Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 27, Number 3—March 2021

Fluconazole-Resistant Candida glabrata Bloodstream Isolates, South Korea, 2008–2018

Eun Jeong Won1, Min Ji Choi1, Mi-Na Kim, Dongeun Yong, Wee Gyo Lee, Young Uh, Taek Soo Kim, Seung Ah Byeon, Seung Yeob Lee, Soo Hyun Kim, and Jong Hee ShinComments to Author 
Author affiliations: Chonnam National University Medical School, Gwangju, South Korea (E.J. Won, M.J. Choi, S.A. Byeon, S.Y. Lee, S.H. Kim, J.H. Shin); Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea (M.-N. Kim); Yonsei University College of Medicine, Seoul (D. Yong); Ajou University School of Medicine, Suwon, South Korea (W.G. Lee); Yonsei University Wonju College of Medicine, Wonju, South Korea (Y. Uh); Seoul National University College of Medicine, Seoul (T.S. Kim)

Main Article

Table 1

Incidence of antifungal resistance in Candida glabrata BSI isolates, based on cultures collected during a multicenter surveillance study, South Korea, 2008–2018*

year No. participating hospitals† % C. glabrata of all Candida BSI isolates No. BSI isolates of C. glabrata tested No. (%) C. glabrata BSI isolates‡
Fluconazole resistance Echinocandin resistance§ Multidrug resistance¶
2008 13 11.7 68 0 0 0
2009 8 16.0 67 4 (6.0) 0 0
2010 8 16.8 60 4 (6.7) 0 0
2011 10 16.0 85 4 (4.7) 0 0
2012 11 17.0 108 3 (2.8) 0 0
2013 7 16.9 73 4 (5.5) 1 (1.4) 1 (1.4)
2014 7 22.1 123 11 (8.9) 0 0
2015 10 17.2 110 5 (4.5) 3 (2.7) 0
2016 10 21.2 123 4 (3.3) 4 (3.3) 2 (1.6)
2017 13 21.6 173 13 (7.5) 4 (2.3) 1 (0.6)
14 (8.3)
4 (2.4)
2 (1.2)
Total 19 18.6 1158 66 (5.7) 16 (1.4) 6 (0.5)

*BSI, bloodstream infection.
†Hospitals participating in this laboratory-based nationwide multicenter surveillance system differed each year.
‡Antifungal susceptibility was determined by using the Clinical and Laboratory Standards Institute M27–4ED broth microdilution method (16). Interpretive categories of resistance were determined by using Clinical and Laboratory Standards Institute document M60-ED (17). We deposited 76 antifungal-resistant isolates of C. glabrata in the Korea Collection for Type Culture (KCTC; Jeongeup-si, Korea), including those showing resistance to fluconazole alone (60 isolates, KCTC nos. 37113–37172), echinocandin alone (10 isolates, KCTC nos. 37176–37185), and both fluconazole and echinocandin (6 multidrug-resistant isolates, KCTC nos. 37110–37112, 37173–37175). All 76 isolates were identified as C. glabrata by sequence analysis using the D1/D2 domain (GenBank accession nos. MW349716–90 and MW351777).
§Echinocandin resistance was confirmed by the identification of resistance hot-spot mutations in FKS1 and FKS2 in isolates that exhibited full or intermediate resistance to micafungin (MIC >0.12 mg/L) or caspofungin MIC (>0.25 mg/L).
¶Multidrug resistance was defined as resistance to both fluconazole and echinocandins.

