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136 Cards in this Set
- Front
- Back
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Griseofulvin is produced by...
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Penicillium griseofulvin.
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Griseofulvin acts by...
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Interacts with tubulin and acts as a mitotic poison
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Griseofulvin is effective only against dermatophytes.
True or False? |
True
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Amphotericin B acts by...
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Combines with membrane sterols to alter permeability with a leak of intracellular contents.
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Amphotericin B' s toxicity is due to...
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The interaction with ergosterol is responsible for the therapeutic effect, while the interaction with cholesterol is responsible for much of the toxicity.
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Resistant Fungi to Amphotericin B
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Pseudallescheria boydii
Trichosporon beigelii Scedosporium inflatum Candida lusitaniae |
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Amphotericin B excretion...
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Renal excretion: 3-5%.
No adjustment in dose needed even in the anephric patient. AMB is not removed by peritoneal or hemodialysis. |
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Amphotericin B toxic side effects...
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Infusion related side effects: Fever, rigors, headache, nausea, vomiting
Ampho Pharmacophobia |
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Amphotericin B & premedication by Meperidine...
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Meperidine (0.5mg/kg) can rapidly eliminate rigors.
Can be used as a premedication to prevent rigors, very effective. |
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Nephrotoxicity caused by Amphotericin B occurs b/c...
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Direct distal tubular toxicity and renal artery constriction, which causes increased renal potassium and magnesium clearance with resultant hypokalemia and hypomagnesemia.
Impaired hydrogen ion excretion. |
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AMB Nephrotoxicity Will increase potassium losses.
True or False |
True
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Salt loading with 500cc NS has become a common practice prior to AMB infusions.
True or False |
True
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Lipid Formulations of Amphotericin B...
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Lipids are more selectively taken up by the reticuloendothelial system in the liver, spleen, lung and lymph nodes.
May be taken up by monocytes further targeting the drug to sites of infection. Renal concentration is saturable, with little increase in concentration as the dose increases. |
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Abelcet is activated by ...
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phospholipases
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Abelcet dose...
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The effective dose is 4 to 5 times higher than for AMB so that the usual dose is 5 mg/kg/day.
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Abelcet Toxicity
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chills and fevers occur at a similar rate as AMB.
decrease in creatinine during therapy. |
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Amphotec has decreased nephrotoxicity, but increased infusion related toxicity compared to AMB; rarely used at the present time.
True or False? |
True
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Ambisome is a true liposomal product & its toxicity...
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Lowest rate of renal and infusion related toxicity
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Amphotericin B Oral Suspension is used for..
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oral thrush (no esophageal symptoms)
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Flucytosine: Mechanism of Action:
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is deaminated by cytosine deaminase to 5-fluorouracil (5-FU), an agent used to treat colon cancer.
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Flucytosine is not directly toxic to human cells b/c...
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Human cells do not contain cytosine deaminase.
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Flucytosine is toxic to humans b/c
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E.coli has high levels of cytosine deaminase, and therefore serum levels can be similar to those seen in chemotherapy with 5-FU.
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Flucytosine is limited to these infections:
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Candida albicans and some other candida species.
Cryptococcus neoformans. Candida glabrata. |
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Flucytosine is almost never used as a single agent & is combined with...
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Synergistic with AMB
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Flucytosine has the same toxicities as 5-FU used to treat cancer
True or False? |
True
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Flucytosine levels are done by bioassay at a reference lab in California with >1 week turnaround.
True or False? |
True
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Itraconazole absorption requires gastric acidity therefore admisnister with...
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Coke or Pepsi (not diet)
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Itraconazole []...
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Low serum levels, high tissue levels
CSF Concentration: negligible. |
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Itraconazole: Drug Interactions
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Increases digoxin and cyclosporin levels
May increase the anticoagulant effect of coumadin and potentiate the effect of oral hypoglycemics |
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Itraconazole dose ...
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200mg/day
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Itraconazole reaches SS in how many days?
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Requires 10-14 days to reach steady state concentration at 200 mg QD
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For life threatening infections, Itraconazole should be given...
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a loading dose of 200mg. TID for three days is recommended.
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Itraconazole is poorly absorbed b/c...
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it is a hydrophobic molecule
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The oral solution of Itraconazole tastes like motor oil.
True or False? |
True
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The oral solution of Itraconazole has absorption that is greater, equal or less to the capsule form?
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absorption is twice as good as the capsule
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The oral solution of Itraconazole should be taken with...
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Oral solution should be taken on an empty stomach (opposite of the capsule)
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Fluconazole mechanism
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Inhibits ergosterol synthesis by inhibition of the P-450 enzyme system, almost 200X higher levels required to inhibit the human enzyme system as compared to ketoconazole.
