Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.
Volume 31, Number 7—July 2025
Research
Emergence of Flucytosine-Resistant Candida tropicalis Clade, the Netherlands
Table
Reported 5-FC resistance rates in different published reports in study of non–wild-type Candida tropicalis clade, the Netherlands*
Total no. isolates | Year collected | Body site of isolation | Methods used† | Country | MIC criteria,‡ mg/L | No. (%) isolates with elevated 5-FC MICs | Reference |
---|---|---|---|---|---|---|---|
70 |
NA |
NA |
NA |
France |
NA |
NA (80) |
(26) |
60 |
NA |
Different sites |
Disc diffusion test, macrodilution with YNBG broth |
United Kingdom |
I, 2–8 | 6 (10) | (27) |
R, >8 |
17 (28) |
||||||
30 |
NA |
NA |
NCCLS |
Italy |
I, 8–16; R, >32 |
0 |
(28) |
117 |
1998–2000 |
Different sites |
NCCLS |
Spain |
I, 8–16 | 6 (5.1) | (29) |
R, >32 |
0 |
||||||
759 |
1992–2001 |
Different sites |
NCCLS |
Worldwide collection§ |
I, 8–16 | 60 (1) | (16) |
R, >32 |
NA (7) |
||||||
33 |
2000–2001 |
Blood |
CLSI M27-A2 |
United States |
I, 8–16 | 0 | (30) |
R, >32 |
1 (3) |
||||||
34 |
NA |
NA |
ATB Fungus |
Spain |
R, >32 |
3 (8.8) |
(31) |
62 |
2001–2002 |
Blood |
NCCLS M27-A2 |
Japan |
R, >32 |
NA (8.1) |
(32) |
60 |
2004–2006 |
Different sites |
CLSI M27-A2, Etest |
Germany |
R, >32 |
NA (58.3) |
(33) |
130 |
2002–2006 |
Blood |
EUCAST |
France |
R, >8 |
45 (35) |
(18) |
97 |
2006 |
NA |
Etest |
Taiwan |
I, 8–16 | 1 (1) | (34) |
R, >32 |
NA |
||||||
303 |
NA |
Blood |
CLSI M27-A3 |
United States |
I, 8–16 | 5 (1.65) | (35) |
R, >32 |
4 (1.32) |
||||||
149 |
2007–2008 |
Blood |
VITEK-2 |
South Korea |
I, 8–16; R, >32 |
0 |
(36) |
126 |
NA |
Blood |
CLSI M27-A3 |
Worldwide collection¶ |
NA |
NA (10.3) |
(37) |
359 | 2008–2024 | Different sites | EUCAST | The Netherlands | >16 | 106 (29.5) | (17) |
*CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing; 5-FC, flucytosine; I, intermediate resistance; NA, not applicable; NCCLS, National Committee for Clinical Laboratory Standards; R, resistant; YNBG, yeast nitrogen base glucose. †CLSI was formerly known as NCCLS. CLSI M27 broth dilution method for yeast (38). ATB Fungus test, Etest, and VITEK-2 were purchased from bioMérieux (https://www.biomerieux.com). ‡Resistance status and MICs used to interpret level of resistance to 5-FC in each study. §North America, Latin America, Europe, and Asia-Pacific. ¶United States, Europe, Latin America, and the Asia-Pacific region.
References
- McCarty TP, Pappas PG. Invasive Candidiasis. Infect Dis Clin North Am. 2016;30:103–24. DOIPubMedGoogle Scholar
- 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
- Guinea J. Global trends in the distribution of Candida species causing candidemia. Clin Microbiol Infect. 2014;20(Suppl 6):5–10. DOIPubMedGoogle Scholar
- 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;65:989–1000. DOIPubMedGoogle Scholar
- Chai LY, Denning DW, Warn P. Candida tropicalis in human disease. Crit Rev Microbiol. 2010;36:282–98. DOIPubMedGoogle Scholar
- 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
- 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
- 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 - Pristov KE, Ghannoum MA. Resistance of Candida to azoles and echinocandins worldwide. Clin Microbiol Infect. 2019;25:792–8. DOIPubMedGoogle Scholar
- 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:e01926–17. DOIPubMedGoogle Scholar
- 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
- 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 - Sigera LSM, Denning DW. Flucytosine and its clinical usage. Ther Adv Infect Dis. 2023;10:
20499361231161387 . DOIPubMedGoogle Scholar - 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:e280–93. DOIPubMedGoogle Scholar
- 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
- 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. DOIPubMedGoogle Scholar
- 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 - 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;14:557–65. DOIPubMedGoogle Scholar
- 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;34:99–105. DOIPubMedGoogle Scholar
- 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 - 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
- Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6. DOIPubMedGoogle Scholar
- 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
- Arentshorst M, Ram AF, Meyer V. Using non-homologous end-joining-deficient strains for functional gene analyses in filamentous fungi. Methods Mol Biol. 2012;835:133–50. DOIPubMedGoogle Scholar
- 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;48:2223–7. DOIPubMedGoogle Scholar
- 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;16:395–8.
- Law D, Moore CB, Joseph LA, Keaney MG, Denning DW. High incidence of antifungal drug resistance in Candida tropicalis. Int J Antimicrob Agents. 1996;7:241–5. DOIPubMedGoogle Scholar
- Barchiesi F, Arzeni D, Caselli F, Scalise G. Primary resistance to flucytosine among clinical isolates of Candida spp. J Antimicrob Chemother. 2000;45:408–9. DOIPubMedGoogle Scholar
- 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;20:276–9. DOIPubMedGoogle Scholar
- 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;45:698–706. DOIPubMedGoogle Scholar
- 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;21:63–9.PubMedGoogle Scholar
- 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;53:283–9. DOIPubMedGoogle Scholar
- 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;59:767–71. DOIPubMedGoogle Scholar
- 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;55:2506–14. DOIPubMedGoogle Scholar
- 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;49:4322–5. DOIPubMedGoogle Scholar
- 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;32:426–8. DOIPubMedGoogle Scholar
- 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;48:2984–7. DOIPubMedGoogle Scholar
- Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts, 4th edition (M27). Wayne (PA): The Institute; 2017.
- 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;43:5593–600. DOIPubMedGoogle Scholar
- 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;31:977–85. DOIPubMedGoogle Scholar
- 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
- 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
- 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 - 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
- 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
1These first authors contributed equally to this article.
2These senior authors contributed equally to this article.