Flucytosine Combined with Amphotericin B for Fungal Infections: A Postmarketing Surveillance and Future Perspectives

Abstract

The incidence of fungal infections depends on the population studied. In immunodepressed patients and critically ill patients, fungal infections are emerging [1, 2]. The clinical course is frequently complicated and prolonged, despite treatment. Treatment is unsuccessful in 30–60% of patients [1, 3]. A number of highly active new agents have recently become available [4]; as a consequence, amphotericin B is used less often [5, 6]. However, until a few years ago, amphotericin B was the gold standard and the low costs of conventional amphotericin B deoxycholate still make this drug attractive for doctors in many countries. Most of the newer agents are used as monotherapy, while amphotericin B combined with flucytosine is usually seen as synergistic and as such is used for the treatment of severe infections [7, 8]. The efficacy of this combination is high for treatment of cryptococcal meningitis [9, 10]. For other infections there are a limited number of reports [11]. The main reason for amphotericin B to be replaced by the newer, equally active agents is renal toxicity [5]. Monotherapy with flucytosine is not advocated because of resistance that can develop relatively easily for this drug. Though mostly used in combination with amphotericin B, flucytosine may be used in combination with the newer antifungal agents too. Flucytosine is a pyrimidine, activated by deamination within the fungal cells to 5-flurouracil. Flucytosine is an antimetabolite, which inhibits fungal protein synthesis by replacing uracil with 5-flurouracil in fungal RNA. In addition, it inhibits thymidylate synthetase resulting in decreased fungal DNA synthesis [12]. Clinical trials involving the efficacy of flucytosine are scarce. The largest dataset on clinical efficacy and safety comes from a postmarketing surveillance.