of Human Viruses
Describe structure (3).
A. All contain a protein shell (capsid) which protects a nucleic acid genome
- Protein Shell - Protects and packages the viral genome
Can be cubic, helical or complex - Nucleic Acid – Contains all genetic information for the virus
B. Some viruses may be enveloped by a lipid membrane derived from the host cell
Classification of Human Viruses
How are viruses classified (3)
List all the 23 viruses that are clinically relevant and provide their appropriate classification
A. Determined by International Committee on Taxonomy of Viruses
B. Based on morphology, genome properties, genomic organization (segmented vs non-segmented), antigens and biological issues
C. Viruses are organized into orders, families, subfamilies, genera and species
- Will discuss 23 families in this course
- DNA viruses: Parvoviridae, Adenoviridae, Herpesviridae, Poxviridae, Polyomaviridae, Papillomaviridae, Hepadnaviridae
- RNA viruses
a. Single Stranded
i. Positive sense:Picornaviridae, Flaviviridae, Togaviridae, Astroviridae, Caliciviridae, Coronaviridae, Hepeviridae, Retroviridae
ii. Negative sense:
(a) Non-segmented: Paramyxoviridae, Rhabdoviridae, Filoviridae, Bornaviridae
(b) Segmented: Orthomyxoviridae
iii. Ambisense: Segmented: Bunyaviridae, Arenaviridae
b. Double Stranded: Reoviridae
Virus Cultivation and Detection
Viruses can be cultured using (3)
Viral detection and quantitation (2)
Viruses can also be detected and quantitated using a variety of physical methods (5)
A. Viruses can be cultured using:
- Animal models: test therapies and vaccines
- Embryonated eggs: High titers, used for vaccine production
- Cell culture: extensively used by virologists - economical and accessible
B. Viral detection and quantitation
- Cytopathic effects: Rounding, fusion, inclusion bodies, lysis etc
- Lysis is the basis of the Plaque Assay which is an effective biological method for detecting and quantitating several viruses
C. Viruses can also be detected and quantitated using a variety of physical methods
- Particle count in EM
- Hemagglutination assay – virus must express hemagluttinin
- ELISAs
- Immunofluorescence
- Molecular Diagnostics
Life Cycle of Viruses
Discuss the Early events (3)
A. The ability to culture viruses in cells allows for detailed molecular analysis of life cycles
B. Early events – adsorption, penetration and uncoating – apply to all viruses
Life Cycle of Viruses
After the early events discuss the next steps for DNA viruses and RNA viruses.
a. DNA Viruses: Generally go to nucleus where they transcribe the genome to make viral proteins necessary for replication
b. RNA Viruses:
i. Positive Sense – Stay in cytoplasm where they directly translate the genome to make proteins necessary for replication. Replicate the genome using a negative sense replication intermediate.
ii. Negative Sense - Stay in cytoplasm – Must replicate before translation therefore must package the polymerase in the vision.
iii. Retroviruses: Two stage replication occurring in both cytoplasm and nucleus. Require reverse transcriptase to convert RNA genome into a DNA genome.
iv. Double Stranded RNA viruses: Replicate in the cytoplasm using a positive sense replication intermediate. Package their polymerase in the virion.
Life Cycle of Viruses
Gene Expression Strategies
Discuss the shift from early expression to late expression of genes in DNA viruses, Retroviruses, and RNA viruses.
Viruses must shift from early expression to late expression
a. DNA viruses: Selective promoter usage
b. Retroviruses: Splicing/polyproteins
c. RNA viruses: Many strategies
i. Positive Sense
(a) One polyprotein – post translational regulation through protease i.e. picornaviridae
(b) Several polyproteins – regulation through protease plus production of subgenomic mRNAs i.e. Togaviridae
(c) Polyproteins plus individual ORFs – regulation through protease and production of subgenomic mRNAs i.e. Coronaviridae
ii. Negative Sense: Single polymerase initiation site – regulation determined by the action of the polymerase – produces subgenomic mRNAs
iii. Segmented: Regulatory elements present in individual segments
Life Cycle of Viruses
Discuss the Late Events (2)
- Viral packaging – self assembly of capsids and insertion of nucleic acid
- Viral release – non-enveloped generally exit by lysis enveloped exit by budding
Viral Pathogenesis
Provide factors to host Susceptibility (5)
List the ways transmission may occur:
Human- Human
Animal-Human
A. Host Susceptibility
i. Genetics: Surprisingly few good examples in humans
ii. Age: Clear differences related to immune status, status of alimentary canal and respiratory muscles.
iii. Gender: Differences not well understood. Males generally more susceptible.
iv. Immunity: Vaccination, previous exposure, immunodeficiency
v. Nutrition: Not as obvious in developed countries but good examples in undeveloped countries (measles)
B. Transmission
i. Human-Human: Horizontal, vertical, germ-line, iatrogenic, nosocomial
ii. Animal-Human: Humans are not always a productive reservoir
VI. Viral Dissemination – Entry and spread
What is typically required for a successful infection?
