Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal

Angela Loyse, Françoise Dromer, Jeremy Day, Olivier Lortholary, Thomas S Harrison, Angela Loyse, Françoise Dromer, Jeremy Day, Olivier Lortholary, Thomas S Harrison

Abstract

Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.

Keywords: 5-FC; 5-FC safety; access to essential antifungals for cryptococcal meningitis; combination antifungal therapy; cryptococcal meningitis; cryptococcal meningitis treatment guidelines; opportunistic infection.

Figures

Figure 1.
Figure 1.
Intracellular pathway and mode of action of 5-fluorouracil (5-FU). Adapted with permission from Vermes et al. 5-FU is converted into 5-fluorouridine triphosphate (FUTP). FUTP alters the aminoacylation of tRNA through its incorporation into fungal RNA in place of uridylic acid, causing RNA miscoding and disturbed synthesis of proteins and carbohydrates. In addition, 5-FU is metabolized to 5-fluorodeoxyuridine monophosphate (FdUMP). FdUMP is a potent inhibitor of thymidylate synthetase, a key enzyme in the biosynthesis of DNA.
Figure 2.
Figure 2.
Survival curves, by treatment group, for patients with HIV-associated cryptococcal meningitis in Vietnam treated with AmB (1 mg/kg/day) (Arm I) alone for 4 weeks (continuous line), with 5-FC (100 mg/kg/day) (Arm II) for 2 weeks (black dashed line) or with fluconazole (800 mg/day for 2 weeks) (grey dotted/dashed line), followed by fluconazole in all three arms. HR (95% CI) at 14/7, II versus I: 0.57 (0.30, 1.08), P = 0.08; III versus I: 0.71 (0.45, 1.11), P = 0.13; at 70/7, II versus I: 0.61 (0.39, 0.97), P = 0.04; III versus I: −0.78 (0.44, 1.41), P = 0.42. From Day JN, Tran TTH, Wolbers M et al.N Engl J Med 2013;368: 1291–302. Copyright Massachusetts Medical Society 2013. Reprinted with permission.
Figure 3.
Figure 3.
Survival curves, by treatment group for patients with HIV-associated cryptococcal meningitis in Malawi treated with fluconazole 1200 mg/day or fluconazole 1200 mg/day plus flucytosine 100 mg/kg/day for the initial 2 weeks. One patient lost to follow up was censored. P = 0.05 at 2 weeks and P = 0.25 at 10 weeks by Cox regression. Reproduced with permission from Day et al.

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