antifungals – Flashcards
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| what is one target for cell wall synthesis via antifungals? why is this a good target? |
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| human cells don't have cell walls. echinocandins are inhibitors of glucan-synthase |
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| what is a unique component of fungal cell membranes that can be targeted with antifungals? |
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| ergosterol, which can be inhibited via azoles and allylamines or directly damaged by polyenes, such as amphotericin B which bind to ergosterol and opens a pore in the membrane |
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| what is antifungal disrupts microtubules and inhibits mitosis, and is used for dermatophytes? |
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| griseofulvin |
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| what antifungals affect nucleic acid synthesis? |
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| flucytosine |
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| what do the echinocandins such as caspofungin inhibit? what is the effect of this inhibition? |
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| inhibit cell wall synthesis by blocking beta glucan synthase, (makes beta 1,3 glucans), disrupting the osmotic environment of the cell, cell division and growth |
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| which fungi are echinocandins such as caspofungin effective against? why? |
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| candida and aspergillus, b/c beta 1,3 glucans are a dominant component of their cell walls and invasive forms of both are non-responsive to amphortericin B |
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| what is the first antifungal used in systemic fungal infections? what is a common second attempt? |
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| amphotericin B and then caspofungin |
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| what does nikkomycin do? |
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| it is an investigational inhibitor of chitin wall synthesis |
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| what are some inhibitors of ergosterol synthesis? |
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| allylamines, azoles, polyenes |
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| what do allyamines do generally? |
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| inhibit an enzyme called squalene epoxidase, causing a buildup of squalene, not ergosterol in the membrane - which is toxic to the cell |
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| what do azoles do generally? |
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| inhibit 14 alpha-demethylase which inhibits another step in the pathway to get ergosterol |
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| what do polyenes do generally? |
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| polyenes such as amphotericin B bind to ergosterol and cause pore formation |
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| what is the difference between allyamines and azoles vs polyenes? |
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| allyamines and azoles inhibit synthesis of ergosterol and polyenes disrupt the membrane by binding to ergosterol, (pore formation) |
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| what enzyme do allyamines inhibit? what does this change in the cell? where does it accumulate, and why is this useful? |
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| allyamines inhibit squalene epoxidase, causing levels of squalene to increase and levels of ergosterol to drop. it accumulates in skin and nails, which is effective against dermatophyte infections of the skin, (ringworm), and onychomycosis, (nail infections) |
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| what is an example of an allyamine? what are the oral/topical forms used for respectively? what are possible side effects? |
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| terbafine is an allylamine, and the oral form is used for nail infections/topical form is for skin infections. side effects include GI upset and headaches |
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| what are the two groups of azoles? what do they do? what is the difference between the two? |
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| imidazole and triazoles are both inhibitors of ergosterol synthesis. imidazoles have 2 N's in their ring, triazoles have 3 N's. individual azoles can have different R side chains |
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| what enzyme do both azoles inhibit? what part do they bind to? |
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| lanosterol 14 alpha demethlyase, which converts lanosterol to ergosterol by binding to the heme moiety of cytochrome P-450 on the enzyme |
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| what are some imidazole examples? |
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| ketoconazole, clotrimazole and miconazole |
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| what are non-ketoconazole imidazoles used for? |
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| clotrimazole, miconazole and others are topical medications for cutaneous and mucocutaneous candida and dermatophyte infections. |
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| what are different forms you can get ketaconazole in? can it be used for cutaneous infections, dimporphic mycoses or cryptococcus neoformans? what are side effects? why might it be used less than triazoles? |
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| tablets, creams and shampoos. it can be used to treat cutaneous infections, dimorphic mycoses, and cryptococcus neoformans. side effects include nausea, vomiting, anorexia, and occasionally hepatotoxicity. triazoles have fewer side effects and are thus favored more. |
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| why do triazoles have less side effects than imidazoles? what is a potential benefit of this? do they still have side effects? |