List the 5 points of entry for viruses and provide some details to the mode of entry and infection.
A. Typically a successful infection requires large quantities of virus, accessible cells, and an ineffective defense system by the host.
B. There are five points of entry for viruses
- Skin – Depth of inoculation often determines spread
- Respiratory tract – Most common site of infection
- Alimentary tract – either by ingestion or sexual contact
- GU tract – transmission generally by sexual contact
- Conjunctiva – generally associated with localized infections
VI. Viral Dissemination – Entry and spread
Describe localized and disseminated infections
Describe shedding.
C. Infections can be either localized or disseminated
- Localized infections generally involve entry and exit through the same cell surface (apical).
a. Allows for the rapid dispersal of enteric viruses in feces - In disseminated infections viral exit is more typically through the basolateral surface.
a. Virus must cross the basement membrane so infections are often associated with localized inflammation.
b. Once through the membrane viruses can enter the lymphatic system, the circulatory system or neurons.
D. Shedding: Viruses generally exit using the same routes as entry: respiratory secretions, saliva, feces, blood, breast milk, skin lesions etc.
VII. Prevention and Treatment
What is the most effective method for preventing viral infections?
A. Vaccines are the most effective method for preventing viral infections.
- Have virtually eradicated over a dozen diseases in the US
- Three types of vaccine are currently in use
a. Attenuated live viruses (Measles)
b. Killed virus Vaccines (Polio, Rabies)
c. Subunit vaccines (Hepatitis B)
VII. Prevention and Treatment
Other than vaccines what two other methods are used for virus infections?
Detail their use and viral targets.
B. A number of antibodies have also been approved for the prevention and treatment of viral diseases in the US:
- Human immunoglobulins are used for pre- and post-exposure prophylaxis for Hepatitis A
- Rabies immunoglobulins can be used for post-exposure prophylaxis
C. There are currently over 85 antiviral drugs in use
1. Most drugs are for use against HIV, HBV, HCV, Influenza and Herpes
- Targets include
a. Viral proteases
b. Viral uncoating
c. Viral entry
d. Viral release
e. DNA synthesis
f. Cellular enzymes involved in protein synthesis (interferon)
Drugs •Metronidazole •Artemisinins •Quinine •Mefloquine •Chloroquine •Primaquine •Pentamidine •Lumefantrine •Sodium stibogluconate •Mebendazole •Albendazole •Ivermectin •Praziquantel
Informational list
METRONIDAZOLE
•Spectrum Drug of choice for: (6)
Route
- Trichomonas vaginalis - Administered to both sexes
- Entameba histolytica
- Giardia lamblia
- Bacteroides fragilis
- Clostridium spp.
- Other anaerobic bacteria
Route - Oral
Metronidazole Mechanism of Action
Type of agent
Microaerophilic organisms—ameba—use ferredoxin-like low redox potential electron transport proteins in order to convert pyruvate to acetyl-CoA
The nitro group of metronidazole can accept electrons from these proteins resulting in cytotoxic products which bind to DNA and proteins.
Metronidazole is CIDAL
Note: Microaerophilic organisms do not like lots of oxygen.
Metronidazole pharmacokinetics
Route, Distribution Half Life Metabolism Excretion
- Orally active
- Well distributed: CSF, breast milk and alveolar bone
- Half-life = 7.5 hours
- Alkyl chain oxidation and glucuronidation
- Parent (50%) and metabolites (50%) are excreted in urine
Metronidazole reactive products bind to what molecules and why?
In susceptible organisms protozoans or anaerobes the reactive products favor areas of electron density e.g. DNA and possibly DNA. The reactive products bind irreversibly to these areas.
Relative selectivity because the microbes have a perodoxin transport system to create these reactive products other than the amine product which is benign.
Humans lack the perodoxin system, but we do make the amine product which is benign.
