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122 Cards in this Set
- Front
- Back
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Definition of Fungus
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Eukaryotic
Membrane bound organelles: mt, nucleus- noncentric, intranuclear chrom. div. Heterotrophic Polymorphic* Cell wall- complex heteropolysaccharides + peptides Cell membrane- sterols- *ergosterol Reproduction- all asexually; 75% have sexual cycle |
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Fungi Taxonomy
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Zygomycetes- produce sexually by prod of diploid zygospores (ex. Rhizopus)
Ascomycetes- reproduce sexually by prod. of asci and ascospore. (ex. Dermatophytes, Histoplasma capsulatum) Basidiomycetes- reproduce sexually by prod of basidia and basidiospores (ex. Cryptococcus neoformans) Deuteromycetes- sexual stage lost thru evolution/unknow (ex. many Candida spp) |
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Fungal Morphologic Forms (Infections)
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Yeast- unicellular fungi that reproduce by an asexual budding process
Filamentous- (mould) fungus whose vegetative form is a mass of individual hyphae, each hypha grows by apical extension -Hyphae- filamentous structure of fungus that may have several characteristics (used for dx in lab) Branching -dichotomous (Y-shaped) -right angles (T-shaped) Septation -Septate: Asperigillus -Non-septate: Zygomycetes (Rhizopus) |
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Dimorphism of Fungi
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Classic:
Fungus exists in nature and at room temp as filamentous fungus (mould) and converts to yeast in tussue or under special cond. in lab Temperature Dependent: raise the temp to 37C triggers conversion of yeast (ex: Blastomyces dermatitidis; Paracoccidiodes brasiliensis) Nutrient and Temp dependent: Require complex nutrients for conversion to yeast (Histoplasma capsulatus, Sporothrix schenckii) Candida spp. display REVERSE of classical dimorphism: yest as colonizer and in lab; filamentous, as well as yeast, in tissue or special lab conditions |
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Structure of Fungus
1. Capsule 2. Cell wall |
Capsule- most lack.
Cryptococcus neoformans produces heteropolysaccharide capsule composed of glucuronoxylomanna (protective effect) Capsular antigen used in detection of organism in CSF Cell Wall: Rigid, heteropolysaccharide wal, very resistant to hydrolysis, confers shape/stability; multi-layered; glucans compose inner fibrillar and inner matrix of wall; glycopeptides compose inner and outer layers NOT barrier to environment! -1-3 beta glucans; 1-6 beta glucans; mannans; chitin More chitin in filamentous fungi; more mannans in yeast Cellular and humoral immune responses directed to cell wall Important receptors for cells, intracellular matrices, and hardware CC: 1. Fungal cell wall biosyn is new target of antifungal Rx (echinocandins) 2. Circulating glucans, mannans are used as surrogate markers in detection of invasive fungal infections |
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Structure of Fungi
1. Septa 2. Fungal cell membrane 3. Internal cell organelles |
Septa:
Ingrowth of polysaccharide cell wall that appears to divide hyphae into individual cells -Zygomycetes- lack septa, coenocytic -Ascomycetes- have simple septa -Basidiomycetes- produce elaborate septa (called dolipore) Fungal cell membrane: Typical bilayer membrane Cell membrane (not cell wall) is real barrier between fungal cell and environment Sterols are incorporated in lipi portion -most common = ergosterol -Help maintain membrane fluidity -Sterols or enzymes in biosythetic pathway are target for polyene, azole, and allylamine classes of antifungal drugs Internal cell organelles: ER and ribosomes Golgi- unstacked Mt- simple Membrane-bound vesicles and vacuoles Membrane bound nuclei- low chromosome #, most haploid in vegetative form |
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Reproduction
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Most fungi- sexually and asexually
Sexual: can occur w/ one strain (homothallism) or two strains differing in compatibility locus (heterothallism) Zygomycetes- zygospores Ascomycetes- ascus/ascopores- most pathogenic fungi Basidiomycetes- basidiospores and basidia Asexual repro: Asexual spores that germinate to yield a colony with an identical genetic make-up as parental strain. Spore are more resistant to environmental stresses & they help dispersion. -Sporangiospores- asexual spores produced in a sac-like cell called a sporangium by Zygomycetes ex. Rhizopus -Conidia- asexual spores (not prod in a sporangium) prod by all other major groups -Importance: freq it is asexual spores that are the infective resp inoculum. Prod of spores is used as basis for ID in clinical lab |
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Principles of human mycoses
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Vary widely in virulence
Fungi, cause wide spectrum of disease when they cause infections -Some infections are due to endogenous flora; others host has contact w/ fungus in nature -Most not transmitted person to person, can clinically mimic TB -Pathogenic fungi exist in several morph forms in tissues, may be diff than forms in vitro |
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Fungal factors associated w/ ability to cause infection
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1. Cell surface receptors- epithelial cells, endothelial cells, vascular catheters
2. Hydrolytic enzymes- hydrolyze complex proteinaceous and lipid substrates 3. Host mimicry- prod of macromolecules that are homologous w/ human molecules 4. Polysaccharide capsule- inhibits phagocytosis 5. Melanin production- inhibits oxidative killing mech. |
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Spectrum of Fungal structures in vivo
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Budding yeast cells- Sporotrichosis, N&S American Blastomycosis, Histoplasmosis, Cryptococcosis
Hyphae- Dermatophytosis, Aspergillosis, Zygomycosis Both Yeast AND Hypahe- Candidiasis and Tinea versicolor Other specialized structures -Spherule- lg spherical structure w/ internal spores seen in Coccidioidomycosis |
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Stains for Fungal Pathogens
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1. H&E- used to differentiate host response, not sensitive for fungi detection
2. Periodic acid-Schiff (PAS)- stains the acid polysaccharide cell wall 3. Gomorri's Methenamine silver (GMS)- deposits silver on cell wall, increases sensitivity 4. Mucicarmine or Alcian blue- specifically stains polysaccharide capsule of Cryptococcos neoformans 5. Fontana Masson- stains melanin that is present in cell wall of some fungi |
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Fungal Infection According to Host Response/Disease
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1. Superficial- no inflammation, cosmetic. ex. tinea versicolor
2. Mucocutaneous- inflammation occurs, but fungi do NOT invade viable tissue. ex. Dermatophytosis; mucocutaneous candidiasis 3. Subcutaneous- localized infection following trauma ex. Chromoblastomycosis; mycetoma; sporotrichosis 4. Deep Mycosis- life threatening -Opportunistic- caused by common fungi in compromised host: PMN-dependent a. Candidiasis b. Aspergillosis c. Zygomycosis -Pathogenic- caused by more virulent species: CMI-dependent a. Histoplasmosis and other endemic mycoses |
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Cutaneous Fungal Infections
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Dermatophytosis
Onychomycosis Tinea Versicolor |
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Cutaneous v. Superficial Mycoses
