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Volume 31, Number 7—July 2025

Research

Emergence of Flucytosine-Resistant Candida tropicalis Clade, the Netherlands

Fatima Zohra Delma1, Bram Spruijtenburg1, Jacques F. Meis, Auke W. de Jong, James Groot, Johanna Rhodes, Willem J.G. Melchers, Paul E. Verweij, Theun de Groot, Eelco F.J. Meijer2, and Jochem B. Buil2Comments to Author 
Author affiliation: Radboud University Medical Center, Nijmegen, the Netherlands (F.Z. Delma, B. Spruijtenburg, J.F. Meis, J. Rhodes, W.J.G. Melchers, P.E. Verweij, T. de Groot, E.F.J. Meijer, J.B. Buil); Canisius-Wilhelmina Hospital (CWZ)/Dicoon, Nijmegen (B. Spruijtenburg, T. de Groot, E.F.J. Meijer); University of Cologne, Cologne, Germany (J.F. Meis); National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands (A.W. de Jong, J. Groot, P.E. Verweij)

Main Article

Figure 1

5-FC MIC distribution for 250 Candida tropicalis isolates collected in the Netherlands in study of emerging 5-FC–resistant clade. MICs were determined according to European Committee on Antimicrobial Susceptibility Testing microdilution method (21). 5-FC, flucytosine.

Figure 1. 5-FC MIC distribution for 250 Candida tropicalis isolates collected in the Netherlands in study of emerging 5-FC–resistant clade. MICs were determined according to European Committee on Antimicrobial Susceptibility Testing microdilution method (21). 5-FC, flucytosine.