Metronidazole Adverse Effects
Common (4)
Less frequent (10)
Avoid _____ (1)
Experimental evidence for what effects?
- Common: nausea, headache, dry mouth, metallic taste
- Less frequent (12%): vomiting, diarrhea, insomnia, weakness, dizziness, stomatitis, rash, urethral burning, vertigo, paraesthesias
- Disulfiram-like effects: No alcohol 24 hrs before or 48 hrs after last dose
- Mutagenicity and carcinogenicity: Experimental evidence for these effects—Ames test and rodent model Humans—20 years of use with no increase in congenital defects, low birth weight or still births
Metronidazole: Drug Interactions (4)
- Potentiation (Enhancement) of oral anticoagulants
- Phenytoin and phenobarbital increase rate of elimination
- Cimetidine decreases metabolism
- Increased risk of lithium toxicity (interferes with lithium excretion)
Antimalarial drugs.
Drugs effective against erythrocytic form (5)
Drugs effective against exoerythrocytic form (1)
Drugs effective against gametocyte form
- Artemisinin, Chloroquine, Quinine, Mefloquine, Pyrimethamine
- Primaquine
- Primaquine
Artemisnins: Pharmacokinetics & Mechanism of Action
Derived from _____ medicine
Three types:
Route
Metabolism
Enhancement of Rx efficacy
- Derived from Chinese medicine:
- Artemisinin: oral only
- Artemether: oral, rectal, IM
- Artesunate: oral, IM and IV (only one)
- All are endoperoxides that are non-enzymatically cleaved to dihydroartemisinin (oral only), a highly reactive substance that forms free radicals that rapidly kills blood schizonts of all 4 human malaria species
- Combination therapy to improve efficacy and prevent selection of resistant parasites FDA approved: Coartem® - artemether + lumefantrine
Note: Lumefantrine is normally given in combination
Artemisinins: adverse effects & therapeutic uses
Common (4)
Rarely (4)
When not to use it
Uses
- Common: nausea, vomiting, diarrhea, dizziness
- Rarely: neutropenia, anemia, hemolysis, liver enzyme elevations
- Do not use in first trimester of pregvancy; can be used in the last two trimesters
- Uses: Uncomplicated and complicated falciparum malaria. Standard of care for severe falciparum malaria (artesunate IV)
Note: administered for Chloroquine resistant malaria
CHLOROQUINE (AKA)
MOA
Effective against
Other uses (2)
- 4-Aminoquinoline
- Mechanism of antimalarial activity: Inhibits hemoglobin polymerase, plasmodial enzyme responsible for removing toxic heme break-down products
- Only effective vs blood trophozoites & schizonts in non-chloroquine resistant falciparum malaria
Other uses
•Treatment of extraintestinal amebiasis
•Anti-inflammatory: high doses relieve symptoms of rheumatoid arthritis and lupus erythmatosus
Chloroquine Pharmacokinetics
Route Bound primarily to \_\_\_\_ Vd; where does it accumulate Excretion Half life
- Orally active
- Protein binding about 55%
- Vd = 115 L/kg; accumulates in tissues by binding to nucleoproteins (200-700 times plasma concentration in liver, spleen, kidney; less concentrated in brain)
- Renal excretion: 70 % unchanged; N-dealkylated metabolites
- Half-life = 7 days; long half life thus give a loading dose
Note: as soon as it crosses the membrane it is bound.
Describe the effects of heme on Plasmodium and how Chloroquine aids in the killing of the parasite.
The parasite digests the RBCs to obtain essential amino acids. Heme is released in the process and proves to be toxic to the parasite.
The parasite polymerizes the heme —> HEMOZOIN
Chloroquine prevents polymerization to the hemozoin. The accumulation of heme results in the lysis of both the parasite and RBCs.
Chloroquine Adverse Effects
Mild and transient (4)
Prolonged use (1)
Rare (3)
Acute toxicity (2)
- Mild and transient GI discomfort, headache, dry skin, pruritus
- Prolonged use (1 year) at high doses Diplopia T wave changes
- Rare: loss of visual acuity; corneal opacities; “Bull’s eye” lesion (not reversible)
- Acute toxicity: cardiac arrhythmias, death
PRIMAQUINE (AKA)
Effective against what forms of plasmodia
•8-aminoquinoline
•Effects on plasmodia:
–Tissue schizonticidal
–Gametocytocidal
–Sporonticidal
- No effect on erythrocytic forms of malaria; component of “radical cure”. Given after the treatment of malaria (erythrocytic form) to prevent reoccurrence from the tissue schizonts.
