Skip to main content
SpringerLink
Log in

Flucytosine Treatment and Resistance Mechanisms

  • Chapter
  • First Online:
Antimicrobial Drug Resistance

Abstract

Flucytosine is a synthetic antimycotic compound which, after being taken up by susceptible fungal cells, is converted to 5-fluorouracil and subsequent intermediate metabolites that are responsible for inhibition of fungal DNA, RNA, and protein synthesis. Due to primary resistance of yeast, flucytosine is used mainly in combination. Flucytosine administered in combination with amphotericin B remains the standard of care for cryptococcal meningitis, and the drug continues to have a role in the treatment of Candida infections which are life threatening or in circumstances where drug penetration may be problematic. It is also used in combination to treat severe systemic mycoses, such as cryptococcosis, chromoblastomycosis, and aspergillosis. Recently, 5-FC has been combined with gene therapy approaches and used as a chemotherapeutic drug to inhibit tumor growth and in curing lesions. In this chapter we review the mechanism of action of flucytosine, its resistance mechanisms, as well as the utility of combining it with other antifungal agents. The available new data may lead to improved dosing practices and a “rebirth” of this agent as a useful adjunct in the treatment of serious fungal infections.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hope WW, Tabernero L, Denning DW, Anderson MJ. Molecular mechanisms of primary resistance to flucytosine in Candida albicans. Antimicrob Agents Chemother. 2004;48:4377–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang F, Zamora G, Sun CH, Trinidad A, Chun C, Kwon YJ, Berg K, Madsen SJ, Hirschberg H. Increased sensitivity of glioma cells to 5-fluorocytosine following photo-chemical internalization enhanced nonviral transfection of the cytosine deaminase suicide gene. J Neurooncol. 2014;118:29–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yurttas C, Berchtold S, Malek NP, Bitzer M, Lauer UM. Pulsed versus continuous application of the prodrug 5-fluorocytosine to enhance the oncolytic effectiveness of a measles vaccine virus armed with a suicide gene. Hum Gene Ther Clin Dev. 2014;25:85–96.

    Article  CAS  PubMed  Google Scholar 

  4. Davoudi N, Tate CA, Warburton C, Murray A, Mahboudi F, McMaster WR. Development of a recombinant Leishmania major strain sensitive to ganciclovir and 5-fluorocytosine for use as a live vaccine challenge in clinical trials. Vaccine. 2005;23:1170–7.

    Article  CAS  PubMed  Google Scholar 

  5. Hope WW, Warn PA, Sharp A, Reed P, Keevil B, Louie A, Walsh TJ, Denning DW, Drusano GL. Optimization of the dosage of flucytosine in combination with amphotericin B for disseminated candidiasis: a pharmacodynamic rationale for reduced dosing. Antimicrob Agents Chemother. 2007;51:3760–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pappas PG, Kauffman CA, Andes D, Benjamin Jr DK, Calandra TF, Edwards Jr JE, Filler SG, Fisher JF, Kullberg BJ, Ostrosky-Zeichner L, Reboli AC, Rex JH, Walsh TJ, Sobel JD, Infectious Diseases Society of America. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–35.

    Article  CAS  PubMed  Google Scholar 

  7. Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, Meersseman W, Akova M, Arendrup MC, Arikan-Akdagli S, Bille J, Castagnola E, Cuenca-Estrella M, Donnelly JP, Groll AH, Herbrecht R, Hope WW, Jensen HE, Lass-Florl C, Petrikkos G, Richardson MD, Roilides E, Verweij PE, Viscoli C, Ullmann AJ, Group EFIS. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect. 2012;18 Suppl 7:19–37.

    Article  CAS  PubMed  Google Scholar 

  8. Day JN, Chau TT, Lalloo DG. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368:2522–3.

    Article  CAS  PubMed  Google Scholar 

  9. Bicanic T, Wood R, Meintjes G, Rebe K, Brouwer A, Loyse A, Bekker LG, Jaffar S, Harrison T. 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.

    Article  CAS  PubMed  Google Scholar 

  10. Storm L, Lausch KR, Arendrup MC, Mortensen KL, Petersen E. Vertebral infection with Candida albicans failing caspofungin and fluconazole combination therapy but successfully treated with high dose liposomal amphotericin B and flucytosine. Med Mycol Case Rep. 2014;6:6–9.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Garcia H, Guitard J, Peltier J, Tligui M, Benbouzid S, Elhaj SA, Rondeau E, Hennequin C. Caspofungin irrigation through percutaneous calicostomy catheter combined with oral flucytosine to treat fluconazole-resistant symptomatic candiduria. J Mycol Med. 2015;25:87–90.

