Eye, Fungi, Antifungals, Parasites (Week 5) Flashcards
Visual parameters
Central visual acuity
Contrast sensitivity
Color vision
Visual field
Dark adaptation
Binocularity
What does 20/40 vision mean?
What you see at 20 feet, normal person can see at 40 feet
Scotomata
Blind spot
Occurs when part of macula not working well
4 things that go wrong to cause vision loss
1) Focused light doesn’t reach the retina (common, fix w/glasses!)
2) Retina doesn’t turn it into nerve impulses
3) Optic nerve doesn’t transmit impulses to the brain
4) Brain doesn’t process them correctly
Pre-retinal and retinal mechanisms for vision
Pre-retinal: barriers to light, misdirection of light
Retinal: tissue loss, disorganization/dysfunctional tissue
Steropsis
Perception of depth
How much refracting of light does the cornea do?
Cornea does 2/3 of refracting of light
(more than lens!)
How does the cornea remain so clear?
Orderly arrangement of collagen fibers
This arrangement is maintained by relative dehydration of stroma (endothelial cells on inner surface of cornea must continually pump water out of corneal stroma)
Abnormalities of the cornea
Epitheliopathies (disruption, edema)
Stromal opacities (scarring, edema)
Irregular shape
Clinical disorders of the cornea
Keratitis sicca
Infectious keratitis
Peripheral ulcerative keratitis (RA)
Pseudophakic corneal edema
Keratoconus
Symptoms and pathology of cornea
Everything is white = opacities
Colored haloes = edema
Distortion = irregularities
Ghost images = refractive errors, epitheliopathies
Abnormalities of the eyelids
Structural defects (tumors)
Entropion/eyelashes hitting eye (trichiasis)
Ectropion/eyelid laxity
Dysfunction (lagophthalmos, ptosis)
Weakness
Anterior segment
Lens forward
How much refracting of light does the lens do?
Lens does 1/3 refracting of light
Only does focus/fine tuning
Does accommodation (change focus for near vision)
Abnormalities of the lens
Dislocation
Opacification (cataract)
Swelling
Hardening with age
Abnormalities of retina
Loss of tissue (infection, degeneration)
Edema
Disturbances of normal position (traction = distortion, retinal detachment = distortion)
Symptoms of macular degeneration
Problem with part of retina
Blurry spot in center of vision
Onchocerciasis
AKA River Blindness
Endemic in equatorial Africa
Transmitted by black fly (filarial nematode)
Tx: Ivermectin (1 x per year for 10 years)
Three serious diseases that cause blindness
Leprosy
Onchocerciasis
Trachoma
Conjunctivitis
Red eye with no pain and nodecreased vision
Cornea clear with good light reflex
Causes: allergic (itching), bacterial (pus, adenopathy, potential source), viral (acute, hx exposure, mucus, preauricular adenopathy)
What causes epidemic conjunctivitis
Adenoviruses
Also could be coxsackie, enterovirus, Strep pneumoniae
Epidemic conjunctivitis
Lasts 10 - 14 days
Highly contagious (for 3 weeks)
Hemorrhagic conjunctivitis
More severe form of conjunctivitis
Vessels of conjunctiva so inflamed that they burst
Herpetic viral conjunctivitis
Due to HSV
Can have recurrences with corneal dendrites
Viral causes of ocular infections
Adenovirus
Coxsackie
Herpes simplex
Herpes zoster
Varicella
CMV
RSV
Bacterial causes of ocular infections
Strep
Staph
Pseudomonas
Neisseria
Syphilis
Borrelia (Lyme disease)
Chlamydia (trachoma)
Mcobacteria (?) that cause ocular infections
Mycobacteria (?) tuberculosis
Leprosy
Atypical forms
Fungal causes of ocular infections
Mucormycosis
Candida
Others
Protozoa and nematodes that cause ocular infections
Acanthamoeba
Filariasis (elephantiasis)
Toxoplasmosis
Toxocara
Methods of infection and spread of ophthalmic disease
1) Direct contact with or without disruption of normal protective barriers (contact lens, trauma, foreign bodies, birth canals, hands; ophthalmia neonatorum)
2) Direct spread (sinus infection spreading into orbit)
3) Hematogenous spread (retinal and choroidal infections, septic embolus from endocarditis, meningitis, fungemia; CMV retinitis)
4) Iatrogenic (post-lasik non-tuberculous mycobacterial infection)
Ophthalmia neonatorum
Spread by direct contact
Chemical conjunctivitis within 24 hours of birth
N. gonorrhoeae within 4 days of birth
Chlamydia within 3 weeks of birth
Herpes simplex
Causes of pediatric acute conjunctivitis
Bacterial (H. influenzae, S. pneumoniae, M. catarrhalis (same as otitis media!))