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Fluconazole is found predominatly in what tissue?
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CNS
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Fluconazole serum levels equivalent with oral or intravenous routes
True or False? |
True
Gastric acidity not required for absorption. Steady State: 5-7 days, usually give double dose on first day |
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Fluconazole Drug Interactions...
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May increase activity of coumadin
Increases dilantin and cyclosporin levels Rifampin significantly decreases Fluconazole serum levels (20-25%) |
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Fluconazole Therapeutic Indications
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Oral and esophageal candidiasis.
Candida UTI. Prevention of relapse of cryptococcal meningitis. Coccidioidal meningitis. Surgical and nosocomial candidiasis. Hepatosplenic candidiasis |
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Voriconazole Side effects
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: reversible, dose related visual disturbances within 30 minutes of dosing: increased brightness, blurred vision, altered color perception and photopsia (sensation of lights, sparks and colors) which resolves in about 30 minutes.
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Voriconazole q12 hour dosing
True or False? |
True
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Posaconazole Represents a major breakthrough for ...
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chromoblastomycosis, mycetoma, zygomycosis, Paecilomyces, Penicillium, Scedosporium apiospermum and other refractory mold infections
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Caspofungin mode of action...
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from the echinocandin class & inhibits the synthesis of B (1,3)-D-glucan, an integral component of the fungal cell wall.
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Caspofungin is active against...
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Active against Aspergillus species and all species of Candida, including fluconazole resistant (except poor activity against C. parapsilosis).
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Caspofungin is drug of choice for...
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Rapidly becoming the drug of choice for candidemia.
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Caspofungin: Adverse Events
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Well tolerated.
Histamine mediated symptoms have been noted (rash, pruritus, sensation of warmth). |
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Terbinafine mode of action...
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inhibits the transformation of squalene to squalene epoxidase which is responsible for the cyclization of squalene to lanosterol; results in a 20% inhibition of ergosterol.
Results in squalene accumulation which is toxic to fungi. |
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Terbinafine spectrum of activity
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Very active against dermatophytes and often used to treat onychomycosis , but poor activity against yeast.
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Histoplasmosis characteristics
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Ohio and Mississippi River Valleys (up to 80% skin test reactivity), also endemic in Virginia and Maryland along the Eastern Seaboard.
Grows in soil enriched by fecal material of chickens, bats and birds, especially starlings. Outbreaks have been associated with spelunking, cleaning chicken coops, and demolishing buildings during urban renewal. |
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Histoplasmosis is found in the tissue state as...
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small (2-5um) budding yeast found inside macrophages
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Histoplasmosis infection characteristics
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Infection is by inhalation followed by transient fungemia which results in calcified granulomas in the liver and spleen (commonly seen in xrays of persons from the midwest).
500,000 persons infected each year in the US, 95% of infections are asymptomatic. 5% develop a self limited illness with fever, cough, headache, myalgias, and anorexia. 1% develop progressive disease, usually immunocompromised or large inoculum. |
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Histoplasmosis is linked to cave exploration
True or false? |
True
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Histoplasmosis: Mediastinal Fibrosis
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Caused by an overly exuberant immune response resulting in a fibrous proliferation in the mediastinum.
Histoplasmosis - DisseminatedMay progress to constrict airways (bronchi) or vasculature (superior vena cava or pulmonary artery constriction). Responds poorly to antifungal therapy or surgery. |
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Histoplasmosis - Disseminated
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Due to defects in cell mediated immunity
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Acute Disseminated Histoplasmosis
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Most frequent in patients with defective T-cell immunity-hematologic malignancies, corticosteroids, AIDS, transplant recipients and infants.
Fever, weight loss, hepatosplenomegaly, and pancytopenia. AIDS patients may present with a fulminating syndrome similar to bacterial sepsis – shock, adult respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC). |
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Chronic Disseminated Histoplasmosis
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Symptoms progress over months (subacute) to years (chronic).
Oral ulcerations, adrenalitis, and rarely endocarditis and meningitis. |
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Histoplasmosis - Diagnosis
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Urine and blood polysaccharide antigen detection by radioimmunoassay and direct stains of buffy coat and tissue biopsy or bone marrow.
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Histoplasmosis – Diagnosis for disseminated disease
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Culture of blood (lysis centrifugation), bone marrow, and urine
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Histoplasmosis – Skin Test
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Used in epidemiologic surveys, 80% of persons in endemic areas may be positive.
No diagnostic value, may falsely elevate serologic tests and often negative with dissemination. |
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Histoplasmosis - Treatment
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Amphotericin B for severely or acutely ill.