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Cutaneous mycoses: fungal infections of epidermis and dermis that evoke inflammatory reaction in host
Superficial mycoses: fungal infections of the superficial stratum corneum that DO NOT elicit host response |
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Dermatophytosis
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Cause:
Epidermophyton floccosum Microsporum spp. Trichophyton spp. Dermatophyte Infections: Tinea pedis- foot Tinea capitis- head Tinea corporis- body Tinea barbae- beard Tinea cruris- groin Tinea unguium- nail Tinea manuum- hand Tinea- "ring worm" Trichophyton- capitis, barbae, corporis, cruris, pedis, unguium (common US) Microsporum- capitis, corporis, cruris, pedis, NOT UNGUIUM (more common worldwide) Epidermophyton floccosum- medically important, tinea cruris Also classified by reservoir: Anthropophilic spp- humans Zoophilic spp- animals Geophilic spp- soil |
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Tinea pedis, corporis, cruris, capitis
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Most common dermatophytosis
Trichophyton rubrum- most common cause Warm, humid climate Enclosed shoes, communal showers, locker rooms Tinea corporis- Infection of non-glabrous skin, usually trunk and extremities Tinea cruris: Invasion of hair follicles that can be confused w/ cutaneous candidal infection Occurs in summer months Young men, or tight-fitting clothing Tinea capitis: Disease of infants, children, young adol. Urban infection Child to chid; animals to humans Trichophyton spp. common for 80% cases in US- Trichophyton tonsurans most common |
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Pathogenesis of Dermatophytosis
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Dermatophytes use keratin as nutrient
Colonize keratinized stratum corneum Cellular immunity key factor of host defense |
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Clinical Manifestations of Dermatophytosis
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Tinea Pedis: interdigital, moccasin, vesiculobullous
Occasionally one hand involved w/ both feet (tinea pedis et manuum) Onychomycosis may be present w/ tinea pedis Tinea corporis, forms erythematous, round, scaly plaque or path w/ red raised advancing border Edge can contain papules or pustules TInea cruris "Jock itch" forms erythematous pruritic patch in groin area, spare scrotum and penis (candida infections are intensely red and shiny, have irregular border, involve scrotum usually) Tinea capitis: primary lesions may be papules, pustules, plaques, nodules on scalp Inflammation-> scaling, alopecia, erythema, exudate, edema Breakage of hairs-> "black dot" alopecia Kerion forms as a result of increased cell-mediated immune response (severe inflammation, hair loss, cervical lymphadenopathy) |
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Mechanism of Hair Invasion:
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Ectothrix invasion: arthroconidia form on otside of hair shaft and cuticle is destroyed
Endothrix invasion: arthroconidia form within hair shaft, leaving cuticle intact |
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Laboratory Dx
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KH or calcofluor prep. of scale scraped from leading edge of lesion
Culture to confirm dx Tinea capitis is dx on KOH exam o extracted hair if caused by Trichophyton species, as spore can attach to or reside on hair shaft. Culture extracted hair. Any growth of dermatophytes = SIGNIFICANT Tinea capitis caused by M. audouinii or M. canis fluoresces blue-green under Wood's light exam. |
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Rx & Prevention of Dermatophytoses
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TOPICAL Antifungal:
Tinea pedis, tinea corporis, tinea cruris, tinea manuum Ex: miconazole, clotrimazole, ciclopirox, econazole, ketoconazole, terbinafine. Oral meds if infection extensive, severe: griseofulvin, itraconazole, fluconazole, terbinafine Tinea capitis: oral antifungal - mainstay Griseofulvin, terbinafine, ketoconazole, itraconazole, fluconazole Reduce fungal shedding: Ketoconazole shampoo Clean EVERTHING! |
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ONYCHOMYCOSIS
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Infection of nail plate and/or nail bed that interferes w/ normal nail fxn
Caused primarily by dermatophytes (T. rubrum, T. mentagrophytes) Source of pain, ambulatory dysfxn, paronchia Three clinical types: Proximal subungual (PSO); distal subungual (DSO); white superficial (WSO) DSO = most common (T. rubrum most common) |
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Distal Subungual Onychomycosis
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Most common type
T. rubrum most common Mech of invasion: Hyphae enter distally under nail plate and spread proximally, digesting stratum corneum of nail bed and nail plate Subungual hyperkeratosis, paronychia, onycholysis can occur |
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Proximal Sugungual Onychomycosis
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Most commonly caused by T. rubrum
Occurs in immunocompromised hosts; early indicator of HIV infection Mech of invasion: Infection enters at cuticle and involves proximal nail bed; spreads distally to involve entire nail plate if untreated |
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White Superficial Onychomycosis
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Occurs in about 10% of cases
Most commonly caused by T. mentagrophytes Dorsal surface of nail plate is attacked, resulting in minimal inflammation |
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Laboratory Dx of Onychomycosis
Rx/Prevention |
KOH w/ calcofluor direct exam and culture of nail
Oral Rx: griseofulvin, terbinafine, itraconazole, fluconazole |
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Tinea Versicolor
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Superficial mycotic infection of young and middle-aged adults caused by lipophilic yeast Malassezia furfur
Upper trunk, neck, arms M. furfur also in folliculitis, seborrheic dermatitis, atopic dermatitis and dandruff Pathogenesis: NO inflammatory response in host; occurs regardless of immune status Clinical Manifestations: Erythematous, hypo- or hyper-pigmented macules or patches, sometimes w/ slight scale, may/may not be pruritic Inhibitory effect on pigmentation and tanning Laboratory Dx: M. furfur fluoresces pale yellow on Wood's light exam. Detected w/ microscopy w/ KOH, demonstrating short angular hyphae and budding yeast "spaghetti & meatballs" appearance Rx/Prevention: Topical treatment: econazole, ketoconazole or selenum sulfide shampoo. Short course: itraconazole, fluconazole, ketoconazole |
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Amphotericin B
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Interacts with ergosterol in cell membrane
Polyene Polyene unit- hydrophobic char. Hydroxyl and carbonyl groups- hydrophilic char. Aminosugar- detergent-like Low solubility in H2O Mech: Binds sterols in membrane of fungi Formation of channel or pores in membrane Leakage of small molecules Specificity: Mammalian cells use cholesterol in membranes for rigidity; fungi use ergosterol. Amphotericin bin more avidly to ergosterol. Clinical Indications: Potentially fatal fungal infections -Invasive Aspergillosis -Disseminated Candidiasis Toxicity: Many SE b/c low selectivity Nephrotoxicity Fever, chills, hypotension "shake n' bake" |
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Nystatin
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Polyene
Topical preparation (suspension) Treatment of oral, vulvovaginal and cutaneous Candidiasis |
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Azoles
