Flucytosine (5-fluorocytosine; 5-flucytosine; 5-FC) is one of the oldest antifungal agents in use [1]. It was initially synthesized in 1957, but was not discovered to possess significant antifungal properties until 1964, when activity against Cryptococcus neoformans and Candida species was shown [2]. Human clinical trials were initiated in the late 1960s for both cryptococcal meningitis and disseminated candidiasis [3, 4]. The rapid emergence of flucytosine resistance was observed, particularly among C. neoformans isolates, limiting its utility as single-agent therapy [5–7]. Presently, flucytosine is utilized as single-agent therapy in only a limited number of settings, including urinary candidiasis and chromoblastomycosis [8]. The seminal studies of combination therapy of flucytosine with amphotericin B for patients with cryptococcal meningitis were the first to firmly establish a role for combination antifungal therapy for a well-defined invasive fungal infection [9, 10].


Candida Species Cryptococcal Meningitis Bone Marrow Toxicity Combination Antifungal Therapy Uridine Monophosphate 
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  1. 1.
    Utz JP. Flucytosine. N Engl J Med. 1972;286:777–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Grunberg E, Titsworth E, Bennett M. Chemotherapeutic activity of 5-flourocytosine. Antimicrob Agents Chemother. 1964;3:566–8.Google Scholar
  3. 3.
    Tassel D, Madoff MA. Treatment of Candida species and Cryptococcus meningitis with 5-fluorocytosine: a new antifungal agent. JAMA. 1968;206:830–2.CrossRefPubMedGoogle Scholar
  4. 4.
    Utz JP, Tynes BS, Shadomy HJ, Duma RJ, Kannan MM, Mason N. 5-fluorocytosine in human cryptococcosis. Antimicrob Agents Chemother. 1968;8:344–6.PubMedGoogle Scholar
  5. 5.
    Normark S, Schönebeck J. In vitro studies of 5-flucytosine resistance in Candida albicans and Torulopsis glabrata. Antimicrob Agents Chemother. 1972;2:114–21.PubMedGoogle Scholar
  6. 6.
    Block ER, Jennings AE, Bennett JE. 5-fluorocytosine resistance in Cryptococcus neoformans. Antimicrob Agents Chemother. 1973;3:649–56.PubMedGoogle Scholar
  7. 7.
    Hospenthal DR, Bennett JE. Flucytosine monotherapy for cryptococcosis. Clin Infect Dis. 1998;27:260–4.CrossRefPubMedGoogle Scholar
  8. 8.
    Graybill JR, Craven PC. Antifungal agents used in systemic mycoses. activity and therapeutic use. Drugs. 1983;25:41–62.CrossRefPubMedGoogle Scholar
  9. 9.
    Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med. 1979;301:126–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Dismukes WE, Cloud G, Gallis HA, et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N Engl J Med. 1987;317:334–41.CrossRefPubMedGoogle Scholar
  11. 11.
    Bennett JE. Flucytosine. Ann Intern Med. 1977;86:319–21.Google Scholar
  12. 12.
    Diasio RB, Bennett JE, Myers CE. Mode of action of 5–fluorocytosine. Biochem Pharmacol. 1978;27:703–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Waldorf R, Polak A. Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother. 1983;23:79–85.PubMedGoogle Scholar
  14. 14.
    Francis P, Walsh TJ. Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy. Clin Infect Dis. 1992;15:1003–18.PubMedGoogle Scholar
  15. 15.
    Cutler RE, Blair AD, Kelly MR. Flucytosine kinetics in subjects with normal and impaired renal function. Clin Pharmacol Ther. 1978;24:333–42.PubMedGoogle Scholar
  16. 16.
    Schönebeck J, Polak A, Fernex M, Scholer HJ. Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney function. Chemotherapy. 1973; 18:321–36.CrossRefPubMedGoogle Scholar
  17. 17.
    Daneshmend TK, Warnock DW. Clinical pharmacokinetics of systemic antifungal drugs. Clin Pharmacokinet. 1983;8:17–42.CrossRefPubMedGoogle Scholar
  18. 18.
    Stamm AM, Diasio RB, Dismukes WE, et al. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med. 1987;83:236–42.CrossRefPubMedGoogle Scholar
  19. 19.