Main Article

  1. Arendrup  MC. Epidemiology of invasive candidiasis. Curr Opin Crit Care. 2010;16:44552. DOIPubMedGoogle Scholar
  2. Arendrup  MC, Patterson  TF. Multidrug-resistant Candida: epidemiology, molecular mechanisms, and treatment. J Infect Dis. 2017;216(suppl_3):S44551. DOIPubMedGoogle Scholar
  3. Jensen  RH, Johansen  HK, Søes  LM, Lemming  LE, Rosenvinge  FS, Nielsen  L, et al. Posttreatment antifungal resistance among colonizing Candida isolates in candidemia patients: results from a systematic multicenter study. Antimicrob Agents Chemother. 2015;60:15008. DOIPubMedGoogle Scholar
  4. Pfaller  MA, Diekema  DJ, Turnidge  JD, Castanheira  M, Jones  RN. Twenty years of the SENTRY antifungal surveillance program: results for Candida species from 1997–2016. Open Forum Infect Dis. 2019;6(Suppl 1):S7994. DOIPubMedGoogle Scholar
  5. Chapman  B, Slavin  M, Marriott  D, Halliday  C, Kidd  S, Arthur  I, et al.; Australian and New Zealand Mycoses Interest Group. Changing epidemiology of candidaemia in Australia. J Antimicrob Chemother. 2017;72:11038. DOIPubMedGoogle Scholar
  6. Tan  TY, Hsu  LY, Alejandria  MM, Chaiwarith  R, Chinniah  T, Chayakulkeeree  M, et al. Antifungal susceptibility of invasive Candida bloodstream isolates from the Asia-Pacific region. Med Mycol. 2016;54:4717. DOIPubMedGoogle Scholar
  7. Ferrari  S, Ischer  F, Calabrese  D, Posteraro  B, Sanguinetti  M, Fadda  G, et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 2009;5:e1000268. DOIPubMedGoogle Scholar
  8. Tsai  HF, Krol  AA, Sarti  KE, Bennett  JE. Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob Agents Chemother. 2006;50:138492. DOIPubMedGoogle Scholar
  9. Hull  CM, Parker  JE, Bader  O, Weig  M, Gross  U, Warrilow  AG, et al. Facultative sterol uptake in an ergosterol-deficient clinical isolate of Candida glabrata harboring a missense mutation in ERG11 and exhibiting cross-resistance to azoles and amphotericin B. Antimicrob Agents Chemother. 2012;56:422332. DOIPubMedGoogle Scholar
  10. Abbes  S, Mary  C, Sellami  H, Michel-Nguyen  A, Ayadi  A, Ranque  S. Interactions between copy number and expression level of genes involved in fluconazole resistance in Candida glabrata. Front Cell Infect Microbiol. 2013;3:74. DOIPubMedGoogle Scholar
  11. Vu  BG, Moye-Rowley  WS. Construction and use of a recyclable marker to examine the role of major facilitator superfamily protein members in Candida glabrata drug resistance phenotypes. MSphere. 2018;3:e0009918. DOIPubMedGoogle Scholar
  12. Ferrari  S, Sanguinetti  M, Torelli  R, Posteraro  B, Sanglard  D. Contribution of CgPDR1-regulated genes in enhanced virulence of azole-resistant Candida glabrata. PLoS One. 2011;6:e17589. DOIPubMedGoogle Scholar
  13. Hou  X, Xiao  M, Wang  H, Yu  SY, Zhang  G, Zhao  Y, et al. Profiling of PDR1 and MSH2 in Candida glabrata bloodstream isolates from a multicenter study in China. Antimicrob Agents Chemother. 2018;62:e0015318. DOIPubMedGoogle Scholar
  14. Arastehfar  A, Daneshnia  F, Zomorodian  K, Najafzadeh  MJ, Khodavaisy  S, Zarrinfar  H, et al. Low level of antifungal resistance in Iranian isolates of Candida glabrata recovered from blood samples in a multicenter study from 2015 to 2018 and potential prognostic values of genotyping and sequencing of PDR1. Antimicrob Agents Chemother. 2019;63:e0250318. DOIPubMedGoogle Scholar
  15. Hou  X, Xiao  M, Chen  SC, Wang  H, Yu  SY, Fan  X, et al. Identification and antifungal susceptibility profiles of Candida nivariensis and Candida bracarensis in a multi-center Chinese collection of yeasts. Front Microbiol. 2017;8:5. DOIPubMedGoogle Scholar
  16. Clinical and Laboratory Standards Institute. M27 reference method for broth dilution antifungal susceptibility testing of yeasts. 4th ed. Wayne (PA): Clinical and Laboratory Standards Institute; 2017.
  17. Clinical and Laboratory Standards Institute. Performance standards for antifungal susceptibility testing of Yeasts. 1st ed. CLSI supplement M60. Wayne (PA): Clinical and Laboratory Standards Institute; 2017.
  18. Clinical and Laboratory Standards Institute. Epidemiological cutoff values for antifungal susceptibility testing. 2nd ed. CLSI supplement M59. Wayne (PA): Clinical and Laboratory Standards Institute; 2018.
