Resistance to flucytosine

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). 

Flucytosine has been successfully used in combination with ketoconazole, fluconazole, and itraconazole. Flucytosine and ketoconazole were synergistic in about 40% of yeast isolates resistant to flucytosine alone. The synergistic action of flucytosine with the triazoles against Candida species was seen both in vitro and in vivo (3-6). 

Flucytosine is used in combination with amphotericin B or fluconazole in the treatment of cryptococcosis or (less commonly) candidiasis. The rapid development of resistance to flucytosine, however, precludes its use as single-agent therapy. Mechanisms for drug resistance may include loss of deaminase and decreased permeability to the drug. ... 

The most common mechanism of intrinsic resistance is a decreased uptake of flucytosine by the fungus by a reduction in cytosine permease activity, which results in reduced concentrations of dmg entering into the cell. The development of resistance to flucytosine during therapy may be a result of reduced expression of, or a deficiency in, an enzyme at any step in the intracellular metabolism of flucytosine. However, the most common resistance mechanisms observed in clinical isolates are due to either reduced cytosine deaminase or URPTase activity. 

Flucytosine is a fluorinated pyrimidine that is transported across the fungal cell wall by a permease, where it is deaminated to the cytotoxic principal fluorouracil. Some fungi may lack the permease and are resistant to the drug and its clinical use is usually restricted to treating Candida spp. infection, although even here resistance may arise. It is synergistic with amphotericin B and... 

Resistance to azole antifungals should be considered in individuals who have persistently positive yeast cultures and fail to respond to therapy despite adherence to prescribed regimens. These infections can be treated with boric acid or 5-flucytosine. Boric acid is administered as a 600-mg intravaginal capsule daily for 14 days of induction therapy, followed by a maintenance regimen of one capsule intravaginally twice weekly. Boric acid is toxic if administered orally. 5-Flucytosine cream is administered vaginally, 1000 mg inserted nightly for 7 days. 

When amphotericin B is combined with flucytosine, a smaller dose of amphotericin B can be employed because of the in vitro and in vivo synergy between the two antifungal agents. Resistance develops to flucytosine in up to 30% of patients treated with flucytosine alone, limiting its usefulness as monotherapy. Combination therapy with amphotericin B and flucytosine will sterilize the CSF within... 

Flucytosine (5-fluorocytosine), 6, is a synthetic nucleoside that is converted intracellularly to 5-fluorouracil which, consequently, interferes with protein synthesis [22]. Although this drug is indicated for disseminated cryptococcosis and disseminated candidiases, flucytosine is rarely used alone due to substantial resistance developed by many opportunistic fungal pathogens. It also has the side effect of suppressing bone marrow production which is particularly problematic in AIDS patients. Flucytosine is sometimes used in combination with amphotericin B to suppress the rapid development of resistance to the flucytosine, but the toxicity appears to increase dramatically in these circumstances [21]. 

Flucytosine is a powerful antifungal agent used in the treatment of serious systemic fungal infections, such as Cryptococcus neoformans and Candida spp (Table 40.2). Flucytosine itself is not cytotoxic but, rather, is a pro-drug that is taken up by fungi and metabolized to 5-fluorouracil (5-FU) by fungal cytidine deaminase (Fig. 40.11) (51). Then, 5-FU is converted to 5-fluorodeoxyuridine, which as a thymidylate synthase inhibitor interferes with both protein and RNA biosynthesis. 5-Fluorouracil is cytotoxic and is employed in cancer chemotherapy (see Chapter 42). Human cells do not contain cytosine deaminase and, therefore, do not convert flucytosine to 5-FU. Some intestinal flora, however, do convert the drug to 5-FU, so human toxicity does result from this metabolism. Resistance rapidly develops to flucytosine when used alone, so it is almost always used in conjunction with amphotericin B. Use of flucytosine has declined since the discovery of fluconazole. 

Response rates are lower for non-albicans infections. Although an optimal regimen is unknown, use of intravaginal azole therapy for 7 to 14 days is recommended. Terconazole may prove more effective than other azoles in the treatment of non-albicans infections since C. glabrata and C. tropicalis are more susceptible to terconazole.17 For second-line therapy, boric acid 600 mg in a gelatin capsule administered vaginally twice daily for 2 weeks followed by once daily during menstruation is effective.18 Local irritation often limits the use of boric acid. Topical 4% flucytosine is also effective but use should be limited due to the potential for resistance. 

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. 

Resistance is thought to be mediated through altered metabolism of flucytosine, and, though uncommon in primary isolates, it develops rapidly in the course of flucytosine monotherapy. 

The spectrum of activity of flucytosine is restricted to C 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 for... 

Resistance Resistance can develop during therapy and is the reason that flucytosine is not used as a single antimycotic drug except for chromoblastomycosis. The rate of emergence of resistant fungal cells is lower with the combination of amphotericin B and flucytosine than it is with flucytosine alone. Decreased levels of any of the enzymes in the conversion of 5-FC to 5-FU and beyond, or increased synthesis of cytosine, can confer resistance. 

Answer C. Fluconazole is distinctive in terms of its ability to penetrate into the CSF, reaching levels similar to those in the blood. It is effective against C. neoformans and has become the most appropriate drug to use in both prophylaxis and suppression because of its oral efficacy and low toxicity compared with amphotericin B. Flucytosine is also active against C. neoformans but is not used alone because of rapid emergence of resistance. Nystatin is too toxic for systemic use. 

Flucytosine - active against most Candida species and C. neoformans but should be used in combination to guard against emergence of resistant strains. 

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