    Article  CAS  PubMed  Google Scholar 

  12. Davoudi N, Khamesipour A, Mahboudi F, McMaster WR. A dual drug sensitive L. major induces protection without lesion in C57BL/6 mice. PLoS Negl Trop Dis. 2014;8, e2785.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Diamond DM, Bauer M, Daniel BE, Leal MA, Johnson D, Williams BK, Thomas AM, Ding JC, Najvar L, Graybill JR, Larsen RA. Amphotericin B colloidal dispersion combined with flucytosine with or without fluconazole for treatment of murine cryptococcal meningitis. Antimicrob Agents Chemother. 1998;42:528–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Dannaoui E, Lortholary O, Dromer F. In vitro evaluation of double and triple combinations of antifungal drugs against Aspergillus fumigatus and Aspergillus terreus. Antimicrob Agents Chemother. 2004;48:970–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ghannoum MA, Fu Y, Ibrahim AS, Mortara LA, Shafiq MC, Edwards Jr JE, Criddle RS. In vitro determination of optimal antifungal combinations against Cryptococcus neoformans and Candida albicans. Antimicrob Agents Chemother. 1995;39:2459–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pai MP, Samples ML, Mercier RC, Spilde MN. Activities and ultrastructural effects of antifungal combinations against simulated Candida endocardial vegetations. Antimicrob Agents Chemother. 2008;52:2367–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Marine M, Pastor FJ, Guarro J. Combined antifungal therapy in a murine model of disseminated infection by Cladophialophora bantiana. Med Mycol. 2009;47:45–9.

    Article  CAS  PubMed  Google Scholar 

  18. Jackson AT, Nussbaum JC, Phulusa J, Namarika D, Chikasema M, Kanyemba C, Jarvis JN, Jaffar S, Hosseinipour MC, van der Horst C, Harrison TS. A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis. AIDS. 2012;26:1363–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jund R, Lacroute F. Genetic and physiological aspects of resistance to 5-fluoropyrimidines in Saccharomyces cerevisiae. J Bacteriol. 1970;102:607–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Whelan WL. The genetic basis of resistance to 5-fluorocytosine in Candida species and Cryptococcus neoformans. Crit Rev Microbiol. 1987;15:45–56.

    Article  CAS  PubMed  Google Scholar 

  21. Polak A. 5-Fluorocytosine—current status with special references to mode of action and drug resistance. Contrib Microbiol Immunol. 1977;4:158–67.

    CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. Song MH, Lee JW, Kim MS, Yoon JK, White TC, Floyd A, Heitman J, Strain AK, Nielsen JN, Nielsen K, Bahn YS. A flucytosine-responsive Mbp1/Swi4-like protein, Mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of Cryptococcus neoformans. Eukaryot Cell. 2012;11:53–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Edlind TD, Katiyar SK. Mutational analysis of flucytosine resistance in Candida glabrata. Antimicrob Agents Chemother. 2010;54:4733–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vandeputte P, Pineau L, Larcher G, Noel T, Brethes D, Chabasse D, Bouchara JP. Molecular mechanisms of resistance to 5-fluorocytosine in laboratory mutants of Candida glabrata. Mycopathologia. 2011;171:11–21.

    Article  CAS  PubMed  Google Scholar 

  26. Florent M, Noel T, Ruprich-Robert G, Da Silva B, Fitton-Ouhabi V, Chastin C, Papon N, Chapeland-Leclerc F. Nonsense and missense mutations in FCY2 and FCY1 genes are responsible for flucytosine resistance and flucytosine-fluconazole cross-resistance in clinical isolates of Candida lusitaniae. Antimicrob Agents Chemother. 2009;53:2982–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao R, Bin W, Diao Y, Yang J, Liu T, Peng J, Jin Q. Global transcriptional profiles of Trichophyton rubrum in response to Flucytosine. Sci China C Life Sci. 2009;52:1173–85.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, Center for Medical Mycology, University Hospitals Cleveland, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH, 44106-5028, USA

    Jyotsna Chandra Ph.D. & Mahmoud A. Ghannoum Ph.D.

Authors
  1. Jyotsna Chandra Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahmoud A. Ghannoum Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mahmoud A. Ghannoum Ph.D. .

Editor information

Editors and Affiliations

  1. Treiber Therapeutics, Cambridge, Massachusetts, USA

    Douglas L. Mayers

  2. Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA

    Jack D. Sobel

  3. Centre de recherche en Infectiologie, University of Laval, Quebec City, Canada

    Marc Ouellette

  4. Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Keith S. Kaye

  5. Infection Control and Prevention Unit of Infectious Diseases, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Dror Marchaim

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Chandra, J., Ghannoum, M.A. (2017). Flucytosine Treatment and Resistance Mechanisms. In: Mayers, D., Sobel, J., Ouellette, M., Kaye, K., Marchaim, D. (eds) Antimicrobial Drug Resistance. Springer, Cham. https://doi.org/10.1007/978-3-319-46718-4_28

Download citation

Publish with us

Policies and ethics

Search

Navigation