  19. Rivero-Menendez  O, Navarro-Rodriguez  P, Bernal-Martinez  L, Martin-Cano  G, Lopez-Perez  L, Sanchez-Romero  I, et al. Clinical and laboratory development of echinocandin resistance in Candida glabrata: molecular characterization. Front Microbiol. 2019;10:1585. DOIPubMedGoogle Scholar
  20. Pappas  PG, Kauffman  CA, Andes  DR, Clancy  CJ, Marr  KA, Ostrosky-Zeichner  L, et al. Executive summary: clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62:40917. DOIPubMedGoogle Scholar
  21. Byun  SA, Won  EJ, Kim  MN, Lee  WG, Lee  K, Lee  HS, et al. Multilocus sequence typing (MLST) genotypes of Candida glabrata bloodstream isolates in Korea: association with antifungal resistance, mutations in mismatch repair gene (Msh2), and clinical outcomes. Front Microbiol. 2018;9:1523. DOIPubMedGoogle Scholar
  22. Kim  MN, Shin  JH, Sung  H, Lee  K, Kim  EC, Ryoo  N, et al. Candida haemulonii and closely related species at 5 university hospitals in Korea: identification, antifungal susceptibility, and clinical features. Clin Infect Dis. 2009;48:e5761. DOIPubMedGoogle Scholar
  23. De Rosa  FG, Trecarichi  EM, Montrucchio  C, Losito  AR, Raviolo  S, Posteraro  B, et al. Mortality in patients with early- or late-onset candidaemia. J Antimicrob Chemother. 2013;68:92735. DOIPubMedGoogle Scholar
  24. Nguyen  MH, Clancy  CJ, Yu  VL, Yu  YC, Morris  AJ, Snydman  DR, et al. Do in vitro susceptibility data predict the microbiologic response to amphotericin B? Results of a prospective study of patients with Candida fungemia. J Infect Dis. 1998;177:42530. DOIPubMedGoogle Scholar
  25. Healey  KR, Zhao  Y, Perez  WB, Lockhart  SR, Sobel  JD, Farmakiotis  D, et al. Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat Commun. 2016;7:11128. DOIPubMedGoogle Scholar
  26. Niimi  M, Nagai  Y, Niimi  K, Wada  S, Cannon  RD, Uehara  Y, et al. Identification of two proteins induced by exposure of the pathogenic fungus Candida glabrata to fluconazole. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;782:24552. DOIPubMedGoogle Scholar
  27. Sanguinetti  M, Posteraro  B, Fiori  B, Ranno  S, Torelli  R, Fadda  G. Mechanisms of azole resistance in clinical isolates of Candida glabrata collected during a hospital survey of antifungal resistance. Antimicrob Agents Chemother. 2005;49:66879. DOIPubMedGoogle Scholar
  28. Won  EJ, Shin  JH, Choi  MJ, Lee  WG, Park  YJ, Uh  Y, et al. Antifungal susceptibilities of bloodstream isolates of Candida species from nine hospitals in Korea: application of new antifungal breakpoints and relationship to antifungal usage. PLoS One. 2015;10:e0118770. DOIPubMedGoogle Scholar
  29. Xiao  M, Sun  ZY, Kang  M, Guo  DW, Liao  K, Chen  SC, et al.; China Hospital Invasive Fungal Surveillance Net (CHIF-NET) Study Group. Five-year national surveillance of invasive candidiasis: species distribution and azole susceptibility from the China Hospital Invasive Fungal Surveillance Net (CHIF–NET) Study. J Clin Microbiol. 2018;56:e0057718. DOIPubMedGoogle Scholar
  30. Hou  X, Xiao  M, Chen  SC, Kong  F, Wang  H, Chu  YZ, et al. Molecular epidemiology and antifungal susceptibility of Candida glabrata in China (August 2009 to July 2014): a multi-center study. Front Microbiol. 2017;8:880. DOIPubMedGoogle Scholar
  31. Ko  JH, Jung  DS, Lee  JY, Kim  HA, Ryu  SY, Jung  SI, et al. Changing epidemiology of non-albicans candidemia in Korea. J Infect Chemother. 2019;25:38891. DOIPubMedGoogle Scholar
  32. Choi  H, Kim  JH, Seong  H, Lee  W, Jeong  W, Ahn  JY, et al. Changes in the utilization patterns of antifungal agents, medical cost and clinical outcomes of candidemia from the health-care benefit expansion to include newer antifungal agents. Int J Infect Dis. 2019;83:4955. DOIPubMedGoogle Scholar
  33. Ruan  SY, Huang  YT, Chu  CC, Yu  CJ, Hsueh  PR. Candida glabrata fungaemia in a tertiary centre in Taiwan: antifungal susceptibility and outcomes. Int J Antimicrob Agents. 2009;34:2369. DOIPubMedGoogle Scholar
  34. Horn  DL, Neofytos  D, Anaissie  EJ, Fishman  JA, Steinbach  WJ, Olyaei  AJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis. 2009;48:1695703. DOIPubMedGoogle Scholar