    Lau AH, Kronfol NO. Elimination of flucytosine by continuous hemofiltration. Am J Nephrol. 1995;15:327–31.CrossRefPubMedGoogle Scholar
  20. 20.
    Kauffman CA, Frame PT. Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob Agents Chemother. 1977; 11:244–7.PubMedGoogle Scholar
  21. 21.
    Larsen RA, Bozzette SA, Jones BE, et al. Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis. 1994;19:741–5.PubMedGoogle Scholar
  22. 22.
    van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med. 1997;337:15–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet. 2004;363:1764–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Brouwer AE, van Kan HJ, Johnson E, et al. Oral versus intravenous flucytosine in patients with human immunodeficiency virus-associated cryptococcal meningitis. Antimicrob Agents Chemother. 2007;51:1038–42.CrossRefPubMedGoogle Scholar
  25. 25.
    Milefchik E, Leal MA, Haubrich R, et al. Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis. Med Mycol. 2008;46:393–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Bicanic T, Wood R, Meintjes G, et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis. 2008;47:123–30.CrossRefPubMedGoogle Scholar
  27. 27.
    Vermes A, Mathot RAA, ven der Sijs IH, Dankert J, Guchelaar HJ. Population pharmacokinetics of flucytosine: comparison and validation of three models using STS, NPEM, and NONMEM. Therapeutic Drug Monitor. 2000;22:676–87.CrossRefGoogle Scholar
  28. 28.
    Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis. 2001;33:690–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:291–322.CrossRefPubMedGoogle Scholar
  30. 30.
    Larsen RA, Leal MA, Chan LS. Fluconazole compared to amphotericin B plus flucytosine for cryptococcal meningitis in AIDS: a randomized trial. Ann Intern Med. 1990;113:183–7.PubMedGoogle Scholar
  31. 31.
    de Gans J, Portegies P, Tiessens G, et al. Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis. AIDS. 1992;6:185–90.CrossRefPubMedGoogle Scholar
  32. 32.
    Mayanja-Kizza H, Oishi K, Mitarai S, et al. Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS. Clin Infect Dis. 1998;26:1362–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Chotmongkol V, Jitpimolmard S. Treatment of cryptococcal meningitis with combination itraconazole and flucytosine. J Med Assoc Thailand. 1994;77:253–6.Google Scholar
  34. 34.
    Chotmongkol V, Jitpimolmard S. Treatment of cryptococcal meningitis with triple combination of amphotericin B, flucytosine and itraconazole. Southeast Asian J Trop Med Pub Health. 1995; 26:381–3.Google Scholar
  35. 35.
    Chotmongkol V, Sukeepaisarncharoen W, Thavornpitak Y. Comparison of amphotericin B, flucytosine and itraconazole with amphotericin B and flucytosine in the treatment of cryptococcal meningitis in AIDS. J Med Assoc Thailand. 1997;80:416–25.Google Scholar
  36. 36.
    Riantawan P, Ponglertnapakorn P. Clinical efficacy of itraconazole with initial flucytosine in AIDS-related cryptococcal meningitis: a preliminary study. J Med Assoc Thailand. 1996;79:429–33.Google Scholar
  37. 37.
    Lopes CF, Alvarenga RJ, Cispalpino EO, Resende MA, Oliveira LG. Six years experience in treatment of chromomycosis with 5-fluorocytosine. Int J Dermatol. 1978;17:414–8.PubMedGoogle Scholar
  38. 38.
    Silber JG, Gombert ME, Green KM, Shalita AR. Treatment of chromomycosis with ketoconazole and 5-fluorocytosine. J Am Acad Dermatol. 1983;8:236–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Restrepo A. Treatment of tropical mycoses. J Am Acad Dermatol. 1994;31:S91–S102.CrossRefPubMedGoogle Scholar
  40. 40.
    Pfaller MA, Messer SA, Boyken L, Huynh H, Hollis RJ, Diekema DJ. In vitro activities of 5-fluorocytosine against 8, 803 clinical isolates of Candida spp global assessment of primary resistance using National Committee for Clinical Laboratory Standards susceptibility testing methods. Antimicrob Agents Chemother. 2002;46:3518–21.CrossRefPubMedGoogle Scholar
  41. 41.
