OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Flucytosine	2022-85-7	C4-H4-F-N3-O

ANNOTATED BIBLIOGRAPHY

References updated: 02 February 2018

• Zimmerman HJ. Antifungal agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 609-11.

  (Expert review of hepatotoxicity of antifungal agents published in 1999; mentions that transient serum enzyme elevations occur in 5-10% of patients treated with flucytosine, and a single case report of severe hepatitis attributed to flucytosine has been published).
• Moseley RH. Antibacterial and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 473.

  (Review of hepatotoxicity of antifungal agents mentions that asymptomatic liver chemistry abnormalities occur in up to 41% of patients, and severe liver injury has been reported in two patients).
• Bennett JE. Antimicrobial agents: antifungal agents. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1571-92.

  (Textbook of pharmacology and therapeutics).
• Record CO, Skinner JM, Sleight P, Speller DCE. Candida endocarditis treated with 5-fluorocytosine. Br Med J 1971; 1: 262-4. [PMC free article: PMC1794961] [PubMed: 5212581]

  (3 patients with candida endocarditis were treated with flucytosine and amphotericin B, one recovered, two died, both with patchy hepatic necrosis on autopsy, but without major aminotransferase elevations or jaundice).
• Steer PL, Marks MI, Klite PD. 5-fluorocytosine oral antifungal compound: a report on clinical and laboratory experience. Ann Intern Med 1972; 76: 15-22. [PubMed: 5063168]

  (Experience in treating 17 patients with invasive fungal infections with flucytosine; two patients developed ALT elevations [3-5 times normal], one resolving with dose reduction and one with discontinuation; both rapidly).
• Harder EJ, Hermans PE. Treatment of fungal infections with flucytosine. Arch Intern Med 1975; 135: 231-7. [PubMed: 1096840]

  (Experience in treating 20 patients with invasive fungal infections with flucytosine alone or with amphotericin B; 6 patients [30%] had “slight” elevations in Alk P and 2 in AST levels, which became normal when flucytosine was stopped).
• Diasio RB, Lakings DE, Bennett JE. Evidence for conversion of 5-fluorocytosine to 5-fluorouracil in humans: possible factor in 5-fluorocytosine clinical toxicity. Antimicrob Agents Chemother 1978; 14: 903-8. [PMC free article: PMC352577] [PubMed: 742878]

  (Significant levels of 5-fluorouracil was found in 41 serum samples from patients receiving flucytosine for fungal infections; levels similar to those in patients on cancer chemotherapy).
• Bennett JE, Dismukes WE, Duma RJ, Medoff G, Sande MA, Gallis H, Leonard J, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N Engl J Med 1979; 301: 126-31. [PubMed: 449951]

  (Trial of amphotericin alone vs its combination with flucytosine in 50 patients with cryptococcal meningitis; “no abnormalities of serum alkaline phosphatase or transaminase were caused by either regimen”).
• Stamm AM, Diasio RB, Dismukes WE, Cloud GA, Bowles CA, Karam GH, Espinel-Ingroff A. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med 1987; 83: 236-42. [PubMed: 3303926]

  (Controlled trial of 4 vs 6 weeks of amphotericin B and flucytosine in 194 patients with cryptococcal meningitis; elevated liver enzymes arose during first 4 weeks in 13 [6.2%] patients, and a 77 year old man with Crohn's disease developed signs and symptoms of hepatitis while on azathioprine as well as flucytosine, dying of acute liver failure one month later; authors attributed liver injury to flucytosine).
• Vermes A, van Der Sijs H, Guchelaar HJ. Flucytosine: correlation between toxicity and pharmacokinetic parameters. Chemotherapy 2000; 46: 86-94. [PubMed: 10671757]

  (No correlation was found between pharmacokinetic parameters and likelihood of ALT or Alk P elevations in 53 patients treated with flucytosine and monitored for side effects; in contrast, there was a correlation with thrombocytopenia).
• Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 2000; 46: 171-9. [PubMed: 10933638]

  (Review of structure, mechanism of action, pharmacokinetics, efficacy and toxicity of flucytosine; reported rates of ALT elevations range from 0-41%, usually reversed with dose reduction and effect may be dose related).
• Song JC, Deresinski S. Hepatotoxicity of antifungal agents. Curr Opin Investig Drugs 2005; 6: 170-7. [PubMed: 15751740]

  (Extensive review of hepatotoxicity from antifungals; wide range of patterns of injury have been reported, typically arising within first month of therapy, may be more common with high plasma levels which can be monitored).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 8 cases were attributed to antifungal agents, but no cases were attributed to flucytosine).
• Antifungal drugs. Treat Guidel Med Lett 2009; 7: 95-102. [PubMed: 19940816]

  (Concise summary of therapy of fungal infections with recommendations on agents, dosage and duration of treatment and safety; mentions that fluctosine has potentially lethal, dose related bone marrow toxicity; no mention of hepatotoxicity).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, 6 of which were attributed to antifungal agents, but none to flucytosine).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 14 cases [1.6%] were attributed to antifungal agents including 7 due to terbinafine, 6 triazoles, 1 micafungin but none to flucytosine).
• Kyriakidis I, Tragiannidis A, Munchen S, Groll AH. Clinical hepatotoxicity associated with antifungal agents. Expert Opin Drug Saf 2017; 16: 149-65. [PubMed: 27927037]

  (Review of the hepatotoxicity of antifungal agents states that all antifungal agents may cause hepatic toxicity, flucytosine being linked to serum enzyme elevations during therapy in a variable proportion of patients and to rare instances of "severe liver necrosis").