- Mechanism is unknown
Primaquine Pharmacokinetics
Route Distribution Metabolism Excretion Half life
- Orally active
- Distributed into tissues but not bound as is chloroquine
- Completely metabolized
- Urinary excretion
- Half-life = 3–8 hours
Primaquine Adverse Effects (4)
- GI disturbances
- Methemoglobinemia
- Arrhythmias
- Hemolytic anemia in G-6-P DH deficient individuals (symptoms: darkened urine; flank pain; weakness & fatigue)
Relate hemolytic anemia to Primaquine
Individuals with G6P DH deficiency there is a decrease in NADPH and GSH making the RBC more sensitive to oxidative agents such as Primaquine.
Primaquine oxidizes GSH to GSSG. Less GSH is available to neutralize toxic compounds.
Many drugs may cause hemolytic anemia including chloroquine, sulfonamides, etc
Quinine: uses & adverse effects
Uses
Combination Tx
Cinchonism (6)
Adverse Effects (3)
- Treatment of serious disease as an alternative to artemisinin-based therapy. All 4 blood schizonts are susceptible
- Often combined with doxycycline to shorten therapy to 3 days. In children substitute with clindamycin
- Cinchonism: cluster of side effects including tinnitus, headache, nausea, dizziness, flushing, visual disturbances
Adverse effects
- Severe hypotension if infused too rapidly
- ECG abnormalities from high doses
- Increased levels of warfarin & digoxin
Mefloquine
Tx for \_\_\_? Recommended for where \_\_\_\_? Route Half life Dosing Adverse Effects (5) Avoid with what patients (3)
- Treatment of chloroquine-resistant falciparum malaria
- Recommended chemoprophylaxis in such areas
- Oral only; long half-life; once a week dosing for prophylaxis
- Nausea, vomiting, dizziness, sleep, behavioral changes
- Avoid in patients with epilepsy, psychological disturbances and arrhythmias
Lumefantrine
Effective against
Available preparation
Possible adverse effect
- Effective against all 4 erythrocytic forms of human malaria
- Only available combined with artemether (Coartem)
- May be embryotoxic
Match the Tx of malaria to clinical setting
- Chloroquine-sensitive P. falciparum & P. malaria infections
- P. vivax & P. ovale infections
- Uncomplicated infections with chloroquine-resistant P. falciparum
- Severe or complicated infections with P. falciparum
- Chloroquine
- Chloroquine
- Artemether + Lumefantrine (Coartem)
- Artesunate (IV) follow with either full course of doxycycline or clindamycin
–OR–
Quninidine
Prevention Therapies
•Chloroquine: 500 mg weekly in areas with sensitive P. falciparum
•Mefloquine: 250 mg weekly in areas with resistant P. falciparum
•Doxycycline: 100 mg daily in areas with multi-drug resistant P. falciparum
•Malarone: 1 tablet daily (250 mg atovaquone/100 mg proguanil) in areas with chloroquine resistant P. falciparum
•Primaquine: 26.3 mg daily for 14 days after travel for terminal prophylaxis of P. vivax and P. ovale infections
Informational
Treatment of leishmaniasis
Discuss the Rx MOA Administration VD Elimination Adverse Effects (5)
- Sodium stibogluconate—pentavalent antimony compound—interferes with glycosome, resulting in decrease in protozoal ATP and GTP
- Administered parenterally; Vd = 0.22 L/kg; biphasic elimination: a) 2 hours; b) 33-76 hours; accumulates
- Adverse effects: muscle & joint pain; fatigue; T-wave changes; transaminase elevations; shock/sudden death
PENTAMIDINE
Tx uses
MOA
- Therapeutic uses: Pneumocystis jiroveci pneumonia; leishmaniasis; African trypanosomiasis
- Mechanism: unknown
Pentamidine Pharmacokinetics
Administration
Distribution
Penetration
Excretion
•Parenteral administration only.