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Drugs that interfere w/ ergosterol biosynthesis
Imidazole (2 N atoms) Triazole (3 N atoms) Mech: At lower dose: inhibits ergosterol biosyn. by blocking demethylation of lanosterol to ergosterol Target = 14-alpha-demethylase Decrease in ergosterol concn --> increase in permeability of cell membrane, leaking Higher dose: directly damages fungal cell membranes SE: GI distress, Rash, severe hepatotoxicity, drug interactions w/ other compounds metab. by cyp3a4 |
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Ketoconazole
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An Azole
PK: Absorption: orally effective, relatively long T1/2 Metab: degraded in liver, excreted in urine Clinical use: alternative to amphotericin B for systemic and mucocutaneous fungal infections |
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Fluconazole
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An Azole
PK: Absorption: oral >90%; independent of gastric acidity Dist: good penetration into CSF, eye Metab: less that 10% hepatic Elim: Primarily renal t1/2 = 20-50 hours Clinical use: Fungistatic, no Post antifungal effect Indications: Maintenance of Cryptococcal meningitis Prevention of Candidal infection: transplant |
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Itraconazole
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An Azole
PK: Absorption: Oral erratic; IV use Improved by acid, food Metab: hepatic Elimination: Inactive metabolites secreted in urine & bile T1/2 20-30 hours Clinical Use: Systemic administration; fewer SE than ketoconazole |
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Voriconazole
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An Azole
PK: Absorption: 80-90% bioavail. Improved on EMPTY stomach Metab: hepatic Elim: Inactive metabolites excreted in urine & bile Primary Indications: invasive aspergillosis & candidemia |
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Allylamines
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Naftifine: topical
Terbinafine: both oral and topical Mech: Inhibition of ergosterol biosynthesis--> higher permeability and leakage Inhibit earlier step in ergosterol biosyn than azoles Inhibit squalene-2,3-epoxidase from Candida Highly selective for fungal squalene epoxidase |
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Flucytosine (5FC)
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Pyrimidine analog
Drug that interferes w/ nucleotide synthesis Mech: 5FC converted to 5-FU in fungi by cytosine deaminase 5-FU metabolized into 5-FUMP, which can be incorp into fungal mRNA, and interfere w/ fungal proein syn, or can be further converted to 5-FdUMP by ribonucleotide reductase, inhibiting thymidylate synthase Selectivity: cytosine deaminase cannot deaminate 5-FC in animals Fungi and GI flora can deaminate 5-FC to 5-FU *Selective pro-drug Resistance: major problem. Rapidly develops Clinical use: Used in combo w/ amphotericin B to treat systemic Candida and Cryptococcus infections Toxicity: Well tolerated, can cause bone marrow depression, GI distress, reversible hepatotoxicity Tox may arise from metab of 5-FC to 5-FU by GI flora Manufacturing impurities |
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Griseofulvin
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Drug that interferes w/ microtubule formation
Mech: ACTIVELY transported into fungal cells Disrupts microtubules (mitotic and cytoplasmic) leading to cell cycle arrest at mitosis and formation of multinucleate cells Selectivity: Lack of active transport of drug in mammalian cells Clinical use: severe infections of hair, nails, palm, soles Toxicit: GI distress, temp headache, relatively safe few SE PK: Absorp: almost complete Dist: highly concn in keratin layer of skin, hair, nails |
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Caspofungin (micafungin, anidulafungin)
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Drugs that inhibit cell wall biosynthesis
Mech: Irreversibly inhibit 1,3-Beta-D-glucan synthase Prevents formation of glucan polymers and cell wall Fungicidal Lack of cross-resistance w/ other classes In vitro activity against Candida spp. and Aspergillus spp. Specificity: Animals lack cell wall Fungi: glucan polymer structure essential for viability Clinical Use: salvage Rx for invasive asperigillosis Esophageal candidiasis Candidemia Pts unresponsive to other Rxs Others: Micafungin: prophylaxis of candidiasis in BMT recipients; Rx of esophageal candidiasis Anidulafungin: Rx of candidemia Toxicity: about 14% caspofungin recipients; fever nausea, vomiting, infusion site complications |
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Host/Fungus Efficiently phagocytosed & killed
NEUTROPHIL CRITICAL |
Invasive Candidiasis
Aspergillosis Zygomycosis |
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Host/Fungus NOT killed or Inefficiently
killed T-CELL IS CRITICAL |
Histoplasmosis
Coccidioidomycosis N&S American Blastomycosis Cryptococcosis Pneumocystosis |
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Opportunistic Mycoses
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Infections only occur in compromised hosts:
Altered T-cell Function: -Mucocutaneous candidiasis -Cryptococcosis -Pneumocystosis Altered phagocytic activity: -Invasive candidiasis -Aspergillosis -Zygomycosis |
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Pathogenic, Deep, Systemic Mycoses
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Cellular, T-cell Function
-Histoplasmosis -North American Blastomycosis -Paracoccidioidomycosis -South American Blastomycosis -Coccidioidomycosis |
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Candidiasis
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Opportunistic infections caused y member of genus Candida
C. albicans most virulent Yeasts- endogenous flora Mucocutaneous candidiasis: oropharyngeal candidiasis (thrush); esophageal candidiasis; cutaneous candidiasis; onychomycosis; keratitis; vulvovaginal candidiasis Deeply invasive candidiasis: candidemia; endocarditis; hepatosplenic candidiasis; acute disseminated candidiasis; renal candidiasis |
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Mucocutaneous Candidiasis
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-Immunosuppresed pts (HIV, diabetes, steroids, pregnancy, age, antibacterial antibiotics)
1. Mucosal- oral, esophageal, GI, vaginal- production of white pseudomembranous plaque w/ fungal hyphae and budding yeast cells 2. Cutaneous- intertriginous (erythematous, scalded lesions w/ punctate satellite lesions), diaper dermatitis, genralized, paronychial/onychomycosis. Smear (KOH) reveals hyphae, pseudohyphae, budding yeast cells 3. Chronic Mucocutaneous Candidiasis -Inherited disorder of CMI w/ polyendocrinopathies Autoimmune Polyendocrinopathy-Candidosis-Ectodermal Dystrophy (APECED) |
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Invasive Candidiasis
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Major mycosis in hospital pts, char by fever unresponsive to antibacterial antibiotics
1. Pt populations/risk -Altered barriers -Neutropenia -Tx pts- BMT and solid tumor -Surgical pts -Broad-spectrum antibiotics, hyperalimentation 2. Incidence- positive blood cx are means of dx, but low sensitivity 3. Pathogenesis -Adherence & colonization -Penetration thru barrier, angioinvasion -Hematogenous dissemination -Organ seeding -Replication in tissue- necrosis +/- abscess w/ budding yeast & hyphae |
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Candida albicans
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Virulence:
Surface receptors- epithelial, endothelial, extracellular matrices, hardware Cell wall acts as immunomodulator Hydrolytic enzyme activity- acid protease, phospholipases Host mimicry- prod of surface comp. C3D receptor Dimorphism- ability to rapidly convert from yeast to hyphal form (germ tube) (used for Id) Rx: Esophageal: Fluconazole Candidemia: systemic- Fluconazole or Amphotericin (nephrotoxic) |
