Antifungal Therapy: New and Evolving Therapies

Yasmine Nivoix; Marie-Pierre Ledoux; Raoul Herbrecht

Disclosures

Semin Respir Crit Care Med. 2020;41(1):158-174. 

In This Article

Flucytosine

Mechanism of Action and Antifungal Spectrum

Flucytosine interferes with the synthesis of nucleic acids through the inhibition of thymidylate synthetase (Figure 1).[89] It is only active on cells that are able to transport it into cytoplasm with a cytosine-permease and to convert it to 5-fluoro-uracil with a cytosine-deaminase. It is then metabolized by a uridine monophosphate pyrophosphorylase and embedded in RNA or transformed to 5-fluorodeoxyuridylate, which strongly inhibits thymidylate synthetase, thus blocking DNA synthesis. It is therefore fungistatic.

Flucytosine is active against Candida spp., C. neoformans, chromomycoses agents, and, to a lesser extent, Aspergillus spp.[90–92] Many cases of secondary resistance have been reported.[93] It is therefore recommended to use flucytosine in combination with AmB or an azole.

Clinical Pharmacokinetics

Flucytosine is well absorbed through the digestive route (90%). Plasma concentration peak is reached 2 to 6 hours after the administration of 2 g orally. After one IV administration, the maximal serum trough is almost equivalent in μg/mL to the administered dose in mg/kg.[94] The volume of distribution is 0.6 to 0.7 L/kg. Protein binding is low (4%). The concentration in spinal fluid reaches 75%. Plasma half-life is 3 to 6 hours. Elimination is rapid through glomerular filtration of the unaltered molecule. In patients with renal impairment, plasma half-life is prolonged, warranting a dose adaptation. Flucytosine is dialyzable.[95] A small proportion is transformed into 5-fluoro-uracil, probably by intestinal flora, leading to hematological toxicity. Ninety percent of the administered dose is found in the urine within 48 hours as an unaltered compound.

Dosage and Adjustments

The usual dosage of flucytosine ranges from 100 to 150 mg/kg/day. It must be adjusted to reach a peak concentration of 70 to 80 μg/mL (not over 100 μg/mL to avoid hematological toxicity) and a trough concentration of 30 to 40 μg/mL (not below 25 μg/mL, which is subtherapeutic). TDM should be performed twice a week. With renal impairment, the interval or dosage must be adjusted according to creatinine clearance.

Tolerability

Flucytosine has minor side effects such as digestive disturbance in 6% of patients, from nausea (frequent) to enterocolitis (rare), but can also cause major hepatic and hematological toxicities.[96] Digestive side effects are best avoided by giving three or four divided doses per day. Hematological toxicity is dose-dependent and consists of leukopenia and thrombocytopenia, all the more so if flucytosine is given with drugs with overlapping toxicities (e.g., zidovudine). Irreversible aplasia has also been reported in patients who develop renal failure and reach serum concentrations higher than 100 μg/mL. Coadministration with AmB can result in greater hematological toxicity through impaired renal elimination. Both blood counts and serum drug levels must be monitored cautiously. Hepatic toxicity can be observed in up to 41% of patients, manifesting as an elevation of transaminases and alkaline phosphatase.[95] The mechanism of this toxicity remains unclear but seems concentration-dependent, reversible, and avoidable if levels are maintained under 100 μg/mL.

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