INDICATIONS

FORMS

*Prices represent the cost per unit specified, are representative of the "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

• 50-150 mg/kg PO daily divided into q6h (typically 25 mg/kg q6h) in combination with amphotericin B products
  
  • Sole exception: monotherapy can be used for Candida UTI, e.g., azole-resistant candiduria (e.g., C. glabrata).
• Dosing in special populations:
  • Obesity: consider IBW for dosing of non-life-threatening infections.
  • Meningitis: consider using adjusted body weight and monitor serum concentrations.
• Therapeutic drug monitoring (TDM) is recommended/should be performed when available, especially in cases of renal dysfunction.
  • NIH specifies 2-hour post-dose peak after 3–5 doses, target 25–100 mg/L. Recommended with renal insufficiency to limit toxicity[11].
    • Peak serum concentrations >100 mcg/mL are associated with increased toxicity.

ADULT RENAL DOSING

PEDIATRIC DOSING

ADVERSE DRUG REACTIONS

DRUG INTERACTIONS

• Drugs that cause bone marrow suppression (e.g., AZT, ganciclovirand interferon): increased risk of bone marrow suppression

SPECTRUM

Cryptococcus neoformans and Candida spp.

• Flucytosine exhibits in vitro minimum inhibitory concentrations (MIC values) of 4 mcg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of flucytosine in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
  • Candida dubliniensis
  • Candida glabrata
  • Candida guilliermondii
  • Candida lusitaniae
  • Candida parapsilosis
  • Candida tropicalis
• Candida krusei should be considered to be resistant to flucytosine.
• In vitro activity of flucytosine is affected by the test conditions.
  • It is essential to follow the approved standard method guidelines.
• No interpretative criteria exist forCryptococcus neoformans.

PHARMACOLOGY

COMMENTS

• 5-FC is generally used in combination with amphotericin B for cryptococcosis and selected severe Candida infections (eg, CNS infection, endocarditis, endophthalmitis) because resistance may emerge rapidly during monotherapy.
• Recommended in combination with amphotericin or liposomal amphotericin for treatment of cryptococcal meningitis for at least 2 weeks.
  • Combination therapy with flucytosine results in more rapid CSF sterilization and improved mortality when compared to amphotericin alone.
  • When compared to amphotericin plus fluconazole, there was no difference in survival outcomes, but combination with flucytosine resulted in more rapid CSF sterilization.
  • The ACTA trial demonstrated that short-course amphotericin B plus flucytosine was noninferior to the prior standard 2-week amphotericin B regimen and was associated with lower toxicity[11].
• Levels should be considered for patients with renal insufficiency to minimize toxicity.
  • Levels >100 ng/mL for >2 weeks have been associated with increased risk of toxicity.
  • Levels < 25 ng/mL have been associated with the emergence of resistance in vitro.
• May be considered in combination with amphotericin (and surgery) in the treatment of candidal endocarditis.
• Flucytosine should never be used as monotherapy due to the rapid development of resistance, with the exception of candiduria without systemic infection.

References

1. Kurland S, Furebring M, Löwdin E, et al. Antifungal Therapy in Candida Infective Endocarditis: A Comparison of Echinocandins and Other Treatment Regimens in a Nationwide Cohort Study. Clin Infect Dis. 2026;82(3):e455-e461.  [PMID:40515674]

   Comment: Evidence is observational and no RCTs define amphotericin/flucytosine vs echinocandin superiority for endocarditis due to CaNDIDA; recent Swedish registry data found no clear outcome difference by backbone regimen.
   

2. Cornely OA, Sprute R, Bassetti M, et al. Global guideline for the diagnosis and management of candidiasis: an initiative of the ECMM in cooperation with ISHAM and ASM. Lancet Infect Dis. 2025;25(5):e280-e293.  [PMID:39956121]

   Comment: Guideline strongly recommends liposomal amphotericin B combined with flucytosine for CNS candidiasis, with fluconazole ± flucytosine as consolidation therapy. For Candida endocarditis, liposomal amphotericin B 3-5 mg/kg daily, with or without flucytosine 25 mg/kg four times daily, is strongly recommended as initial therapy, alongside high-dose echinocandins.
   

3. Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024;24(8):e495-e512.  [PMID:38346436]

   Comment: Establishes two setting-specific preferred induction regimens for cryptococcal meningitis, both of which include flucytosine as an essential component. The guideline emphasizes that flucytosine is the preferred partner antifungal in any combination regimen, with a demonstrated survival advantage over fluconazole when combined with amphotericin B.
   

4. Jarvis JN, Lawrence DS, Meya DB, et al. Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis. N Engl J Med. 2022;386(12):1109-1120.  [PMID:35320642]

   Comment: Groundbreaking trial in Sub-Saharan Africa that only used a single dose of LamB +14d 5-FC, which allowed for easier therapy in resource-limited settings compared to amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). Mortality was similar between the arms, but remained substantial at 24.8% vs 28.7% at ten weeks.
   

5. Delma FZ, Al-Hatmi AMS, Brüggemann RJM, et al. Molecular Mechanisms of 5-Fluorocytosine Resistance in Yeasts and Filamentous Fungi. J Fungi (Basel). 2021;7(11).  [PMID:34829198]

   Comment: Excellent review of the mechanisms of resistance (FCY1, FCY2, FUR1 pathways), intrinsic vs acquired resistance and resistance emergence during monotherapy. Authors include differences among Candida, Cryptococcus, and filamentous fungi, along with implications for susceptibility testing and combination therapy
   

6. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50.  [PMID:26679628]

   Comment: Updated IDSA guidelines on the treatment of candidiasis.
   

7. Day JN, Chau TT, Wolbers M, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368(14):1291-302.  [PMID:23550668]

   Comment: Amphotericin B (1 mg/kg/day) plus flucytosine (100 mg/kg/day) was associated with improved survival at day 70 as compared with amphotericin B (1 mg/kg/day) alone. Combination therapy with flucytosine also resulted in more rapid yeast clearance from CSF when compared to amphotericin monotherapy or amphotericin B plus fluconazole (800 mg/kg/day). There was no survival benefit found for those treated with amphotericin B plus fluconazole.
   

8. 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(3):291-322.  [PMID:20047480]

   Comment: Flucytosine plus AmphoB, liposomal AmB, or AmB lipid complex (for a minimum of 2 weeks) is recommended for the treatment of cryptococcal meningoencephalitis. Without flucytosine, the recommended amphoB treatment duration is 4-6 weeks. Fluconazole 1200 mg/day plus flucytosine x 6 weeks can be considered as an alternative in patients unable to tolerate amphoB.
   

9. van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997;337(1):15-21.  [PMID:9203426]

   Comment: The addition of 5FC to amphotericin resulted in faster CSF sterilization but did not improve clinical outcomes.
   

10. Gillum JG, Johnson M, Lavoie S, et al. Flucytosine dosing in an obese patient with extrameningeal cryptococcal infection. Pharmacotherapy. 1995;15(2):251-3.  [PMID:7624273]

    Comment: A case report of a morbidly obese patient who received 150 mg/kg/day IBW for treatment of extrameningeal cryptococcal infection. Pharmacokinetic parameters were similar to those reported in non-obese patients receiving the same dose.
    

11. DHHS/NIH. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a...
    
    Updated 10/29/24; last reviewed 3/16/26; accessed 6/10/2026.

    Comment: Bible for OIs in HIV/AIDS treatment, including cryptococcal meningitis management.
    
    
    

12. Sigera LSM, Denning DW. Flucytosine and its clinical usage. Ther Adv Infect Dis. 2023;10:20499361231161387.  [PMID:37051439]

    Comment: Helpful review of current use of flucytosine including discussion of resistance mechanisms and emergence, PK/PD, TDM, tissue penetration and global accesses issues. .