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| triazoles have greater specificity for the fungal cytochrome P-450 then imidazoles, (leading to less reactivity with human cytochromes). pt's can thuse probably tolerate a higher dose of triazoles than ketonazoles. they can still have side effects including nausea, vomiting, diarrhea, occasional liver abnormalities. |
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| what are examples of some triazoles? what can they be used to treat? |
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| fluconazole, itraconazole, voriconazole, and posaconazole. these have a broad spectrum of activity, effective with both cutaneous and invasive candidiasis, dermatophytes, dimorphic mycoses, cryptococcus neoformans (cryptococcus meningitis) & aspergillus infections |
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| why might there be decreased plasma concentrations with azoles than the amount intended for prescription? |
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| there could be decreased absorbtion or increased metabolism of the drug, because it affects the human P-450 cytochrome, this could then lead to the intended dose not being delivered |
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| what is a consideration for prescribing other drugs along with azoles? |
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| azoles can enhance the toxicity of other drugs by altering the patient's hepatic metabolism via changes with the P-450 system, (may increase plasma conc.) |
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| what is the most important polyene? what is its structure? what is it used for and what is a caveat for its use? |
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| amphotericin B, which has a large lactone ring with both lipophilic and hydrophilic regions. one of the first antifungals, it is effective against systemic infections, but also has a high degree of toxicity. |
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| how does the structure of amphotericin B allow it to work? what does amphotericin B bind to? |
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| its large lactone ring has both lipophilic and hydrophilic regions that allow it to insert into the membrane and create a pore which ions can leak out of = cell death. amphotericin B has an affinity for and binds to ergosterol. |
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| what is another way that amphotericin B can kill fungus? |
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| oxidation of amphotericin B generates free radicals toxic to the fungus |
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| can amphotericin B bind to cholesterol? |
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| yes, but with a lower affinity. amphotericin B binding to cholesterol can lead to a small amount of toxicity in mammalian cells |
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| what are other general toxicity problems with amphotericin B? |
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| renal impairment, loss of potassium & magnesium, infusion reaction (fever, chills, tachypnea), occasional abnormal liver function tests |
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| what formulations of amphotericin B are less toxic and can therefore be given in higher doses? why are these better? |
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| lipid formulations, which absorb better into cells |
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| given that amphotericin B is a good broad spectrum polyene antifungal used for systemic infections, can it develop resistance? |
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| yes, resistance to amphotericin B occurs via a decrease in the amount of ergosterol in the fungal cell wall or reduced ergosterol affinity for the drug |
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| how are nystatin and amphotericin B similar/how are they different? what is nystatin used for? |
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| amphotericin B and nystatin are both polyenes, but it cannot be absorbed into tissues and therefore is not used for systemic infections. nystatin can be used for dermatophyes and cutaneous or mucocutaneuous candidiasis, (oropharyngeal or vaginal), and can cause vomiting, nausea & diarrhea |
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| what is the basic action of flucytosine, (5-fluorocytosine)? what is its structure? |
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| DNA synthesis inhibition. it is a fluorinated pyrimidine, (1 ring), similar to cytosine replaces it and disrupts DNA synthesis. |
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| how does flucytosine enter cells? what does it need to do once it enters the cell? |
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| it enters via cytosine permease and then it needs to be phosphorylated to become its active form |
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| how is flucytosine activated once it enters the cell? how does it affect both DNA and RNA synthesis? |
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| flucytosine enters via cytosine permease, then cytosine deaminase deaminates it giving 5-FU, which is phosphorylated to give 5-FUMP. 5-FUMP either goes to 5-FUDP -> 5-FUTP to compete for uracil in RNA or 5-FUMP goes to 5-dFUMP which competes with dUMP for the activity of thymidylate synthase, and less dTMP is made in DNA synthesis |
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| what 2 molecules can flucytosine mimic to lessen DNA and RNA synthesis? |
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| flucytosine can become molecules similar to uracil and deoxyuracil respectively |
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| what kinds of infections is flucytosine used against? where does it have good penetration. |
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| flucytosine is used against crytococcal menigitis, some candida, (esp systemtic endocarditis/meningitis). flucytosine has good CNS penetration, (which candida can sometimes invade) |
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| why is flucytosine not used as monotherapy? what is it used with? |
