Flucytosine and amphotericin

Flucytosine is contraindicated in patients with known hypersensitivity to the drug. Flucytosine is used cautiously in patients with bone marrow depression and with extreme caution in those with renal impairment. The drug is also used cautiously during pregnancy (Category C) and lactation. When flucytosine and amphotericin B are administered concurrently, the risk of flucytosine toxicity is increased. 

AMPHOTERICIN ANTI FUNG ALS -FLUCYTOSINE t flucytosine levels, with risk of toxic effects Amphotericin causes 1 renal excretion of flucytosine and t cellular uptake The combination of flucytosine and amphotericin may be used therapeutically. Watch for early features of flucytosine toxicity (gastrointestinal upset) monitor renal and liver function closely... 

Patients with AIDS, treated for antifungal disease with flucytosine and amphotericin, are particularly susceptible to develop bone marrow depression (1,3). On the other hand, flucytosine can be safely administered to patients with cancer (6) or AIDS (12,20), if toxic concentrations are avoided and blood counts monitored. 

White DJ, Habib AR, Vanthuyne A, et al Combined topical flucytosine and amphotericin B for refrac-... 

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

The combined use of flucytosine and amphotericin B is more effective than flucytosine alone in the treatment of cryptococcal meningitis, as demonstrated in an early study, and is still the recommended treatment. However, amphotericin B can cause deterioration in renal function, which reduces flucytosine elimination, and may result in raised flucytosine blood levels. In addition, amphotericin may increase the cellular uptake of flucytosine. Whatever the exact mechanism, combined use increases flucytosine bone marrow toxicity. A study of 194 patients randomised to either a 4 or 6-week course of low-dose amphotericin B (initially 0.3 mg/kg daily) and maximal dose flucytosine (150 mg/kg daily, adjusted for renal function) found that severe adverse effects were common. These included azotaemia (51 patients), blood dyscrasias (52 patients), and hepatitis (13 patients). ... 

Synergy with amphotericin has been demonstrated in vitro and in vivo. It may be related to enhanced penetration of the flucytosine through amphotericin-damaged fungal cell membranes. In vitro synergy with azole drugs has also been seen, although the mechanism is unclear. 

The drugs used in the treatment of subcutaneous and systemic mycoses are amphotericin B, flucytosine, and the new group of azoles, ketoconazole, fluconazole and itraconazole. 

To enable reduction of the dose of one component and hence reduce the risks of adverse drug reactions, e.g. flucytosine plus amphotericin B for Cryptococcus neoformans meningitis. 

There was bone marrow suppression in the second patient shortly after the withdrawal of flucytosine (because of failure to respond) later resumption of flucytosine during amphotericin therapy for this critically ill patient was associated with severe bone marrow suppression and death. 

Heidemann HT, Brune KH, Sabra R, Branch RA. Acute and chronic effects of flucytosine on amphotericin B nephrotoxicity in rats. Antimicrob Agents Chemother 1992 36 2670-5. 

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. 

The combination of flucytosine with amphotericin B may be more effective than flucytosine alone for some fungal infections, but amphotericin B increases the toxicity of flucytosine. Close monitoring of flucytosine levels and renal function is required. Other drugs that impair glomerular filtration might also decrease flucytosine elimination and increase toxicity. 

Amphotericin B is the drug of choice for treatment of acute C. neoformans meningitis. Amphotericin B, 0.5 to 1 mg/kg/day, combined with flucytosine, 100 mg/kg/day, is more effective than amphotericin alone. In the acquired immune deficiency syndrome (AIDS) population, flucytosine is often poorly tolerated, causing bone marrow suppression and GI distress. 

Flucytosine is converted in Candida fungi to 5-fluorouracil by the action of a specific cytosine deaminase. As an antimetabolite, this compound disrupts DNA and RNA synthesis (p. 298), resulting in a fungicidal effect Given orally, flucytosine is rapidly absorbed. It is well tolerated and often combined with amphotericin B to allow dose reduction of the lattet... 

Flucytosine is a fluorinated derivative of pyrimidine. Its spectrum of activity is narrower than that of amphotericin B. However, it exhibits a synergetic effect when used in combination with amphotericin B. In sensitive fungi, flucytosine is transformed into 5-fluorouracil, which in turn is turned into 5-fluorodeoxyuracilic acid, an inhibitor of thymidylate synthetase, and correspondingly, DNA synthesis. 5-Fluorouracil triphosphate, which causes the formation of defective RNA, may also be involved in this process. The mechanism is highly selective because mammahan cells are not able to turn a large amount of flucytosine into 5-fluorouracil. 

Flucytosine is used with amphotericin for treating certain systemic fungal infections, in particular for treating subcutaneous chromobastomycosis. It is used intensively for treating systemic infections of the urinary tract that are caused by various strains of Candida. Synonyms of this drag are ancobon, ancotil, and others. 

Combinations of amphotericin-B with flucytosine are sometimes used to reduce the occurrence of resistance. Amphotericin-B is not absorbed from the gastrointestinal tract which necessitates intravenous administration. It is 90% protein bound and widely distributed, except for the CNS. For the treatment of fungal meningitis therefore only intrathecal drug administrations can be effective. Amphotericin-B is eliminated very slowly in urine, mainly in an inactive form, with an elimination half-life of about 24 hours which can increase to up to 15 days with repeated doses. 

Flucytosine is an oral antifungal pro-drug. It has to be enzymatically deaminated by the fungi to the active metabolite, fluorouracil. Fluorouracil inhibits thymidylate synthetase and DNA synthesis. Its indications are treatment of cryptococcal meningitis and serious systemic candidiasis. Resistance develops rapidly, due to altered drug-permeability. For this reason Amphotericin B and flucytosine are often given in combination as they have synergistic effects. 

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