Viral infection (adenovirus)
Allergy
Polytrim
Good ophthalmic antibiotic
Polymyxin: Gram - coverage
Trimethoprim: Gram + coverage
3 ways to deliver antibiotic therapy for the eye
1) Topical
2) Intravitreal injection
3) Systemic
Fungi
Eukaryotes (have nuclear membrane, chromosomes, mitochondria)
Cell walls made of complex polysaccharides (chitin, chitosan, glucans, mannans)
Plasma membrane contains ergosterol (rather than cholesterol)
Yeasts
Unicellular fungi
Reproduce by budding or fission
Form colonies in culture (similar to bacteria)
Molds
Multicellular fungi
Germ tubes grow with extension of hyphae (either septate or non-septate)
Form cottony colony called mycelium
Fungal reproduction
Asexual reproduction without propagules (hyphae form new mycelium)
Asexual reproduction by propagules (either conida or sporangia)
Dimorphism
In environment, grow as mold
In infected host, grow as yeast
This is temperature dependent
Fungal pathogenesis in human disease
Hypersensitivity
Mycotoxicoses (release toxin)
Colonization
Invasive disease (but virulence factors not as well understood)
Hypersensitivity disease
Allergic reaction to fungal spores or other components
Can cause pneumonitis, rhinitis, asthma, alveolitis, sinusitis
Can do skin tests with purified antigens to diagnose
Mycotoxicoses
Ergot alkaloids: alpha-adrenergic agonist caused vasoconstriction and gangrene, and interaction with dopaminergic and serotinergic receptors caused hallucinations
Aflatoxins (Aspergillus flavus) causes liver disease, and is possible carcinogen (contaminated peanuts)
Psychotropics (psilocybin and psilocin used in rituals and as recreational drugs)
Different layers fungi can colonize
1) Superficial: outermost layer of skin and hair, colonization of mucosa
2) Cutaneous: extend into epidermis, invade hair and nail
3) Subcutaneous: invade dermis, subcutaneous tissue, muscle, fascia
4) Systemic: originate in lung, may disseminate to other organs
Superficial mycoses
Colonize dead tissue from dying skin cells and lipids
Usually cosmetic problems
Tinea versicolor (M. furfur; pigmented macules, “spaghetti and meatballs” and likes fatty acid)
Tinea nigra (H. werneckii; produces melanin)
White or black piedra (Trichosporon species)
Cutaneous mycoses
“Dermatophytes” = Microsporum, Trichophyton, Epidermophyton
In epidermis
Skin, hair, nails
Clinical manifestation called “tinea” or “ringworm”
Named for structure infected: Tinea pedis, capitis, magnus, unguium, cororis, cruris
Different kinds of dermatophytes
Geophilic: reservoir in environment, soil
Zoophilic: reservoir in animals
Anthropophilic: like covered areas of skin
All use keratin as nutritional substrate
Subcutaneous mycoses
Fungal infections invasive into soft tissue
Sporotrichosis (sporothrix shenkii) is only one in US
Usually at site of trauma
May require surgery and antifungal therapy
Lymphocutaneous sporotrichosis
Sporothrix schneckii
Dimorphic
Get from rose thorn scrape –> tracks up lymphatics
Causes ulcerating lesions, nodules, adenitis and rarely pulmonary and disseminated disease
Dematiaceous fungi
“Black molds”
Chromoblastomycosis
Phaeohyphomycosis (chronic allergic sinusitis)
Eumycotic mycetoma (madura foot)
Systemic mycoses
Dimorphic: histoplasma, blastomyces, coccidioides (spherules), paracoccidioides