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Aspergillus/Aspergillosis
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Clinical dzs caused by genus Aspergillus
-Filamentous fungi -ALL infections OPPORTUNISTIC Clinical Disease: Toxins- aflatoxins, hepatotoxin/carcinogen prod on grains/peanuts Allergic syndromes Colonization- fungal ball in old TB cavity, impacted paranasal sinuses Infections: -Keratitis- following corneal trauma -Invasive disease- pulm +/- dissemination Pathology: septate hyphae; branching pseudodichotomously w/ acute angles in tissue. Hyphal invasion and occlusion of blood vessels w/ necrosis of tissue is hallmark Aspergillus species: rapid growing filamentou sfungus w/ extensive conidial prod. = powdery surface. Conidia prod. in chains from conidiophore 1. common pathogenic spp- A. fumigatus, A. flavus., A. terreus 2. Common saprophytic species- A. niger Virulence: Adherence receptors Hydrolytic enzymes- collagenases, elastases, hemolysins Complement inhibitor Toxin Rx: Voriconazole or Amphotericin Need to reverse immunosuppression for success! |
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Aspergillus- Invasive Disease
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Highly compromised populations: neutropenic, altered neutrophil fxn (CGD), BMT, high dose steroids, end stage HIV
Pathogenesis: Inhalation of conidia Normal host- phagocytosis by macrophages & killing Compromised = +/- phagocytosis, no killing -Germination of conidia w/ hyphal invasion of lung parenchyma -Angioinvasion w/ thrombus formation and tissue necrosis Hematogenous dissemination from lung to other organs (GI, brain, liver, kidney...) |
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Zygomycosis (mucormycosis)
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Opportunistic mycoses caused by several zygomycetous fungi that are ubiquitous so we are freq. challenged w/o disease
Clinical disease: 1.Colonization- old TB lung cavity, no invasion of parenchyma 2. Invasive infections: -Rhinocerebral Zygomycosis- DM in acidosis -Pulmonary +/- dissemination Pathogenesis of Rhinocerebral Zygomycosis: -Inhalation/contact w/ asexual spore -Infection begins in paranasal sinuses, less commonly in nasal or oral mucosa -Tissue invasion w/ common invasion of nerves and blood vessels = palsy and thrombosis and necrosis may invade orbit and eye -Direct extension to brain Pathology: wide hyphae, ribbony, NONseptate hyphae that branch infrequently, but at right angles in tissue Invasion of blood vessel walls and nerves are classic w/ extensive necrosis in advance of fungus Zygomycetous Fungi: 1. Most common- Rhizopus Others- Absidia and Mucor 2. Char.- very rapid growing colonies, nonspetate hyphae, extensive aerial hyphae, SPORANGIOPHORES, bearing lg. sac-like structures called sporangia filled w/ sporangiospores (asexual) prod internally 3. Virulence factors- Unknown Rx: Amphotericin |
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Cryptococcosis/ Cryptococcus neoformans
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General: opportunistic infection caused by Cryptococcus neoformans, an ENCAPSULATED yeast
Neurotrophic, freq causes meningioencephalitis Clinical Diseases: -Pulmonary- asymptomatic to mild to progressive, depending on pt and inoculum size -CNS: Meningioencephalitis and Encephalitis -Disseminated disease Patients at risk- T-cell compromised pts: High dose steroids, solid organ tx, HIV+ CD4+<100 Pathogenesis: Inhalation of yeast from environ Replication in lung Recruitment of CD4+ and CD8+ cells Clearance of pulmonary infection w/ specific cellular immune response; progressive pulm in compromised +/- Hematogenous dissemination crossing BBB Replication of yeast w/ gelatinous lesion due to CAPSULE Breakdown of meninges w/ release of org. into CSF Pathology: -Noraml host- chronic inf. and granulomatous responses -Compromised host- mild to non-inflammatory rxn -Lesions gelatinous due to excess capsule -Spherical yeast cells -Yeasts stain poorly w/ H&E, require PAS, GMS, or mucicarmine Biology of Cryptococcus neoformans -Basidiomycetous yeast, encapsulate, not dimorphic -Neurotropic -Found in nature (bird fecal material) Virulence: -Heteropolysaccharide capsule --detectable as antigen --inhibits extracellular phagocytosis --poor antigen and leukotactic molecule -Phenoloxidase- intial enzyme in prod of melanin --Specific for C. neoformans --Melanin inhibits oxygen dependent killing mechanisms! --Can be visualized in tissue w/ Fontana-Masson Rx: Amphotericin + 5-FC |
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Pneumocystosis/Pneumocystis carinii
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Opportunistic pneumonia
Obligate parasite-fungus Predominantly an alveolar-interstitial pneumonia --presents w/ fever, dyspnea, non-productive cough Extrapulmonary dz uncommon RIsk factors: immunosuppression, corticosteroids, HIV, age Rx: TMP-SMX |
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Deep mycoses caused by "Pathogenic" Fungi
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1. Infection in normal host
2. Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis 3. Classical endemic dimorphic fungi 4. Niches: -H. capsulatum- soil, caves enriched w/ bird, bat fecatl material, OH,MS- River -C. immitis- desert soil in SW USA -B. dermtitidis- water in N., C., SE USA -P. brasiliensis- S. America (Columbia, Brasil) 4. Pathogenesis: -portal of entry- inhale asexual spores -Dz asymptomatic or mild in most, others symptomatic -Disseminated, progresive infection 1/1000 -Disseminated infections in normal individuals in normal indiv, but more common in T-cell compromised -Path usually chronic infl. and granuloma formation |
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Histoplasmosis/ Histoplasma capsulatum
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Dimorphic fungus
Common in Central USA Clinical Disease: Pulmonary portal of entry- 90-95% after low inoculum exposure = asymp., or mild resp. sx 5% mod. mild to severe resp. dz Disease of reticuloendothelial system- liver, spleen, lymph nodes, bone marrow, adrenals Pathogenesis: INhalation of asexual spores Conversion to yeast phase Phagocytosed, not killed Replication in phagolysosome +/- dissemination to visceral organs Normal host- CMI, granuloma form. Highly compromised- progressive infection Pathology: Early, active infection- intracellular; budding yeast cells in cytoplasm of macrophages, histiocyts, lymphocytes Normal host- granuloma formation Old lesions- fibrosis and calcification occur Immunosuppresssed- no well-formed granulomas; histiocytosis- each histiocyte has many intracellular yeasts Biology: Dimorphic fungus Filamentous at room temp/nature; produce micro and macroconidida In vivo, yeast DNA probes for ID Virulence: -Ability to evade killing by nonimmune phagocytic cells -Ability to replicate in phagolsosome, (neutralizing acid environ needed by enzymes?) -Evolution of ability to convert to yeast phase |
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Coccidioides immitis
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Characteristic Structures:
Arthroconidia (environment, in vitro, room temp) Spherules (in vivo) |
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Malaria Epidemiology
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Parasitic disease transmitted by mosquitoes
85% deaths in sub-Saharan Africa -Lgst. burden- children <5 & preg. women -Seeing tip of iceberg- many cases do not reach formal health services Resurgent du to drug resistance No vaccine |
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Malaria Parasitology
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4 species:
Plasmodium falciparum (90% of infection; responsible for almost all malaria death in africa; multi-drug resistance; target of vaccine efforts) -P. vivax (major contributer to morbidity & mortality in SE Asia) -P. ovale (only in Africa) -P. malariae |
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Malaria Epidemiology II
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Highly variable around world and w/in countries
Coastal Kenya- <10 bites/person/yr cerebral malaria Western Kenya- >300 bits/person/yr; severe anemia Related of intensity & duration of transmission Classic definitions: -Hypoendemic -Mesoendemic -Hyperendemic -Holoendemic Epidemic -Outbreaks where transmission low to absent -Population movements, environmental changes |
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Epidemiology and Immunity- Malaria
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Acquired immunity and epidemiology of disease
-Stable & unstable malaria Stable -Heavy, perennial transmission After age >5, protected from severe disease Unstable malaria: -Transmission less intense and more episodic or epidemic -Protective immunity is either acquired at later age or not at all -All ages vulnerable |
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Immunity to Malaria
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Host immunity:
-Both humoral and CMI -Initial non-specific defense & spleen -Maternal antibodies up to 6 mo -Protection from disease acquired slowly w/ prolonged, repeated exposure; protection from infection not achieved -Diminished immunity in pregnancy -Limited interaction w/ HIV (loss of protection) Innate immunity: Malaria Hypothesis- Red cell polymorphisms due to selective effect of malaria on heterozygote RBC poymorphisms: Hemoglobin structure Thalassemias (Hg synthesis) G6PD deficiency (red cell enzymes) Duffy-negative blood type Duffy receptor -Chemokine receptor -Fxn as binding receptor for P. vivax (only) entry into RBCs -Duffy-negative individuals lack Duffy protein (mut in FY promoter) -Predominantly in Africans |
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Plasmodium life cycle
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-Sporozoites injected by female Anopheles mosquitoes
-Take <1hr to reach liver; clinically asymptomatic Hepatic Stage: -Undergo mult stages in hepatocytes -Duration 6 days-weeks -End result: hepatic schizont filled w/ thousands of merozoites; rupture and release merozoites into blood P. vivax and P. ovale- can stay arrested as Hypnozoites- repsonsible for relapxse Erythrocytic Stage: -Invasion of RBCs- undergo mult stage -Duration 48-72 hours -Ring structure -Trophozoite- vegetative, asexual -End result: erythrocytic schizonts w/ merozoities- rupture and release- invasion of more RBCs -Only clinically symptomatic stage -Some merozoites develop into male and female gametes- taken up by Anopheles mosquito -Sexual mult and dev. in mosquito midgut- sporozoites enter salivary gland -Sexual forms respons. for malaria transmission Recrudescence- P. falciparum and P. malariae; reappearnce of parasite s in blood Relapse: P. vivax and P. ovale- revival of hypnozoites in liver Reinfection- new infection To eradicate malaria, you need to deal with TRANSMISSION OF GAMETES! |
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Parasitemia and pyrogenic threshold
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P. vivax invades predominately reticulocytes (low parasitemia)
P. falciparum can invade all ages of RBCs (high parasitemia) Pyrogenic density for P. falciparum Non-immune <<Immune Pyrogenic density for P. vivax << P. falciparum |
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Clinical Presentation of Malaria
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Periodic fever paroxysms:
chill-rigors-high fever-sweating-relative relief Symptoms: headache, body aches, malaise, cough, weakness, prostration, diarrhea Signs: fever, anemia, jaundice, enlarged spleen, liver Lab findings: low platelets (first to go), low WBC, low RBC Uncomplicated malaria: -fever paroxysms, shaking chills -treat w/ oral antimalarial drugs -Must confirm drug susceptibility by region -Must follow decline of parasitemia after rx Severe malaria: -Progression to profound anemia, seizures, coma, death -Progression may be rapid, esp in non-immune -High mortality -Treat w/ intravenous drugs and intensive care |
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Cerebral malaria
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Altered consciousness
Seizures common Rapid onset Rapid recovery if not fatal Pathogenesis not well understood Immune-mediated |
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Severe anemia
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Hemolysis, destruction of infected and uninfected RBC in spleen, bone marrow suppressive effect, ineffective erythropoiesis
SPLENOMEGALY -Peak incidence: African children (6mo-2yr) living in holoendemic areas Assoc. w/ secondary bacterial infections Transfusion may be life saving "Do no harm" |
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When to suspect malaria in U.S.
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Any fever in exposed person
-cough, diarrhea do not rule out malaria -usual time from exposure 7-25 days -Incubation period prolonged by incmplete prophylaxis P. vivax and p. ovale relapse up to 3-5 yrs P. malriae recrudescence up to 50+rs Fever of unknown origin in "unexposed" |
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Important to know!
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Malaria dx needs to be done no later than 1 hr after malaria is suspected!
Malaria treatment needs to be started no later than 1 hr after smear is read! Treatment plan determined by: Speciation Quantification Geography (drug susceptibility) Assessment of severe malaria |
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P falciparum cytoadherence
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Parasitaemia very high
Parasites in ring stage, circulate freely Schizont stage- mostly sequested in capillaries Binding of infected RBC receptors bind endothelium = SEQUESTRATION ROSETTING - binding of uninfected RBCs to infected RBCs **Severe malaria |
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Placental malaria
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Cytoadherence of parasitized RBCs to placental endothelium
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Impact of malaria on preg and birth outcome
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Mother- severe malaria & complications
Fetus- still birth, prematurity, congenital infection, spon abortion Newborn- Low birthweight is single and most important predictor of infant mortality |
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If you suspect malaria
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Ideal: Giemsa stain thick and thin smears
Ask lab to make multiple smear so some can be "quick-dried" and read immediately Thick smear- more sensitive; harder to read Thin smear- helps speciation to determine Rx Quantification necessary to determine risk of severe disease & drug susceptibility One neg smear DOES NOT rule out malaria Delayed dx (or mis-dx) and treatment can be FATAL |
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Parasitological Dx: new methods
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Useful for rapid dx in absence of infrastructure- expensive
HRP-2 dipstick (antigen detection) pLDH dipstick (antigen detection) -only positive when live parasites in circulation PCR- highly sensitive to DNA; useful for detection/monitoring of drug resistant markers, distinguishing recrudescence vs. new infection |
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Malaria Chemotherapy
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KNOW malaria biology and drug pharmacology!