Itraconazole for moderately ill and for chronic suppression as is needed for AIDS patients to prevent relapse. |
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Blastomycosis characteristics
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Dimorphic.
broad based buds. Endemic in the Ohio and Mississippi River Valley regions, as well as the Missouri and Arkansas River basins. Most frequently reported from Kentucky, Arkansas, Mississippi, North Carolina, Tennessee and Louisiana ( in descending order of incidence). Also found in Wisconsin, Minnesota, Illinois, Virginia (microfocus in Franklin, ,Va). |
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Blastomycosis - Epidemiology
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Outbreaks have involved dogs and humans together, among raccoon hunters and their dogs in Southampton Co., Va.
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Blastomycosis - Clinical, typical patient and symptoms
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Typical patient is a middle aged male with extensive outdoor occupational or recreational exposure.
May have pulmonary, cutaneous, bone, genitourinary or CNS involvement. |
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Blastomycosis: specific Clinical manifestations
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25-50% of cases have osteomyelitis, any bone may be involved.
Prostatitis and epididymo-orchitis are the next most common. Pulmonary infection may be acute with ARDS with heavy inoculation, self limited pneumonitis or chronic disease. |
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Blastomycosis - Diagnosis
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Most diagnoses are made by identification of the broad based budding yeast in tissue biopsy or purulent material or by culture.
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Blastomycosis - Treatment
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Itraconazole is the drug of choice for non-life threatening disease.
Amphotericin B is the treatment of choice for life threatening acute infections. |
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Paracoccidioidomycosis characteristics
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Caused by Paracoccidioides brasiliensis.
Dimorphic fungus with multiple buds in the yeast phase, which looks like a “pilots wheel”. Size: 15-30um with 5-10um buds. Portal of entry is by inhalation. |
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Paracoccidioidomycosis: Epidemiology
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Central and South America, esp. Brazil, Venezuela and Columbia.
Males have clinical disease 9x more common than women. Estradiol inhibits the mycelia to yeast transformation. |
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Paracoccidioidomycosis: Clinical
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pneumonia
Most typical are oral, nasal and facial nodular ulcerative lesions. |
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Paracoccidioidomycosis: Diagnosis
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Serologic tests use both yeast and mycelial antigens and are considered reliable (EIA, CF and agar gel diffusions).
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Up to 300,000 new cases/year of
Coccidioidomycosis True or False? |
True
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Mycelial Phase of Coccidioidomycosis
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Mycelial phase grows in soil and on lab media.
Highly infectious. Warn laboratory about potential isolate. |
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Spherule Phase of Coccidioidomycosis
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Parasitic, phase in humans.
Non-infectious. -Endospores (2-5u). -Spherules (10-80u). |
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Portal of Entry of Coccidioidomycosis
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Inhalation of arthrospores in dust.
Infective dose: 10 arthrospores. Endemic in southern California, esp. the San Joaquin Valley, New Mexico, west Texas and Arizona. |
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Primary Infection of Coccidioidomycosis
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60% subclinical, asymptomatic, detected by positive skin test.
40% clinical pulmonary disease; causes 30% of all community acquired pneumonia in Arizona, esp. those who have lived in the area <10 years. 1% disseminated. |
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Coccidioidomycosis clinical
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Primary infection may be associated with a hypersensitivity reaction, such as erythema nodosum and arthralgias, often referred to as Valley fever or “miners bumps.”
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Disseminated Cocci clinical
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Marked increase in the rate of dissemination among African Americans (10-15X) and Filipinos (50X), pregnancy, immunosuppression and AIDS (most common cause of death in AIDS in Tucson, 25% of deaths).
Clues: persistent symptoms, negative skin tests, rising eosinophilia. |
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Coccidioidin Skin Test Measures delayed hypersensitivity; excellent prognosticator.
True or False? |
True
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Complement Fixation: Diagnostic Value in Coccidioidomycosis
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Rising titer of concern, falling titers with therapy or time is good prognostically.
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Disseminated Coccidioidomycosis: Drug of Choice
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AMB for fulminant or life threatening infection.
Fluconazole for moderate disease and meningitis. |
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Risk Factors for Fungal Infections
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Underlying host defects:
Neutropenia. T-cell dysfunction. Diabetes. Immunosuppression: Cytoxic chemotherapy. High dose corticosteroids. Bone Marrow/Organ transplantation. |
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Outcomes are more closely related to the degree of immunosuppression rather than the particular fungus.
True or False? |
True
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Candida Species characteristics
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Normal inhabitants of the oral cavity, vagina and GI tract.