    Record CO, Skinner JM, Sleight P, Speller DC. Candida endocarditis treated with 5-fluorocytosine. Brit Med J. 1971;1:262–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Smego Jr RA, Perfect JR, Durack DT. Combined therapy with amphotericin B and 5-fluorocytosine for Candida meningitis. Rev Infect Dis. 1984;6:791–801.PubMedGoogle Scholar
  43. 43.
    Kujath P, Lerch K, Kochendorfer P, Boos C. Comparative study of the efficacy of fluconazole versus amphotericin B/flucytosine in surgical patients with systemic mycoses. Infection. 1993;21:376–82.CrossRefPubMedGoogle Scholar
  44. 44.
    Abele-Horn M, Kopp A, Sternberg U, et al. A randomized study comparing fluconazole with amphotericin B/5-flucytosine for the treatment of systemic Candida infections in intensive care patients. Infection. 1996;24:426–32.CrossRefPubMedGoogle Scholar
  45. 45.
    Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis. 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–35.CrossRefPubMedGoogle Scholar
  46. 46.
    Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis. 1990;12:1147–201 [erratum appears in Rev Infect Dis 13:345, 1991].PubMedGoogle Scholar
  47. 47.
    Pogliani E, Clini E. Association therapy as a prognostic factor in deep fungal infection complicating oncohaematological diseases. Supportive Care Cancer. 1994;2:385–8.CrossRefGoogle Scholar
  48. 48.
    Denning DW, Marinus A, Cohen J, et al. An EORTC multicentre prospective survey of invasive aspergillosis in haematological patients: diagnosis and therapeutic outcome. EORTC Invasive Fungal Infections Cooperative Group. J Infect. 1998;37:173–80.CrossRefPubMedGoogle Scholar
  49. 49.
    Yu VL, Wagner GE, Shadomy S. Sino-orbital aspergillosis treated with combination antifungal therapy. Successful therapy after failure with amphotericin B and surgery. JAMA. 1980;244:814–5.CrossRefPubMedGoogle Scholar
  50. 50.
    Supparatpinyo K, Nelson KE, Merz WG, et al. Response to antifungal therapy by human immunodeficiency virus-infected patients with disseminated Penicillium marneffei infections and in vitro susceptibilities of isolates from clinical specimens. Antimicrob Agents Chemother. 1993;37:2407–11.PubMedGoogle Scholar
  51. 51.
    Scholer HJ. Flucytosine. In: Speller DCE, editor. Antifungal Chemotherapy. Chichester: Wiley; 1980. p. 35–106.Google Scholar
  52. 52.
    Vermes A, van der Sijs IH, Guchelaar J. Flucytosine: correlation between toxicity and pharmacokinetic parameters. Chemotherapy. 2000;46:86–94.CrossRefPubMedGoogle Scholar
  53. 53.
    Harris BE, Manning WB, Federle TW, Diasio RB. Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora. Antimicrob Agents Chemother. 1986;29:44–8.PubMedGoogle Scholar
  54. 54.
    Malet-Marino MC, Martino R, de Forni M, Andremont A, Hartman O, Armand JP. Flucytosine conversion to fluorouracil in humans: does a correlation with gut flora status exist? Infection. 1991;19:178–80.CrossRefGoogle Scholar
  55. 55.
    Holt RJ. Clinical problems with 5-fluorocytosine. Mykosen. 1978;21:363–9.PubMedGoogle Scholar
  56. 56.
    Ely EW, Peacock Jr JE, Haponik EF, Washburn RG. Cryptococcal pneumonia complicating pregnancy. Medicine (Baltimore). 1998;77:153–67.CrossRefGoogle Scholar
  57. 57.
    Chen CP, Wang KG. Cryptococcal meningitis in pregnancy. Am J Perinatol. 1996;13:35–6.CrossRefPubMedGoogle Scholar
  58. 58.
    Stamos JK, Rowley AH. Candidemia in a pediatric population. Clin Infect Dis. 1995;20:571–5.PubMedGoogle Scholar
  59. 59.
    Rowen JL, Tate JM. Management of neonatal candidiasis. Neonatal Candidiasis Study Group. Pediat Infect Dis J. 1998;17:1007–11.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Internal MedicineLos Angeles County/USC Medical CenterLos AngelesUSA

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