Monomorphic yeast: cryptococcus
Usually enter by inhalation in lung –> short or asymptomatic respiratory infection –> secondary spread or dissemination
Coccidioides immitis
Coccidioidomycosis = “San Joaquin Valley Fever”
Inhaled from soil in southwest US
Mild respiratory infection
Some may get progressive pulmonary infection
Dissemination to skin, bones, CNS (especially in dark skinned people)
Erythema nodosum or erythema marginatum with associated non-infectious arthritis
Unique yeast form (spherule with tiny coccidioides inside)
Thin walled cavity
Directly infectious to microbiologists because of environment
Complement fixation (IgG to chitinase) correlates with active disease, use to monitor infection
Opportunistic mycoses
Candida
Aspergillus
Zygomyces
Fusarium
Scedosporium
Penicillium
Pneumocystis
3 targets for antifungal drgus
1) Fungal cell wall
2) Cell membrane (ergosterol)
3) Nucleotide metabolism
Antifungals that disrupt fungal cell wall
Echinocandins: capsofungin, anidulafungin, micafungin
Antifungals that disrupt fungal cell membrane
Allyamine: terbinafine
Azoles: ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole
Polyenes: amphotericin B (including lipid formulations)
Antifungals that are antimetabolites
Pyrimidine analogue: 5-flucytosine
Antifungal that is a microtubule assembly inhibitor
Griseofulvin
Amphotericin B
Polyene antifungal
“Atomic bomb” of fungal infection
Extremely broad spectrum; used for cryptococcus and aspergillus fumigatus
Disrupt fungal cell membrane by binding directly to ergosterol and opening up a channel that lets intracellular cations out
IV for systemic or topical for sinus
Adverse effects: fast infusion can cause fever, chills, nausea; nephrotoxicity
Lipid formulations show better tissue distribution and lower toxicity
Ketoconazole
Azole
Not as well absorbed
Not great spectrum of activity
Antifungal triazoles
Inhibit ergosterol synthesis by interfering with lanosterol 14alpha demethylase (fungal CYP450 molecule)
Ex: fluconazole, voriconazole, posaconazole
Fluconazole
Triazole
IV or PO
Active against cryptococcus, candida (best drug for candida), coccidioimycosis
Gets into CSF
Voriconazole
Triazole
IV or PO
Treatment of choice for invasive aspergillosis
Active against candida
Gets into CSF
Posaconazole
Triazole
PO
Active against zygomycosis, candida, aspergillus
Terbafine
Allylamine
Inhibits squalene epoxidase step to inhibit ergosterol synthesis
Oral or topical
Used for onychomycosis, tinea
Adverse effects: GI upset, hematotoxocity
Echinocandins
Inhibits beta glucan synthetase activity so cannot synthesize cell wall
IV
Ex: caspofungin, anidulafungin, micafungin
Caspofungin
Echinocandin
IV
Use to treat invasive candida, invasive aspergillosis (second line or together with voriconazole)
5-flucytosine
Antimetabolite (prevents DNA and RNA synthesis)
PO
Used to treat candida and cryptococcal meningitis (together with amphotericin B)
Topical antifungals
Polyenes: amphotericin, nystatin
Azoles: ketoconazole, butoconazole, clotrimazole, econazole, miconazole
Allylamine: terbinafine, naftifine
Antimetabolites: ciclopirox, tolnaftate, others
How to treat different dermatophytoses
Treat tinea corporis, cruris, pedis with topical antifungal (clotrimazole, econazole; don’t use products containing corticosteroids!)