Main Article

References
  1. McCarty  TP, Pappas  PG. Invasive Candidiasis. Infect Dis Clin North Am. 2016;30:10324. DOIPubMedGoogle Scholar
  2. Lass-Flörl  C, Kanj  SS, Govender  NP, Thompson  GR III, Ostrosky-Zeichner  L, Govrins  MA. Invasive candidiasis. Nat Rev Dis Primers. 2024;10:20. DOIPubMedGoogle Scholar
  3. Guinea  J. Global trends in the distribution of Candida species causing candidemia. Clin Microbiol Infect. 2014;20(Suppl 6):510. DOIPubMedGoogle Scholar
  4. Dougue  AN, El-Kholy  MA, Giuffrè  L, Galeano  G, D Aleo  F, Kountchou  CL, et al. Multilocus sequence typing (MLST) analysis reveals many novel genotypes and a high level of genetic diversity in Candida tropicalis isolates from Italy and Africa. Mycoses. 2022;65:9891000. DOIPubMedGoogle Scholar
  5. Chai  LY, Denning  DW, Warn  P. Candida tropicalis in human disease. Crit Rev Microbiol. 2010;36:28298. DOIPubMedGoogle Scholar
  6. Zuza-Alves  DL, Silva-Rocha  WP, Chaves  GM. An update on Candida tropicalis based on basic and clinical approaches. Front Microbiol. 2017;8:1927. DOIPubMedGoogle Scholar
  7. Spruijtenburg  B, Baqueiro  CCSZ, Colombo  AL, Meijer  EFJ, de Almeida  JN Jr, Berrio  I, et al.; On Behalf Of The Latin American Group For Investigating Candida Tropicalis Resistance. on behalf of the Latin American Group For Investigating Candida tropicalis Resistance. Short tandem repeat genotyping and antifungal susceptibility testing of Latin American Candida tropicalis isolates. J Fungi (Basel). 2023;9:207. DOIPubMedGoogle Scholar
  8. Paul  S, Shaw  D, Joshi  H, Singh  S, Chakrabarti  A, Rudramurthy  SM, et al. Mechanisms of azole antifungal resistance in clinical isolates of Candida tropicalis. PLoS One. 2022;17:e0269721. DOIPubMedGoogle Scholar
  9. Pristov  KE, Ghannoum  MA. Resistance of Candida to azoles and echinocandins worldwide. Clin Microbiol Infect. 2019;25:7928. DOIPubMedGoogle Scholar
  10. Khan  Z, Ahmad  S, Mokaddas  E, Meis  JF, Joseph  L, Abdullah  A, et al. Development of echinocandin resistance in Candida tropicalis following short-term exposure to caspofungin for empiric therapy. Antimicrob Agents Chemother. 2018;62:e0192617. DOIPubMedGoogle Scholar
  11. World Health Organization. WHO fungal priority pathogens list to guide research, development and public health action. October 25, 2022 [cited 2025 May 2]. https://www.who.int/publications/i/item/9789240060241
  12. Keighley  C, Kim  HY, Kidd  S, Chen  SC, Alastruey  A, Dao  A, et al. Candida tropicalis-A systematic review to inform the World Health Organization of a fungal priority pathogens list. Med Mycol. 2024;62:myae040. DOIPubMedGoogle Scholar
  13. Sigera  LSM, Denning  DW. Flucytosine and its clinical usage. Ther Adv Infect Dis. 2023;10:20499361231161387. DOIPubMedGoogle Scholar
  14. Cornely  OA, Sprute  R, Bassetti  M, Chen  SC, Groll  AH, Kurzai  O, 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:e28093. DOIPubMedGoogle Scholar
  15. Delma  FZ, Al-Hatmi  AMS, Brüggemann  RJM, Melchers  WJG, de Hoog  S, Verweij  PE, et al. Molecular nechanisms of 5-fluorocytosine resistance in yeasts and filamentous fungi. J Fungi (Basel). 2021;7:909. DOIPubMedGoogle Scholar
  16. 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;46:351821. DOIPubMedGoogle Scholar
  17. Delma  FZ, Melchers  WJG, Verweij  PE, Buil  JB. Wild-type MIC distributions and epidemiological cutoff values for 5-flucytosine and Candida species as determined by EUCAST broth microdilution. JAC Antimicrob Resist. 2024;6:dlae153. DOIPubMedGoogle Scholar
  18. Desnos-Ollivier  M, Bretagne  S, Bernède  C, Robert  V, Raoux  D, Chachaty  E, et al.; Yeasts Group. Clonal population of flucytosine-resistant Candida tropicalis from blood cultures, Paris, France. Emerg Infect Dis. 2008;14:55765. DOIPubMedGoogle Scholar
  19. Spruijtenburg  B, Meijer  EFJ, Xiao  M, Shawky  SM, Meis  JF, de Groot  T, et al. Genotyping and susceptibility testing uncovers large azole-resistant Candida tropicalis clade in Alexandria, Egypt. J Glob Antimicrob Resist. 2023;34:99105. DOIPubMedGoogle Scholar
  20. Spruijtenburg  B, van Haren  MHI, Chowdhary  A, Meis  JF, de Groot  T. Development and application of a short tandem repeat multiplex typing assay for Candida tropicalis. Microbiol Spectr. 2023;11:e0461822. DOIPubMedGoogle Scholar
  21. European Committee for Antimicrobial Susceptibility Testing. EUCAST Definitive Document E.Def 7.4. Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for yeasts. October 2023 [cited 2024 Mar 20]. https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Files/EUCAST_E.Def_7.4_Yeast_definitive_revised_2023.pdf
  22. Robinson  JT, Thorvaldsdóttir  H, Winckler  W, Guttman  M, Lander  ES, Getz  G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:246. DOIPubMedGoogle Scholar
  23. Abbey  DA, Funt  J, Lurie-Weinberger  MN, Thompson  DA, Regev  A, Myers  CL, et al. YMAP: a pipeline for visualization of copy number variation and loss of heterozygosity in eukaryotic pathogens. Genome Med. 2014;6:100. DOIPubMedGoogle Scholar
  24. Arentshorst  M, Ram  AF, Meyer  V. Using non-homologous end-joining-deficient strains for functional gene analyses in filamentous fungi. Methods Mol Biol. 2012;835:13350. DOIPubMedGoogle Scholar
  25. Dodgson  AR, Dodgson  KJ, Pujol  C, Pfaller  MA, Soll  DR. Clade-specific flucytosine resistance is due to a single nucleotide change in the FUR1 gene of Candida albicans. Antimicrob Agents Chemother. 2004;48:22237. DOIPubMedGoogle Scholar