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| flucytosine is not used alone, because fungi can develop resistance to it, it is usually used with amphotericin B or azoles |
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| what are adverse effects of flucytosine? |
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| myelosuppression, (esp neutropenia), as well as possible renal insufficiency, diarrhea, vomiting, nausea and liver enzyme abnormalities |
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| what does griseofulvin bind? what might it interact with? what is it used for? is there anything currently preferred to griseofulvin? |
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| griseofulvin binds keratin and prevents infection of cells, (dermatophytes bind keratin in the hair, nails, skin etc). it may interact with fungal cell microtubules & inhibit mitosis. it is only used for dermatophytes. newer azoles such as ketoconazole are preferred to griseofulvin |
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| is candida albicans normal flora? where is it found? are infections endogenous? |
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| candida albicans are normal flora of the oral cavity, lower GI, and female genital tract. most infections are endogenous where candida simply overgrows, though it can be transmitted from person to person |
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| how does candida albicans grow in the body? |
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| candida albicans is dimorphic, but when it is normal flora, it grows as yeast. septated hyphae and pseudohyphae are seen with invasive disease, though yeast will still be visible. |
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| why was the germ tube test run? how does the test work? |
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| candida albicans is the most common species of candida, and at one point, all that was done with fungal cx's was test for candida albicans or non-candida albicans via the germ tube test. when candida albicans was cultured in serum it would send out hyphae-like growth, (germ tubes), which is diagnostic for this particular strain. |
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| what is the second most common species of candida? what differentiates it from albicans? |
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| c. galbrata, a nosocomial pathogen, it does not form hyphae, pseudohyphae or germ tubes and only grows as a yeast |
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| of these opportunistic candida: c. albicans, c. parapsilosis, c. tropicalis, c. krusei, and c. galbrata, which have the most problems with antifungal resistance? |
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| c. galbrata & c. krusei |
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| what antifungal is c. krusei resistant to? what antifungal is c. krusei becoming resistant to? |
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| fluconazole, (and by extension it is starting becoming resistant to itraconazole and ketoconazole), it is also starting to become resistant to flucystosine to some extent |
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| what antifungal is c. galbrata becoming resistant to? |
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| fluconazole |
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| is candida albicans becoming resistant to fluconazole? |
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| yes |
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| where are most antifungal resistant strains popping up? |
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| in hospital settings |
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| what is the 4th most common blood isolate in hospitals? who does this affect the most? |
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| opportunistic candida is the 4th most common blood cx isolate and it is the most common cause of fungal infections in immunocompromised individuals |
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| which candida are responsible for 70-80% of invasive candidiasis? |
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| c. albicans & c. glabrata |
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| what hospital patients are at a higher risk for candidemia, (more invasive candida of the blood)? |
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| cancer patients – hematologic malignancy, patients with neutropenia, GI surgery, pts in extremes of age – very young and elderly |
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| what are other factors that increase the risk of candidiasis? |
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| antibiotics, central catheter, hemodialysis, ICU stay greater than 3 days, candida colonization, (from skin) |
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| why is candidemia such a severe infection? |
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| 49% die from this infection, 40% survive, and 12% will die from the underlying disease |
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| what are different clinical manifestations of candida? |
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| cutaneous, mucocutaneous, chronic mucocutaneous, and systemic infections: candidemia, if compromised- opportunistic pathogen, and candida that disseminates and invades tissues |
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| what are the 2 candidiasis of mucous membranes? |
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| oral thrush and vaginal candidiasis |
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| when is oral thrush seen? |
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| in infants and immunocompromised pts, diabetics, and after significant antibiotic use |
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| when is vaginal candidiasis seen? |
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| during childbearing years, pregnancy, hormone tx, diabetics, and during significant antitbiotic therapy |
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| what are symptoms of mucocutaneous candidiasis? |
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| white, "cottage cheese-like" patches on mucosal surfaces that can bleed when scraped. in the vagina, itching is the most common symptom and discharge may range from absent to watery to thick |