Inhalation for pneumocystis prophylaxis
- Rapidly distributed to liver, spleen & kidney
- Does not cross blood-brain barrier but does cross the placenta
- Excreted unchanged in urine
Pentamidine Adverse Effects
Adverse Effect (6)
- Pain at injection site
- Sympathoplegic (interfering with nervous system)—severe hypotension
- Release histamine from mast cells (also causes hypotension)
- Toxic to pancreatic islet cells: initially releases insulin causing hypoglycemia; later causes suppression of insulin release—diabetes
- Renal toxicity: hyperkalemia, hypocalcemia
- Rare: pancreatitis, toxic epidermal necrolysis thrombocytopenia
Antihelmintic Drugs: Overview Nematode infections (roundworms) Ascaris lumbricoides – roundworm Trichuris trichiura – whipworm Necator americanus & Ancylostoma duodenale – hookworm Enterobius vermicularis – pinworm Trichinella spiralis – trichinosis
Drug of choice: _______
Mebendazole
Antihelmintics: Overview
Rx
Drug of choice for: Strongyloides stercoralis – threadworm Onchocerca volvulus – river blindness
Rx:
Trematodes (flukes) and cestodes (tapeworms)
Rx:
Cysticercosis and hydatid disease
Ivermectin
Praziquantel
Albendazole
Benzimadazoles: mebendazole and albendazole
MOA
Selective toxicity
- Mechanism: bind to helmintic tubulin preventing microtubule formation. Results in block of glucose uptake and depletion of ATP. Organism is immobilized and eventually dies
- Selective toxicity: affinity of helmintic tubulin is two orders of magnitude greater than mammalian
Mebendazole
Route, absorption
Metabolism
Adverse Effects (5)
- Only 10% absorbed after oral administration; tablets must be thoroughly chewed prior to swallowing
- Rapidly metabolized and excreted in urine
- Adverse effects: GI including nausea, vomiting & pain; headache, dizziness
Albendazole Pharmacokinetics
Absorption
Active metabolite
Half-life
- Rapidly absorbed
- Active metabolite (sulfoxide)
- Half-life 8–9 hours
- Primarily renal excretion
Albendazole Adverse Effects
Adverse Effects (5) Type of response and effects upon death of organisms
- Low incidence (6%) of GI disturbance and CNS effects similar to mebendazole. Adverse effects: GI including nausea, vomiting & pain; headache, dizziness
- Inflammatory response following death of organisms in the CNS leads to headache, vomiting, hyperthermia, mental changes. Administer corticosteroids to reduce or prevent the inflammatory response
- Long-term therapy (3 months); hepatic enzyme elevations; rash, pruritus; alopecia; leukopenia
IVERMECTIN
Derived from _____
Activates ________ in invertebrates including nematodes and insects
Enhances _____ activity.
- Natural antihelmintic derived from soil actinomycete Streptomyces avermitilis
- Activates glutamate-gated Cl– channels found only in invertebrates including nematodes and insects
- Enhances GABA activated chloride channel activity also but pharmacological significance is not known
Ivermectin Pharmacokinetics
Route Vd Penetration Distribution Half-life Excretion
- Only given orally to humans
- Vd = 0.7 L/kg
- Does not penetrate into CNS
- Slow distribution into the eye
- Half-life - 28 hours
- Excreted in the feces
Ivermectin Adverse Effects (3)
•Most serious are Mazotti reaction— inflammatory response due to death of large numbers of microfilariae. In a small fraction (0.3%) can be life-threatening: high fever, hypotension and bronchospasm.
- Give corticosteroids to prevent or reduce intensity
- May cause corneal opacities; conjunctivitis, optic neuritis
- Avoid co-administration of benzodiazepines, barbiturates and valproic acid
PRAZIQUANTEL
DOC for (2) infestations MOA
- Drug of choice for most trematode and cestode infestations
- Target is a Ca++ channel of susceptible organisms. Enhances Ca++ influx which causes contraction followed by paralysis of the worm musculature. Vacuolization and disintegration of worm tegmen occurs and death ensues.
Praziquantel Pharmacokinetics
Absorption Bioavailability Route and precaution Bound to \_\_\_\_ Distribution (3) Half life Metabolized to \_\_\_\_\_\_ derivatives
- Rapidly absorbed; 80% bioavailability. Swallow tablets immediately—bitter taste causes retching and vomiting
- 80% protein bound
- Distributes into CSF, bile, breast milk and feces
- Short half-life: 0.8-1.5 hours
- Metabolized to inactive hydroxy derivatives
- Primarily renal excretion; some biliary
Praziquantel Adverse Effects
Frequent (5)
Occasional (3)
Rare (3)
•Frequent
–GI: abdominal pain; diarrhea
–CNS: headache, dizziness
–Malaise
•Occasional
–fever, sedation, sweating
•Rare
–Pruritus, rash; edema