80% of normal person are colonized. Reproduces by forming buds and pseudohyphae. |
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C. krusei is always resistant to fluconazole
True or False? |
True
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C. glabrata has intermediate resistant to fluconazole requiring higher than usual doses because of drug efflux
True or False? |
True
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C. parapsilosis- almost always related to intravascular catheter infections (forms extensive biofilms)
True or False? |
True
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Candida-Host Defense
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Dry intact skin.
Normal gastrointestinal flora, esp. the anaerobic flora. Phagocytosis by neutrophils and macrophages. Cell mediated immunity. |
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Candidiasis: Predisposing Factors
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Neutropenia (chemotherapy).
Depressed cell medicate immunity (AIDS). Mucositis (chemotherapy). Broad spectrum antibiotics. Intravenous catheters (hyperalimentation). Abdominal surgery (esp. upper intestinal). Diabetes. |
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Candidiasis – Skin symptoms and treatment
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skin-intertriginous areas
Erythematous, macerated skin with vesiculopustular satellite lesions. Treatment: Dry skin, azole creams (Lotrimin, 1%, miconazole). |
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Vulvovaginitis predisposing factors
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75% of women have suffered at least one episode.
Predisposition: antibiotics, steroids, BCP, pregnancy, diabetes. |
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Oral Thrush-Epidemiology
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Neonates
Recent antibiotics Denture wearers Inhaled corticosteroids HIV/AIDS |
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Oral Thrush - Clinical
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Angular chelitis.
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Oral Candidiasis (Thrush)
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84% of persons with HIV will have positive cultures for Candida: don’t culture, for diagnosis use KOH or gram stain or clinical recognition.
Esophageal symptoms plus oral Candida: 90-100% PPV for esophageal disease. Esophageal symptoms without oral Candida: 82-96% NPV for esophageal disease. |
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Chronic Mucocutaneous Candidiasis
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Severe chronic cutaneous (skin and nails) and mucosal infections.
Most commonly a narrow and specific problem with cell mediated immunity against Candida. Almost never develop systemic or disseminated disease. |
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Hepatosplenic Candidiasis
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Hepatomegaly, elevated alkaline phosphatase, leukocytosis, CAT scan with multiple nodular densities in the liver or spleen.
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Candidiasis: Diagnosis
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KOH or gram stain of mucosal scrapings.
Will grow rapidly as a yeast on most laboratory media. Does not require special fungal media or fungal blood cultures, although may improve yield. C. albicans is identified by the germ tube test-production of hyphal outgrowths (germ tubes) when grown in serum at 37ºC, examine at 2-3 hours. |
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Cryptococcosis
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inhalation of Cryptococcus
Capsular mucopolysaccharide inhibits phagocytosis. Not dimorphic, grows as encapsulated budding yeast at 25º C and 37º C, 4-10 um in size. |
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Cryptococcosis - Clinical
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Can cause acute and chronic pneumonia, often appears as a mass lesion with a pleural base.
Predilection for CNS infection; most common cause of fungal meningitis, may also cause mass lesions (Cryptococcomas). Most common cause of meningitis in AIDS patients. Skin lesions often misdiagnosed as molluscum contagiosum. |
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Cryptococcosis - Diagnosis
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Rapid diagnosis of meningitis can be made with an India ink preparation.
50% sensitive, may be confused with lymphocytes and other artifacts. In tissue, mucicarmine will stain the capsule |
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Cryptococcosis results in...
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Results in minimal tissue inflammation, may be a mass of yeasts or meningitis without pleocytosis, especially in immunocompromised.
May use bird seed agar |
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A. terreus, which is more resistant to AMB
True or False? |
True due to decreased ergosterol content in the cell membrane.
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Aspergillosis - transmission
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Inhalation of conidia which germinate to form hyphae which are involved in disease.
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Allergic Bronchopulmonary Aspergillosis
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Episodic asthma, expectoration of brown mucous plugs, pulmonary infiltrates.
Eosinophilia, immediate skin test reactivity to Aspergillus antigens, elevated IgE antibodies to A. fumigatus, elevated total IgE. Corticosteroids are the treatment of choice. |
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Aspergillus – Fungus Balls
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Saprophytic colonization of old cavities; a mass of intertwined hyphae.
Solitary, oval mass within a cavity which produces a “crescent sign.” Hemoptysis is the most common symptom, may be massive. |
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Aspergillosis - Invasive Associated with ...
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profound immunosuppression with prolonged neutropenia or corticosteroids, especially transplants, AML and multiple myeloma.
