Flucytosine

Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication that has been licensed since the 1970s[1]. Despite its long history, its clinical value has often been overlooked, and its availability remains limited in many parts of the world[1].

Indications

Flucytosine is indicated for the treatment of severe infections caused by susceptible strains of Candida or Cryptococcus[2]. It is particularly effective against Cryptococcal meningitis, Candida endocarditis, endophthalmitis, meningitis, and symptomatic urinary tract infections caused by azole-resistant Candida species[1]. Additionally, it is used to treat dematiaceous fungi infections, such as phaeohyphomycosis and chromoblastomycosis[1].

Spectrum of Activity

Flucytosine has a limited spectrum of activity, primarily targeting yeast species including Candida and Cryptococcus, as well as certain molds like dematiaceous molds[1]. However, it is not effective against Aspergillus species, Mucorales, or endemic primary pathogens[1].

Mechanism of Action

The exact mode of action is not fully understood, but it is proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil[2]. This leads to unbalanced growth and death of the fungal organism[2].

Pharmacokinetics

Flucytosine is rapidly and virtually completely absorbed following oral administration, with a bioavailability of 78% to 89%[2]. It is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption, with a half-life of 2.4 to 4.8 hours[2].

Adverse Effects

Common side effects of flucytosine include bone marrow suppression, loss of appetite, diarrhea, vomiting, and psychosis[4]. Anaphylaxis and other allergic reactions can also occur[4]. The drug is contraindicated in patients with a hypersensitivity to the medication, and its use during pregnancy is not recommended during the first trimester due to potential anatomic irregularities[3].

Monitoring and Toxicity

Regular monitoring of liver enzymes, complete blood count (CBC), and kidney functions is crucial for patients taking flucytosine[3]. Serum drug concentrations should also be monitored, as levels above 100 mg/L can lead to toxicity[3]. In cases of severe toxicity, the drug can be managed through hemodialysis or peritoneal dialysis[3].

Interactions

Flucytosine may increase the toxicity of amphotericin B and vice versa, although the combination may be life-saving in certain situations, such as cryptococcal meningitis[4]. The cytostatic cytarabine inhibits the antimycotic activity of flucytosine[4].

Overdose

The symptoms and severity of flucytosine overdose are unknown, as it is used under close medical supervision[4]. However, it is expected to exacerbate the usual side effects on the bone marrow, gastrointestinal tract, liver, and kidney function[4]. Vigorous hydration and hemodialysis may be helpful in removing the drug from the body[4].

Availability and Cost

As of 2016, flucytosine was not licensed in 71.2% of countries and was unavailable in 76.0% of countries with a population over 1 million[1]. In the United States, the medication cost around US$2,000 per day, while in the United Kingdom, it cost about US$22 per day[4]. Unfortunately, it is not widely available in the developing world[4].

Citations:

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10084540/

[2] https://go.drugbank.com/drugs/DB01099

[3] https://www.ncbi.nlm.nih.gov/books/NBK557607/

[4] https://en.wikipedia.org/wiki/Flucytosine

[5] https://www.mayoclinic.org/drugs-supplements/flucytosine-oral-route/description/drg-20063847