Malaria in travelers- chemoprophylaxis Non-immune Travelers- drugs Malaria prev in vulnerable pop: Pregnant women, infants Malaria in endemic countries: Rx tailored by specie and severity -Treatment failure- drug resistance, PK failure, fake drug?? |
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Malaria Vaccine obstacles
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Natural protective immunity
-partial, temporary, genetically restricted -Immune response likely contributes to pathology of dz -Efficiency of parasite amp and complexity of parasite antigenic variation -Availability of parasite antigen Lack of correlates of protection and good outcome measures |
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Clinical Significance of P. falciparum
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MEDICAL EMERGENCY in non-immune individual: rapid progression
Severity of falciparum infection: -able to infect all age RBCs (Severe Anemia!) -Higher multiplication capacity -Sequestration (cytoadherence and rosetting) of mature parasites (microvascular obstruction, tissue hypoxia, capillary leak syndrome, end organ failure) |
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Complicated or severe anemia
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P. falciparum:
Almost always cause of severe malaria Cerebral malaria- seizures obtundation, coma Severe anemia- Hemoglobin <6% Hyperparasitemia Severe protration Resp failure, hypoglycemia, acidosis, diffuse bleeding, kidney failure, liver failure P. vivax- anemia, ruptured spleen P. malariae -nephrotic syndrome in African children |
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Parasite
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Organism living in complete dependency in or on another living organism, the host
Host shields parasite from harsh outer world and supplies its food Host is parasite's Restaurant Hosts: -Definitive- organism in which sexual repro of parasite occurs -Intermediate: Organism that hosts an immature parasite stage, or stage that reproduces asexually Transmitting organism = vector Protozoa, worms, and arthropods in medicine! |
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Parasitism:
Attachment/Adhesion |
Molecular receptor/ligand interactions
-Plasmodium- binding of parasite membrane proteins to molecules on host cell surface -Hookworm- attaching itself to tissue using sharp teeth/hooklets |
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Parasitism:
Host Invasion |
Helminth larvae have different modes to invade host
-Direct invasion from environment (schistosomes, hookworm) -Along vector bite path (Brugia) mosquito injects larvae into capillary -Dispersed from vector bite (Onchocerca) Parasites needing to enter host cell to survive and replicate = obligate intracellular parasites -receptor-ligand -subversion of host cell transmembrane signaling pathways -modification of host cytoskeleton Toxoplasma gondii invasion- moving junction formation |
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Host-parasite interaction
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Dynamic
Host cell rarely passive vessel for parasite Host cells may signal immune system by releasing cytokines, such as IL-8 Parasites might "de-differentiate" host cells to suit their needs -Trichinella de-differentiates host muscle cells by secreting transcription factor-like proteins into cell which shut don muscle-specific genes Parasites "redecorate" host cells to suit needs -P. falciparum inserts parasite protein into plasma membrane of infected RBCs RBCs bind host endothelium -RBCs bind host endothelium, preventing destruction by spleen |
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Obtaining Nutrients
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Plasmodium digests hemoglobin from RBC
-AA used for development |
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Immune Evasion
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To co-exist w/ host, protozoa/worms release molecules that interfere w/ host's immune system
-Block Ag processing by APCs -Inhibit T-cells by inducing regulatory T cells Some Protozoa can multiply w/in macrophages and escape digestion by lysosomal enzymes African trypanosomes- elaborate antigenic variation; single trypanosome can express hundreds of different surface proteins (VSG) |
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Encystation: eggs/cysts
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Parasites often produce stable forms when leaving 1 host
--thick walled cysts in many protozoa, eggs in worms --often used to dx parasitic infections (stool ova and parasite exams) |
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Parasites may alter host behavior
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Ex: T. gondii-infected rats
("I ain't 'fraid of no cats!" |
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How do parasites cause disease?
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DIrect cellular damage
-lysing during egress -secretion of pore-forming peptides -secretion of proteolytic enzymes Ex: Toxoplasma gondii Mechanical obstruction or compression -Helminths obstruct lumina of intestinal tract or lymphatics Ex: tangled masses of nematode, Ascaris, can case intestinal obs. in children of developing countries Ex: Parasite-filled abscesses or cysts can compress vital organs Ex: pork tapeworm larvae- space occupying lesion in brain -> seizures Ex: Lymphatic filariasis, parasites block lymph nodes causing enlargement and backup of lymph Host immunologic response* -Eosinophilia- worms increase perm to large undigested molecules- activate immune response to prod more Eosinophils Ex: Granulomas- often develop in colon, rectal walls Ex: Cytokines (IL-8, TNF-alpha) Schistosomiasis, eggs deposited in bladder elicit florid granulomatous reaction that can lead to fibrosis and obstruction of ureters |
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Other disease manifestations caused by parasites
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Anemia
Fever Organomegaly Malnutrition Diarrhea Rash |
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Intestinal protozoa
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Transmitted fecal-oral rote
Cyst stage and tryphozoite stage Ex: Giardiasis, Amebiasis, Cryptosporidiosis Cysts: resistant wall- infective and excreted w/ feces Fecal-oral transmission- ingestion of cyst contaminated food/water Cysts transform into trophozoites- metabolically active and usually motile |
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Entamoeba histolytica
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Protozoan parasite
Common cause of dysentery Invasion of intestinal mucosa and spreading to other organs, esp liver, where it produces abscesses Colitis = most common form of disease associated w/ ameae Ameba invade mucosa and erode lamina propria- flask shaped ulcers contained by lamina muscularis mucosa |
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Trypanosoma brucei gambiense
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Disease: Human African Trypanosomiasis (HAT)
"sleeping sickness" Parasitic protozoa 2 subspecies: -T.b. rhodesiense T.b. gambiense Transmitted by tsetse flies 100% fatal if not treated Clinical features: irregular spiking fevers, enlarged lymph nodes in neck (Winterbottom's sign- gambiense HAT); Inflammatory rxn at bite site "Chancre" (rhodesiense HAT); Rashes in fair-skinned Delayed pain- Kerandel's sign CNS: parasite crosses BBB- white matter encephalitis, psychiatric symptoms; motor system disturbances; Unpleasant and painful sensations (arms and legs) Intense itching* Sleep disturbances Seizures, incontinence, coma, death Rx: Early stage -Suramin for rhodesiense HAT -Pentamidine for gambiense HAT Late stage: -Melarsoprol: for both types; high tox -Eflornithine: for both types, expensive Vaniqa = eflornithine; removes unwanted facial hair |
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Helminth Disease- Important principles
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1. Most adult helminths DO NOT multiply w/in definitive host. They reproduce sexually to prod transmission stages. Exceptions: strongyloidiasis and capillariasis
2. Most infected patients have low worm burdens. Minority w/ high burdens- most pathology, transmission importance 3. Disease corelates w/ worm burdens. Endemic areas- heavily parasitized w/ little disease from inflammation. Expatriates have exuberant inflammatory responses w/ severe disease and low worm burdens. 4. Long term infection of adult worms in absence of Rx. 5. Most tissue-dwelling helminths produce a eosonophilia elevated IgE and IgG4 levels and mast cell proliferation. T-cell dependent, down-reg w/ continued exposure to helminth, responsible for pathology in many cases |
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Helminth Pathogenesis
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Mechanical attachment and damage
-Blockage of internal organs- Ascaris, tapeworms, flukes -Pressure atrophy- Cysticercus, Echinococcus -Tissue migration- helminthic larvae Nutritional depletions- iron- hookworm Metaplastic changes- liver flukes- hepatoma; Schistosomes- bladder cancer Immunopathology -Anaphylactic- IgE and histamine release Immune complex- Ab and Ag complex deposition in tissues of brain, kidney, joints, skin... Cell-mediated reaction- w/ antigen w/ mononuclear and macrophage tissue damage Schistosomiasis |
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Unholy Trinity of...