Nodular or patchy lung infiltration, single or multiple, with a surrounding ground-glass infiltrate (“halo sign”) which reflects hemorrhage secondary to blood vessel invasion or an area of tissue necrosis and cavitation “crescent sign.” |
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Cutaneous Aspergillosis Present with ...
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progressive ulcers with a thick black eschar.
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Aspergillosis - Diagnosis
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No antibody or skin tests.
Blood cultures almost never positive even with widely disseminated disease or endocarditis. Expectorated sputum often contaminated. Biopsy of affected tissue with culture or histologic examination for septate hyphae with acute angle branching with a 3um diameter. |
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Beta-D-Glucan Detection Assay
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Beta-D-Glucan (BG) is a component of the cell wall of a wide variety of fungi.
Absent with cryptococcus and zygomycosis |
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Aspergillus: Treatment
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Voriconazole has become drug of choice
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Zygomycosis: Risk Factors
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Metabolic acidosis
Hyperglycemia Corticosteroids Profound leukopenia Deferoxamine therapy Long term prophylaxis with voriconazole |
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Zygomycosis: Mycology
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Form coenocytic hyphae
For R. arrhizus, optimum growth occurs in acid pH or high glucose content, 39 degrees C, and it possesses a ketoreductase. |
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Zygomycosis: Rhinocerebral
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Most common in diabetics with ketoacidosis
Originates in the paranasal sinus, spreads to orbit, hard palate and brain. Periorbital edema, proptosis, epistaxis, necrotic black eschars in the nares or on the hard palate |
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Zygomycosis: Clinical
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Angioinvasive fungus which results in tissue infarction, necrosis and hemorrhage
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Zygomycosis: Diagnosis
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No serologic or skin test.
Histologic examination of biopsy of involved tissue with broad, irregular, non-septate hyphae with wide angle branching, “ribbon-like”. |
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Zygomycosis: Treatment
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Correction of underlying metabolic abnormality.
Amphotericin B, high dose but responses are low with mortality of 75%. Surgical debridement, often extensive and mutilating. |
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Hyalohyphomycosis is a Disease due to...
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molds with hyaline, light-colored hyphal elements without pigment in their cell walls. (Fusarium, Scedosporium, Penicillium, Paecilomyces)
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Fusariosis diagnosis, symptoms & treatment
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Blood cultures are positive in 60% (capable of adventitious conidiation, i.e. generation of spores in tissue).
Similar to Aspergillus on histopathologic examination of biopsy specimens. may respond to voriconazole. |
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Scedosporium Infection has blood cultures (+) in 80% with disseminated disease.
True or False? |
True
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Penicillium marneffei is
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Third most common infection in AIDS patients in Thailand, found throughout southeast Asia and China
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Diagnosis of Penicillium marneffei is by...
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biopsy of bone marrow or skin lesions revealing intracellular yeast cells on Wright’s stain which are small (3-8um) with a clear central septation.
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Pneumocystis - Epidemiology
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Most humans infected before 4 y.o., probably by inhalation.
Cell mediated immunity plays a major role in defense. |
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PCP and AIDS
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Occurs before death in 80% without prophylaxis.
Almost all cases occur with CD4 count < 200. Remains the most common opportunistic infection among AIDS patients. |
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PCP - Clinical
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Fever, non-productive cough.
Dyspnea on exertion (DOE). May be subacute with symptoms for weeks prior to onset. |
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PCP - Diagnosis
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WBC low or normal, increased LDH.
CXR: diffuse bilateral interstitial infiltrates are most common, but may be normal (5-20%). desaturation with exercise. |
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PCP - Diagnosis special technics
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Silver stain (GMS) of expectorated or induced sputum (low sensitivity).
Bronchoscopy with bronchoalveolar lavage (BAL) has significantly higher yield than sputum or transbronchial lung biopsy (TBLB). |
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PCP - Therapy
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Prednisone
Abrupt discontinuation or too rapid a taper can result in relapse. |
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Pneumocystis Prophylaxis
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TMP-SMZ ds daily
30% will develop allergic manifestations, fever and/or a rash. |
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Pythiosis presentation
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Most human cases have been reported from Thailand where most common presentation is arterial invasion with arterial insufficiency after cutaneous innoculation, almost all have thalassemia.
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Protothecosis is an...
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Achlorophyllic alga found widely distributed in the environment.
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Protothecosis: Clinical
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Most often presents as cutaneous or subcutaneous involvement, often involves the olecranon bursa, rare disseminated cases have occurred.
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Definitive Host harbors the ...
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sexually mature parasite
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Intermediate Host
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where the parasite may undergo development but does reach maturity.
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Reservoir Host – harbors the ...
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same parasite species and stage as the definitive host
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Vectors ...
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transfer parasites from host to host
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