Treat tinea capitis with systemic therapy (terbinafine, itraconazole, griseofulvin, fluconazole)
Treat onychomycosis (nail infections) with systemic therapy (terbinafine, itraconazole, griseofulvin, fluconazole)
Kerion
Fungal infection of the hair follicles accompanied by secondary bacterial infection and marked by raised, usually pus-filled and spongy lesions
Parasite
Free-living, eukaryotic cells (?)
Parasite depends metabolically on host and causes harm to host
Have mouth called cytostome
Reproduce sexually or asexually
Secrete protective coat and become cyst to infect humans; after ingestion can convert back into motile form called trophozoite
Protozoa
Single celled parasites
Amoebae: entamoeba; have no distinct shape
Apicomplexa: plasmodium, toxoplasma, cryptosporidium; have group of organelles at one end of cell
Flagellates: giardia, leishmania, trypanosoma, trichomonas; have flagella
Helminths
Multicellular parasites
Nematodes: round worms
Platyhelminths: flat worms (cestodes/tapeworms, trematodes/flukes)
Transmission of parasites
1) Direct contamination (ingestion/fecal-oral, active penetration, passive transfer)
2) Vector borne (mosquitoes or other insects)
Ova and parasite test (O&P)
Microscopic observation of stool sample
If do test 3x, is 98% effective
Cyst
Form the parasite is in when it infects humans (we eat cysts)
To form cyst, the protozoa secrete protective coat and shrink into round armored form
Non-dividing, rigid cell coat, resistant to water and dessication
Trophozoite
Form the parasite is in when it causes disease (after we eat cyst, it gets into our intestine and converts back into trophozoite)
Motile, dividing (binary fission), labile cell membrane
Excystation
When trophozoites “hatch” from initial cyst
How do you differentiate Entamoeba histolytica from Entamoeba dispar?
Have to do PCR assay because they look identical
Anthroponosis vs. zoonosis
Anthroponosis: only humans
Zoonosis: humans and other animals (reservoir host is animal that maintains parasite in nature)
Cyclospora cayetenensis
Cyclosporiasis
AKA Cyanobacteria-like Bodies (CLBs)
May cause diarrhea lasting up to 6 weeks
Occurs in immunodeficient adults and travelers
Diagnosis with acid-fast stain (acid-variable cysts in feces)
Fluoresce under UV light
Naegleria fowleri
Causes Primary Amebic Meningoencephalitis
Acute infection in normal host
Enters through nasal passage when in fresh warm water (hot springs, hot tubs)
“Fowl” play! 95% of people die within 1 week of infection
Exist as cysts, trophozoites, flagellates but amebic/trophozoite form is what infects us
Diagnose by seeing amebic trophozoites in CSF and tissue, or flagellates in tissue
Looks exactly like bacterial meningitis (high neutrophils, high protein, low glucose) but obvi no bacteria when you culture
Treatment: amphotericin B
Acanthamoeba
Causes Granulomatous Amebic Encephalitis (GAE) by entering lower respiratory tract
or broken skin
Chronic infection in immunocompromised host
Causes Ocular Keratitis (in normal hosts) if contaminates contact lenses!
Kinetoplast
Part of the flagella of protozoa
Terms for flagellated (kinetoplastid) protozoa
Trypomastigote: has flagella, is highly motile, is extracellular form of parasite
Amastigote: no flagella, intracellular form of parasite
Trypanosoma brucei brucei
Does not affect humans, only infects cows
Still carried by tsetse fly
Human resistance to T. b. brucei
Human HDL component ApoL1 lyses T. b. brucei
However, some people have mutation in ApoL1 that also causes lysis of T. b. rhodesiense, which sounds good but actually correlates with greater incidence of kidney disease
Are trypomastigotes detectable in the blood in Chagas Disease?