  35. Lee  I, Morales  KH, Zaoutis  TE, Fishman  NO, Nachamkin  I, Lautenbach  E. Clinical and economic outcomes of decreased fluconazole susceptibility in patients with Candida glabrata bloodstream infections. Am J Infect Control. 2010;38:7405. DOIPubMedGoogle Scholar
  36. Eschenauer  GA, Carver  PL, Patel  TS, Lin  SW, Klinker  KP, Pai  MP, et al. Survival in patients with Candida glabrata bloodstream infection is associated with fluconazole dose. Antimicrob Agents Chemother. 2018;62:e0256617. DOIPubMedGoogle Scholar
  37. Ko  JH, Peck  KR, Jung  DS, Lee  JY, Kim  HA, Ryu  SY, et al. Impact of high MIC of fluconazole on outcomes of Candida glabrata bloodstream infection: a retrospective multicenter cohort study. Diagn Microbiol Infect Dis. 2018;92:12732. DOIPubMedGoogle Scholar
  38. Tortorano  AM, Dho  G, Prigitano  A, Breda  G, Grancini  A, Emmi  V, et al.; ECMM-FIMUA Study Group. Invasive fungal infections in the intensive care unit: a multicentre, prospective, observational study in Italy (2006-2008). Mycoses. 2012;55:739. DOIPubMedGoogle Scholar
  39. Lortholary  O, Renaudat  C, Sitbon  K, Madec  Y, Denoeud-Ndam  L, Wolff  M, et al.; French Mycosis Study Group. Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002-2010). Intensive Care Med. 2014;40:130312. DOIPubMedGoogle Scholar
  40. Pfaller  MA, Andes  DR, Diekema  DJ, Horn  DL, Reboli  AC, Rotstein  C, et al. Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) registry 2004-2008. PLoS One. 2014;9:e101510. DOIPubMedGoogle Scholar
  41. Singh  A, Healey  KR, Yadav  P, Upadhyaya  G, Sachdeva  N, Sarma  S, et al. Absence of azole or echinocandin resistance in Candida glabrata isolates in India despite background prevalence of strains with defects in the DNA mismatch repair pathway. Antimicrob Agents Chemother. 2018;62:e0019518. DOIPubMedGoogle Scholar
  42. Bordallo-Cardona  , Agnelli  C, Gómez-Nuñez  A, Sánchez-Carrillo  C, Bouza  E, Muñoz  P, et al. MSH2 gene point mutations are not antifungal resistance markers in Candida glabrata. Antimicrob Agents Chemother. 2018;63:e0187618. DOIPubMedGoogle Scholar
  43. Biswas  C, Marcelino  VR, Van Hal  S, Halliday  C, Martinez  E, Wang  Q, et al. Whole genome sequencing of Australian Candida glabrata isolates reveals genetic diversity and novel sequence types. Front Microbiol. 2018;9:2946. DOIPubMedGoogle Scholar
  44. Yao  D, Chen  J, Chen  W, Li  Z, Hu  X. Mechanisms of azole resistance in clinical isolates of Candida glabrata from two hospitals in China. Infect Drug Resist. 2019;12:77181. DOIPubMedGoogle Scholar
  45. Whaley  SG, Berkow  EL, Rybak  JM, Nishimoto  AT, Barker  KS, Rogers  PD. Azole antifungal resistance in Candida albicans and emerging non–albicans Candida species. Front Microbiol. 2017;7:2173. DOIPubMedGoogle Scholar
  46. Tantivitayakul  P, Lapirattanakul  J, Kaypetch  R, Muadcheingka  T. Missense mutation in CgPDR1 regulator associated with azole-resistant Candida glabrata recovered from Thai oral candidiasis patients. J Glob Antimicrob Resist. 2019;17:2216. DOIPubMedGoogle Scholar
  47. Pais  P, Galocha  M, Viana  R, Cavalheiro  M, Pereira  D, Teixeira  MC. Microevolution of the pathogenic yeasts Candida albicans and Candida glabrata during antifungal therapy and host infection. Microb Cell. 2019;6:14259. DOIPubMedGoogle Scholar
  48. Ni  Q, Wang  C, Tian  Y, Dong  D, Jiang  C, Mao  E, et al. CgPDR1 gain-of-function mutations lead to azole-resistance and increased adhesion in clinical Candida glabrata strains. Mycoses. 2018;61:43040. DOIPubMedGoogle Scholar
  49. Brunke  S, Hube  B. Two unlike cousins: Candida albicans and C. glabrata infection strategies. Cell Microbiol. 2013;15:7018. DOIPubMedGoogle Scholar
  50. Lortholary  O, Desnos-Ollivier  M, Sitbon  K, Fontanet  A, Bretagne  S, Dromer  F; French Mycosis Study Group. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients. Antimicrob Agents Chemother. 2011;55:5328. DOIPubMedGoogle Scholar

Main Article

1These first authors contributed equally to this article.

Page created: January 04, 2021
Page updated: March 01, 2021
Page reviewed: March 01, 2021
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.