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| what is cutaneous candidiasis, what does it resemble? |
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| cutaneous candidiasis is either onychomycosis, a chronic nail infection that resembles dermatophyte infections, (may infact have been initiated by dermatophytes), or candidiasis of warm, moist areas of skin, (eg. diaper rash) |
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| what can cause chronic mucocutaneous candidiasis? when is it seen? what are symptoms? |
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| endocrine disorders and defects in T cell immunity. it is seen in early childhood and marked by chronic & recurrent infections of red, pustular, thickened lesions on the nose and forehead. nail, hair & mucus membrane involvement is also possible |
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| what are some predisposing factors for systemic candidasis? |
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| pts with cellular immunodeficiency (HIV, AIDS, chronic granulomatous disease, cancer patients), pts on immunosuppressive treatment (bone marrow transplant patients, leukemia patients, long hospital stays), pts with indwelling catheters, intravenous lines, prosthetic devices, or heart valve replacements. |
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| what is a problem with neutropenic patients often being given fluconazole as a prophylaxis? |
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| c. glabrata is being seen more often in ICUs because of widespread fluconazole use |
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| why do corticosteroids increase risk of candidiasis? |
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| hormones set up environment that favors growth of candida |
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| what is the most important risk factor for invasise candiasis? |
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| a prolonged stay in the ICU |
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| can candida infect any organ system? |
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| yes, though candida esp infects the kidney, brain, liver, skin and eye |
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| can systemic candidiasis be fatal to immunocompromised pts? |
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| yes |
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| what are common manifestations of candida in AIDs pts? |
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| oral thruch or esophagitis, (vaginal infections in women) |
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| what is systemic candidiasis often a complication following? |
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| transplants, (liver, kidney, bone marrow), abdominal sx, (peritonitis), cardiac sx, (endocarditis) |
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| what specimens are commonly taken to diagnose candidiasis? |
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| tissue bx, sputum, CSF, blood, urine. |
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| why are urine, blood + CSF findings significant? |
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| positive cx from a normally sterile site is significant. also, blood cx are positive in only 40-60% of candidemia cases depending on level of organism in the blood |
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| what can looking for yeast and hyphae tell? |
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| differing species of candida |
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| what does selective chromogenic medium allow in candida diagnosis? |
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| allows different species of candida grow in different colors |
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| what are circulating candidal antigens indicative of? why aren't antibody titers diagnostic? |
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| systemic infection, (means organism is in the blood). antibody titers aren't diagnostic b/c candida is normal flora |
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| is the germ tube still used to ID C. albicans? |
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| yes |
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| what does the commercial fungal test looking for a component of the fungal cell wall look for? |
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| beta-D-glucan |
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| what do topical creams treat? what do they usually contain? |
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| topical creams are usually used to treat mucosal and cutaneous infections. they contain azoles and nystatin |
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| is removal of infected catheters/implants effective treatment? |
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| yes |
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| should antibiotic broad-spectrum use be avoided? why? |
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| yes, it increases the likelihood of wiping out your normal flora and increases risk factor of having the candida grow out |
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| what are antifungals commonly used in systemic therapy? |
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| fluconazole, amphotericin B, caspofungin |
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| is fluconazole used as a prophylaxis in high-risk pts? |
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| yes, but resistance should be considered |
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| what species of candida is fluconazole resistance becoming a concern? |
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| C. krusei & C. glabrata (some isolates of C. albicans) |
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| what are fluconazole resistant candida still susceptible to? |
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| fluconazole resistant candida are still susceptible to posaconazole |
