Cryptococcus neoformans combination

Due to the rapid appearance of resistance, 5FC is only used as a combination partner for the intensive therapy of established severe fungal infections caused by Candida spp., Cryptococcus neoformans and Aspergillus sp. Anorexia, nausea, vomiting, diarrhoea and or abdominal pain occur in 6% of the patients. Of greater concern is the potential for bone marrow depression (seen in 5% of the patients, all with elevated 5FC levels). 

The combined synergistic effects of cyclo(Leu-Pro) and cyclo(Phe-Pro) were effective against five vancomycin-resistant enterococci (VRE) strains Enterococcus faecium (K-99-38), E. faecalis (K-99-17), E. faecalis (K-99-258), E. faecium (K-01-312), and E. faecalis (K-01-511) with MIC values of 0.25—1 mgl . It also showed activity against E. coli, Staphylococcus aureus. Micrococcus luteus, Candida albicans, and Cryptococcus neoformans with MIC values of 0.25—0.5 mg 1. This combination also showed mutagenic activity against Salmonella typhimurium TA98 and TAIOO strains in a Salmonella mutation assay. ... 

Flucytosine (Ancobon) possesses clinically useful activity against Cryptococcus neoformans, Candida species, Torulopsis glabrata, and the agents of chromomycosis. Susceptible fungi deam-inate flucytosine to 5-fluorouracil, which becomes an antimetabolite. Flucytosine, which is excreted by the kidney, should be used cautiously in the setting of renal impairment. Flucytosine is a bone marrow depressant. Flucytosine is used in combination with amphotericin B. 

The spectrum of activity of flucytosine is restricted to Cryptococcus neoformans, some Candida species, and the dematiaceous molds that cause chromoblastomycosis. Flucytosine is not used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance. Clinical use at present is confined to combination therapy, either with amphotericin B for cryptococcal meningitis or with itraconazole for chromoblastomycosis. 

Flucytosine [floo SYE toe seen] (5-FC) is a synthetic pyrimidine anti metabolite used only in combination with amphotericin for the treatment of systemic mycoses and meningitis caused by Cryptococcus neoformans and Candida. 

Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil which inhibits nucleic acid synthesis. It is weU absorbed from the gut, penetrates effectively into tissues and almost all is excreted unchanged in the urine (t) 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration should be monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine which ought not to be used alone it may be combined with amphotericin (see Table 14.2) but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk-benefit balance is favourable (e.g. Cryptococcus neoformans meningitis). 

Banters et al. (2003) demonstrated Cryptococcus neoformans in cerebrospinal fluid (CSF) and serum. Their 30-min procedure was based on the non-specific labelling with ChemChrome V3 in combination with a second analysis using immunofluorescence. To that end, cells were labelled with a specific primary antibody against a capsular polysaccharide and a secondary antibody conjugated with FITC. 

Finally, the combination of flucytosine and amphotericin B is synergistic against Cryptococcus neoformans and is often employed in AIDS patients with cryptococcal meningitis. 

Flucytosine (ancobon) is clinically useful for Cryptococcus neoformans, Candida spp., and chromoblastomycosis. It is given orally at 100 mgAg/day, in divided doses at 6-hour intervals and is used predominantly in combination with amphotericin B. An all-oral regimen of flucytosine plus fluconazole has been advocated for therapy of AIDS patients with cryptococcosis, but the combination has substantial Gl toxicity without evidence that flucytosine improves the outcome. The combination of flucytosine with C-AMB runs the risk of substantial bone marrow suppression or colitis if the flucytosine dose is not promptly adjusted downward if amphotericin B—induced azotemia occurs. It is common practice in HIV-negative patients with cryptococcal meningitis to begin with C-AMB or ambisome plus flucytosine and change to fluconazole after the patient has improved. 

Preliminary data were reported on the successful use of combinations of amphotericin B and 5-fluorocytosine in treatment of human cryptococcosis. 37 This mode of therapy, based on the earlier demonstration of a synergistic action between the two drugs vitro against yeasts,33 was validated experimentally in animals. In one study in mice infected with Candida albicans, CD50 dosages of amphotericin B were reduced in the presence of an otherwise inactive dose of 5-fluorocytosine.39 An additive effect for the two drugs was observed in mice infected with Cryptococcus neoformans. 0... 

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