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Ascaris
Hookworm Whipworm |
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Ascaris
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Case: "Irritable infant"
Pathology: mechanical blockage Low worm burden- asymptomatic infection High worm burden- abdominal pain, intestinal obstruction Migrating larvae, adults= pulmonary eosinophilia syndrom, biliary and liver inflammatin, intestinal obstruction Life cycle: egg ingested; larva penetrate gut; migrate to lung; coughed back into intestine as adult |
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Hookworms
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Case: Coolie chest pain
Pathology: blood loss Worms make unique anticoagulant Life cycle: larva penetrate skin (barefoot); migrate to lung; coughed into gut for adult that lives 1-2 years |
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Whipworm
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Trichuris trichiura
Case: Bloody stools Pathology= GI local damage and rectal prolapse Most freq asymptomatic Heavy infections, esp small children, cause GI probs (abdominal pain, diarrhea, rectal prolapse); growth retardation Life cycle: all in gut- egg, larva, adult |
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Strongyloidiasis
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Pathology: local GI damage
Hyperinfection into tissues in Tx patients Autoinfection in transplant pts; larva migrate to brain, muscle and other organs carrying gut flora to produce sepsis |
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Pinworm
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Enterobius vermicularis
Pathology: perianal pruritus Life cycle: all in gut- egg, larva, adult Scotch tape test- eggs on tape Pinworm and appendicitis? |
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Filiariasis- Wucheria and Brugia species
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Pathology= adults damage lymph vessels leading to lymphitis and elephatiasis
Microfiliaria infectious to mosquitos cause fever Fever at night w/ circulating microfiliariae Fevers and microfiliariae absent during day Loa Loa: Calabar swelling and eye migration Life cycle: fly transmitted; adults in subcutaneous tissues and microfiliaria in blood Onchocerciasis: River blindness; subcutaneous nodules; microfiliaria cause chronic inflammation of eye Life cycle: fly transmitted; adults in subcutaneous tissues, microfiliaria in blood Inflammatory response from endosymbiotic Wolbchia bacteria Rx w/ doxycycline reduces embryogenesis |
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Schistosomiasis
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Trematode- flat worms
Pathology- granuloma reaction to eggs- liver and bladder fibrosis and cancer S. mansoni (lateral spine) and S. japonicum (no spine) reside in portal veins S. haematobium (terminal spine) reside in bladder veins---> bladder cancer Pathway to CNS from mesenteric veins/vesical plexi Dx- eggs in stool or urine |
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Tapeworm- cestode
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Taenia solium
T. saginata Dx: eggs in feces for adult Western blot for larval forms |
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Cysticercosis
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T. solium larval stage
Infection from ABERRANT EGG INGESTION, not cysticercus larva Neurocysticercosis most serious manifestation Clinical pres. depends on whether cysts are active (alive) or inactive (dead_, host immune response, number of cysts present, location of cysts Egg ingestin leads to larval, cysticercus, in tissues of human Human becomes intermediate host w/ pathology |
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Neurocysticercosis
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Neurologic deficits to Psychiatric syndromes
Epilepsy most common Cysts in fluid around brain or ventricles Cysticerci often in MUSCLE at time of Neurocysticercosis Dx by ct scan; ELISA; Western Blot; Ab in serum Rx: combo steroids and albendazole or Prziquantel w or w/o surgery |
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Eosinophils
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Associated w/ IL-5 mediated, Th2-like response from CD4+ T lymphocytes
Worms, Wheezes, adn Weird Diseases |
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Eosinophilia
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Caused primarily by tissue dwelling helminths, not protozoan parasites
Degree of eosinophilia higher in short-term visitors than long-term residents Infections w/ eosinophilia often asymptomatic for months/yrs Acute bacterial, viral and protozoan (malaria) infection SUPPRESSES eosinophilia High sustained e. can cause endomyocardial fibrosis |
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Leishmania
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Transmitted by sandfly; needle sharing among injection rug users in endemic regions
Dimorphic life cycle: -Intracellular amastigotes live in macrophages and RES cells -In sandfly, resides as promastigote in digestive tract Syndromes: -Cutaneous ulcer -Visceral (liver, spleen, bone marrow) -mucosal |
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Cutaneous Leishmaniasis
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Endemic throughout world
Incubation period 2 weeks-several yrs Clinical: non (to slow) healing ulcer on exposed skin |
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Mucosal (Mucocutaneous) Leishmaniasis
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Certain species cause involvement in nose, oral cavity, pharynx, larynxx
Dx by biopsy Clinical: Deformed mouth, nose, etc. |
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Visceral Leishmaniasis
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Disseminated infection w/in cells on reticuloendothelial system (liver, spleen, bone marrow)
Incubation 3-8 mo Clinical: fever, weakness, weight loss; nontender hepatosplenomegaly; gray discoloration of extremities Secondary bacterial infections can lead to death Big round abdomen Dx: Giemsa; culture |
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Toxoplasmosis
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T. gandii
Protozoan parasite Transmitted thru undercooked heat (beef or pork) or oocysts in cat feces Major morbidity in immunocompromised, pregnant women/fetus- DO NOT LET PREGNANT WOMEN CHANGE CAT LITTER! Primary infection- usually subclinical in imune competent, can produce mononucleosis-like syn. w/ painless lymphadenitis Disease in immunocompromised- reactivation of dormant infection- encephalitis, brain lesions, myocarditis Pregnant women w/ primary infection during preg- transplacental infection of fetus-> CNS sequelae, chorioretinitis, systemic disease Dx: Serological tests to determine if someone has acute (IgM) taxoplasmosis or is chronically infected (IgG) (IgG- don't know if recent or acquired decades earlier) Biopsy lesions |
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Trichomoniasis
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Trichomonas vaginalis (TV)
Pear-shaped Trophozoite stage only Leading curable STI in US Spectrum of disease W: asymptomatic infection to severe infection w/ complicating PID Spectrum of disease M: asymptomatic infection to severe infection complicating epididymitis or prostatitis Can survive up to 45 min on clothing! Transmission= sexual intercourse |
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Entamoeba
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A diarrheal causing protozoa!