Only during the acute phase
Not in the indeterminate and chronic phases (but do see amastigotes in muscle)
This means that we can do microscopy to see flagellated protozoa in blood during the acute stage but must do serology/PCR/xenodiagnosis in the indeterminate and chronic phase
Modes of transmission of Chagas Disease
1) Reduviid bug feces (vector-borne)
2) Congenital (vertical transmission)
3) Blood transfusion
4) Ingestion (drink sugar cane juice)
Different kinds of leishmaniasis
Old world cutaneous: Africa, Middle East (L. major) = oriental sores
New World cutaneous: Latin America (L. mexicana) = Chiclera’s ulcer
New World mucocutaneous: Latin America (L. braziliensis)
Visceral: Africa, India, Brazil (L. donovani)
Leishmaniasis infantum
In Southern Europe
Infects children and HIV positive people
Lifecycle of leishmaniasis
1) Promastigote exits sand fly’s mouth and goes into human bloodstream
2) Engulfed by macrophage
3) Amastigotes divide within macrophage
4) Amastigotes released and infect other cells
Recurrence of symptoms in malaria
Chills –> fever –> sweats
Parasites invade RBCs –> RBCs burst they release lots of foreign material and the immune system responds to those antigens by creating fever (inflammation, cytokines, etc) –> hypothalamus resets and causes profuse sweating to stop fever
Plasmodium (malaria) lifecycle
1) Sporozoite comes out of mosquito and goes into human blood
2) Sporozoite gets to liver within 30 seconds
3) Sporozoite gets into hepatocyte and turns into merozoite, which replicates
4) Merozoites released into bloodstream and infect RBCs
5) In RBCs, merozoites replicate (by schizogony, NOT binary fission) then turn into trophozoites
6) Trophozoites turn into schizonts which undergo nuclear division but NOT cytoplasmic division so get multinucleated RBC
7) RBC bursts and merozoites spread to other RBCs (?)
Different manifestations of P. malariae compared to other plasmodium species
P. malariae causes immune complex disease and renal failure
Other Plasmodium species cause splenomegaly, hepatomegaly, immunosuppression
Relapse vs. recrudescence
P. vivax causes relapsing disease due to reactivation of hypnozoite stage in liver
P. falciparum causes recrudescence due to residual low levels of merozoites in RBCs
Hypnozoite
Only exists in P. vivax (and P. ovale)
Some sporozoites don’t divide in hepatocytes but form dormant hypnozoites in liver and can cause relapse of malaria months to years later
Which receptors do P. vivax and P. falciparum bind to in order to enter RBCs?
P. vivax binds duffy antigen receptor on immature RBCs and causes them to enlarge
P. falciparum binds several receptors on immature and mature RBCs (which can’t enlarge)
How does P. falciparum cause attachment of RBCs to epithelial cells in brain capillaries?
P. falciparum secretes protein that inserts into RBC membrane causing “sticky knobs” on outside of RBC that let RBCs attach to capillary walls
Note: can undergo antigenic variation so host cannot mount successful immune response to clear parasite
Malaria treatment
Primaquine prevents relapse by P. vivax
Quinine 100% effective but try not to use all the time because P. falciparum resistance is a problem
Chloroquine only works in some regions because lots of resistance now (and toxicity)
Mefloquine (LARIUM) causes GI and CNS disorders, vivid dreams
Atovaquone/proguanil (MALARONE) is a mitochondrial and DHFR inhibitor used for P. falciparum
Pyrimethamine (FANSIDAR) is a DHFR inhibitor
Artemisinin (Qinghaosu) has been used in China for thousands of years but only limited FDA approval in US
Why haven’t we developed a good malaria vaccine yet?
Need to stimulate cell-mediated immune system and haven’t been able to do that yet
Babesia microti
Babesiosis (Nantucket Fever)
Worldwide, but in NE and NW states of US
Transmitted via ixodes deer tick, but mouse is reservoir host
Trophozoites asexually bud and divide into 4 merozoites that stick together to form an x-shaped tetrad (“Maltese cross”)
Treat with quinine and clindamycin
Toxoplasmosis infection during pregnancy
1st trimester: spontaneous abortion, stillbirth
2nd/3rd trimester: chorioretinitis, hydrocephalus
Toxoplasma lifecycle
Rodent eats spore –> cyst forms in rodent (intermediate host = asexual replication cycle) –> cat eats rodent –> oocysts form in cat (definitive host = sexual replication cycle) –> cat poops out oocysts –> oocysts form spores
How do humans get toxoplasma?