  26. Nerson  D, De Closets  F, Dupouy-Camet  J, Kures  L, Marjollet  M, Poirot  J, et al. Antifungal susceptibility of yeasts (and a few filamentous fungi) by a standardized micromethod [in French]. Bulletin de la Société Francaise de Mycologie Médicale. 1987;16:3958.
  27. Law  D, Moore  CB, Joseph  LA, Keaney  MG, Denning  DW. High incidence of antifungal drug resistance in Candida tropicalis. Int J Antimicrob Agents. 1996;7:2415. DOIPubMedGoogle Scholar
  28. Barchiesi  F, Arzeni  D, Caselli  F, Scalise  G. Primary resistance to flucytosine among clinical isolates of Candida spp. J Antimicrob Chemother. 2000;45:4089. DOIPubMedGoogle Scholar
  29. Cuenca-Estrella  M, Díaz-Guerra  TM, Mellado  E, Rodríguez-Tudela  JL. Flucytosine primary resistance in Candida species and Cryptococcus neoformans. Eur J Clin Microbiol Infect Dis. 2001;20:2769. DOIPubMedGoogle Scholar
  30. Alexander  BD, Byrne  TC, Smith  KL, Hanson  KE, Anstrom  KJ, Perfect  JR, et al. Comparative evaluation of Etest and sensititre yeastone panels against the Clinical and Laboratory Standards Institute M27-A2 reference broth microdilution method for testing Candida susceptibility to seven antifungal agents. J Clin Microbiol. 2007;45:698706. DOIPubMedGoogle Scholar
  31. Quindós  G, Ruesga  MT, Martín-Mazuelos  E, Salesa  R, Alonso-Vargas  R, Carrillo-Muñoz  AJ, et al. In-vitro activity of 5-fluorocytosine against 1,021 Spanish clinical isolates of Candida and other medically important yeasts. Rev Iberoam Micol. 2004;21:639.PubMedGoogle Scholar
  32. Takakura  S, Fujihara  N, Saito  T, Kudo  T, Iinuma  Y, Ichiyama  S. National surveillance of species distribution in blood isolates of Candida species in Japan and their susceptibility to six antifungal agents including voriconazole and micafungin. J Antimicrob Chemother. 2004;53:2839. DOIPubMedGoogle Scholar
  33. Fleck  R, Dietz  A, Hof  H. In vitro susceptibility of Candida species to five antifungal agents in a German university hospital assessed by the reference broth microdilution method and Etest. J Antimicrob Chemother. 2007;59:76771. DOIPubMedGoogle Scholar
  34. Chen  YN, Lo  HJ, Wu  CC, Ko  HC, Chang  TP, Yang  YL. Loss of heterozygosity of FCY2 leading to the development of flucytosine resistance in Candida tropicalis. Antimicrob Agents Chemother. 2011;55:250614. DOIPubMedGoogle Scholar
  35. Lockhart  SR, Bolden  CB, Iqbal  N, Kuykendall  RJ. Validation of 24-hour flucytosine MIC determination by comparison with 48-hour determination by the Clinical and Laboratory Standards Institute M27-A3 broth microdilution reference method. J Clin Microbiol. 2011;49:43225. DOIPubMedGoogle Scholar
  36. Jung  SI, Shin  JH, Choi  HJ, Ju  MY, Kim  SH, Lee  WG, et al.; Korean Study Group for Candidemia. Antifungal susceptibility to amphotericin B, fluconazole, voriconazole, and flucytosine in Candida bloodstream isolates from 15 tertiary hospitals in Korea. Ann Lab Med. 2012;32:4268. DOIPubMedGoogle Scholar
  37. Messer  SA, Jones  RN, Moet  GJ, Kirby  JT, Castanheira  M. Potency of anidulafungin compared to nine other antifungal agents tested against Candida spp., Cryptococcus spp., and Aspergillus spp.: results from the global SENTRY Antimicrobial Surveillance Program (2008). J Clin Microbiol. 2010;48:29847. DOIPubMedGoogle Scholar
  38. Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts, 4th edition (M27). Wayne (PA): The Institute; 2017.
  39. Tavanti  A, Davidson  AD, Johnson  EM, Maiden  MC, Shaw  DJ, Gow  NA, et al. Multilocus sequence typing for differentiation of strains of Candida tropicalis. J Clin Microbiol. 2005;43:5593600. DOIPubMedGoogle Scholar
  40. Abou-Chakra  N, Astvad  KMT, Martinussen  J, Munksgaard  ASE, Arendrup  MC. Exponential clonal expansion of 5-fluorocytosine–resistant C. tropicalis and new insights into underlying molecular mechanisms. Emerg Infect Dis. 2025;31:97785. DOIPubMedGoogle Scholar
  41. Szarvas  J, Rebelo  AR, Bortolaia  V, Leekitcharoenphon  P, Schrøder Hansen  D, Nielsen  HL, et al. Danish whole-genome-sequenced Candida albicans and Candida glabrata samples fit into globally prevalent clades. J Fungi (Basel). 2021;7:962. DOIPubMedGoogle Scholar
  42. Fan  X, Dai  RC, Zhang  S, Geng  YY, Kang  M, Guo  DW, et al. Tandem gene duplications contributed to high-level azole resistance in a rapidly expanding Candida tropicalis population. Nat Commun. 2023;14:8369. DOIPubMedGoogle Scholar
  43. O’Brien  CE, Oliveira-Pacheco  J, Ó Cinnéide  E, Haase  MAB, Hittinger  CT, Rogers  TR, et al. Population genomics of the pathogenic yeast Candida tropicalis identifies hybrid isolates in environmental samples. PLoS Pathog. 2021;17:e1009138. DOIPubMedGoogle Scholar
  44. Tulyaprawat  O, Pharkjaksu  S, Chongtrakool  P, Ngamskulrungroj  P. An association of an eBURST group with triazole resistance of Candida tropicalis blood isolates. Front Microbiol. 2020;11:934. DOIPubMedGoogle Scholar
  45. Megri  Y, Arastehfar  A, Boekhout  T, Daneshnia  F, Hörtnagl  C, Sartori  B, et al. Candida tropicalis is the most prevalent yeast species causing candidemia in Algeria: the urgent need for antifungal stewardship and infection control measures. Antimicrob Resist Infect Control. 2020;9:50. DOIPubMedGoogle Scholar

Main Article

1These first authors contributed equally to this article.

2These senior authors contributed equally to this article.

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