Protozoan parasite Active, trophozoites in host and fresh feces Cyst can survive outside host Ingested cysts turn to trophozoite stage in GI tract Cause of diarrhea (often bloody, severe dysentery) Causes liver abscess Can be transported by blood to brain- brain abscesses Dx: stoop o+p; serology |
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Cryptosporidium
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Intracellular protozoan parasite
Worldwide Epi: major cause of epidemic diarrhea from contaminated water and severe diarrhea in AIDS pts w/ low CD4. Can cause sporadic diarrhea in immunocompetend pts (ingesting contaminated water/food, children at day care, child care workers, travelers, backpackers/hikers/swimmers); found in wells Symptoms: large volume secretory diarrhea, w/ nausea, cramps, vomiting, weigh loss Course: self-limited in immune competent, lasts 2-3 wks AIDS pts- severe diarrhea >2mo Dx: Stool O&P exam w/ AFB, IFA o EIA stains ( w/o special stains, not visualized) |
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Giardia lamblia
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Protozoan parasite
Causes diarrhea, abdominal cramping, bloating, flatulence, chronic diarrhea, malabsorption, weight loss In North America- most commonly id-ed fecal parasite responsible for diarrhea Ingestion as few as 15-25 cysts can cause infection Suspects: children at daycare, travel to endemic areas, ingestion of unfiltered water camping, fecal-oral sex contact Typical presentation: acute onset diarrhea, bloating, flatulence, anorexia, "sulfuric belching" Stools profuse, watery, become greasy and foul smelling (NO blood, pus, mucus) Dx: stool O&P exam for cysts/trophozoites; can get stool Giardia antigen |
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Chemotherapy of Parasitic Infection
-General principles |
Selective Toxicity Based on:
-Parasite location (lumen of bowel) -Differences in host and parasite metabolic pathways -Differences in isofunctional enzymes -Concentration of drug by parasite Parasites- several forms in humans, each w/ diff drug susceptibilities NO vaccines to prevent; myst rely on drugs for prophylaxis and Rx Antiparasitic drugs- used in mass campaigns to control/eradicate...thus should be: -safe -orally effective -curative in single dose -inexpensive |
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Treatment of Helminth Infections
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Adult worms do not multiply in humans; most effective chemotherapeutic targets:
Motility Energy generation |
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Helminth Drugs-
Drugs affecting motility |
Worms have complex nervous system (to control musculature to keep them in place in host)
Active motility is essential to worms to resist expulsion bowel peristalsis 1. Achetylcholine- muscle contraction- micotinic NM agonists 2. Bephenium- muscle contraction; spastic paralysis; NM blocking agent- poorly absorbed 3. Pyrantel- muscle contraction; spastic paralysis; NM blocking agent; AchE inhibitor- pamoate salt; poorly absorbed 4. Piperazine- muscle relaxation- flaccid paralysis- comp inhib of Ach; mimics natural transmitter= mammalian muscle less susceptible Praziquantel -modernized rx of cestode/trematode -causes tetanic contraction of schistotomes by altering Ca2+ transport and membrane integrity Bugs swept to liver, lung |
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Helminth Drugs-
Drugs affecting Energy Generation |
Enteric helminths exist in anaerobic environ
Developed special mech for generating energy Malate transported into mt Terminal oxidase O2-> H2O2 Benzimidazoles -interfere w/ generation of energy from glucose by blocking glucose transport and inhibiting succinate DH activity ALBENDAZOLE- *approved for tapeworm MEBENDAZOLE- approved for most round worms (Broad spectrum drugs for round worms; potent teratogens) |
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Chloroquine
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Antimalarial drug
4-substituted Quinoline Selectively inhibits detoxication of heme in parasites (preventing formation of polymer "malaria pigment" "hemozoin" DRUG OF CHOICE for ovale and malariae malaria High doses- permanent retinopathy Chloroquine-resistant P. falciparum= major public health problems Molec. mech. of resistance = mutations of transporter proteins- efflux Virtually ALL Africa is resistant |
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Mefloquine
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Antimalarial drug
4-substituted Quinoline Selectively inhibits detoxication of heme in parasites (preventing formation of polymer "malaria pigment" "hemozoin" DRUG OF CHOICE for prophylaxis against chloroquine-resistant P. falciparum Expensive CNS toxicity Rapidly emerging resistance |
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Quinine
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Antimalarial drug
4-substituted Quinoline Selectively inhibits detoxication of heme in parasites (preventing formation of polymer "malaria pigment" "hemozoin" DRUG OF CHOICE for TREATMENT of chloroquine-resistant falciparum SHORT halflife compared to others Rapid antiparasitic action Narrow therapeutic window Classic symptoms of CINCHONISM (tinnitus, blurred vision, impaired hearing, confusion, etc) Antiarrhythmic drug quinidine = stereoisomer of quinine- IN EMERGENCY ROOMS IN IV FORM if substituted quinine not available |
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Pyrimethamine plus sulfadoxine (Fansidar)
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Antimalarial
Synergistic antifolate-sulfonamide combination Sequentially and selectively blocks folate synthesis by parasite Widespread resistance and FATAL cutaneous rxns, so use no limited (Steven-Johnson Syndrome) |
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Artemether plus lumefantrine (Coartem)
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Antimalarial
NON-synergistic fixed combination Treatment of uncomplicated falciparum malaria Activation by iron in parasite, artemether and active metabolite form free radicals that alkylate macromolecules Lumefatrine MAY act by preventing heme polymerization Mismatched T1/2s Artemether- brisk and potent reduction in parasite Lumefantrine- has to take care of remainder Limited ability for resistance Efficacy in nonimmune pts not well char. |
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Primaquine
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8-Substituted Quinoline
Significant reliable activity against exoerythrocytic parasites G6PD deficiency, discovered via hemolytic anemia in some indiv by primaquine |