1) Ingest cyst (oocyst) in cat feces from changing litter box
2) Ingest tissue cyst (pseudocyst) in raw beef
3) Congenital if mother gets initial/active infection during pregnancy
Stages of life of helminths
1) Egg: dormant, transmission (like cyst of protozoa)
2) Larva: immature, disease
3) Adult: mature, disease
Note: 1 egg –> 1 helminth
Definitive vs. intermediate host
Definitive host: harbors adult stage
Intermediate host: harbors larval stage
Note: this is different from indeterminate host!
When are humans accidental intermediate hosts?
Cutaneous larva migrans (dog hookworm)
When are humans definitive hosts?
Taenia solium, Taenia saginata
Schistosoma species
S. mansoni: in adult inferior mesenteric venules and near rectum; eggs in feces; fibrosis around eggs trapped in liver and intestinal tract; chronic Salmonella infection
S. japonicum: adult in superior mesenteric venules; eggs in feces
S. haematobium: adult in venules around urinary bladder; eggs in urine; correlation with bladder cancer
Trichuris trichura
Whipworm
Similar to Pinworm (Enterobius vermicularis) but no perianal itching
Bloody diarrhea, malnutrition, anemia, rectal prolapse
Baylisascaris procyon
Raccoon roundworm
Possible bioterrorism agent because eggs can be distributed in aerosol
Visceral larva migrans can be asymptomatic but can cause blindness, neurologic damage, death
No treatment
Autoinfection
The entire lifecycle of the parasite occurs in the host without need for another host
Usually eggs or larvae are ingested, grow into adults and then produce eggs or larvae that must exit the host (to incubate in soil, etc) in order to go infect a new host
With autoinfection, adult produces larvae that can penetrate intestinal wall (etc) and infect the host again right away without leaving!
Ex: Strongyloides stercoralis, Enteroius vermicularis, Taenia solium
Classes of protozoa
Amoebae: entamoeba
Apicomplexa: plasmodium, toxoplasma, cryptosporidium
Flagellates: giardia, leishmania, trypanosoma, trichomonas
Classes of helminths
Nematodes (roundworms): Ascaris lumbricoides, Enterobias vermicularis, Trichinella spiralis, Strongyloides stercoralis, Necator americanus, Ancyclostoma duodenale, Onchocerca volvulus, Wuchereria bancrofti
Platyhelminths (flatworms), Cestodes (tapeworms): Taenia saginata, Taenia solium, Echinococcus granulosus
Platyhelminths (flatworms), Trematodes (flukes): Schistosoma
Mucormycosis (zygomycosis)
Due to fungal infection with Mucor, Rhizopus
Rhinocerebral (sinuses, orbits, brain), pulmonary, cutaneous, GI, often fatal
Diagnosis: necrotic palate, CT imaging of sinus, brain, non-septate hyphae at 45 degree angle (or 90??)
Treatment: surgical debridement, amphotericin B synergy with rifampin, posaconazole
Fusarium
Mold with banana shaped macroconidia
Skin disease, disseminated disease (hematologic malignancy, bone marrow transplant)
Diagnose by blood culture in dissemination
Use voriconazole, posaconazole (resistant to amphotericin B and caspofungin)
Scedosporium
S apiospermum, S prolificans
Local disease in immunocompetent hosts: bone, joint, skin, eye
Immunocompromised hosts: pulmonary infection, dissemination, brain
Culture from tissue
Treat with voriconazole, itraconazole, caspofungin (may be resistant to amphotericin B)
Penicillium
P marnefeii
Dimorphic found in SEA
Immunocompromised hosts: disseminated infection with skin manifestation
Culture from blood or tissue
Treat with amphotericin B, itraconazole, voriconazole, terbinafine
