The association between fluconazole dose and MIC with mortality and persistence in candidemia

  • Nesrin Ghanem-ZoubiEmail author
  • Majd Qasum
  • Johad Khoury
  • Danny Zorbavel
  • Merav Arnon
  • Yuval Geffen
  • Mical Paul
Original Article


To evaluate the association between fluconazole exposure parameters and clinical outcomes in patients with candidemia. We retrospectively included all adults with candidemia in a single center from January 2009 to December 2017, treated initially with fluconazole for fluconazole-susceptible candidemia. We assessed the association between fluconazole exposure parameters and 30-day mortality or 14-day clinical failure, a composite of mortality at day 14 or persistent candidemia ≥ 72 h, in all patients and in patients with C. glabrata candidemia. During the study period, 158 patients fulfilled the inclusion criteria. Main species were C. albicans 66 (41.8%), C. glabrata 35 (22.2%), and C. parapsilosis 31 (19.6%). Sixty patients (38%) died within 30 days. Sixty-one patients (38.6%) experienced 14-day failure. In 30-day survivors, the median AUC24/MIC was 2279 [398, 5989] versus 1764 [238, 6714] h in non-survivors, p = 0.75. Median fluconazole MIC was 0.75 [0.25, 4] and 1 [0.22, 5.50] mg/L, p = 0.54, respectively. Similar non-significant differences were found for other fluconazole exposure parameters and in the 14-day clinical failure analysis. For C. glabrata, a higher AUC24/MIC was observed among 30-day survivors with a median of 230 [77, 539] compared to 96 [75, 164] h in non-survivors, p = 0.008, in parallel with a trend for lower MIC values (median 7 [1, 2] versus 16 [8, 24] mg/L, p = 0.06, respectively). Currently used fluconazole dosing has no association with clinical outcome in Candida with low MIC values. For Candida species with high MICs, attention to dosing is needed.


Candidemia Fluconazole Mortality Area under curve Minimal inhibitory concentration 



The study was presented in the 29th European Congress of Clinical Microbiology and Infectious Diseases that was held in Amsterdam, Netherlands, April 2019.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The study was approved by the ethics committee at Rambam Hospital.

Informed consent

Not required; not applicable.

Supplementary material

10096_2019_3611_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 20 kb)


  1. 1.
    Clinical and laboratory standards institute reference method for broth dilution antifungal susceptibility testing of yeasts: Fourth informational supplement M27-S4. Wayne, PA: USACLSI; 2012Google Scholar
  2. 2.
    Koga-Ito CY, Lyon JP, de Resende MA Comparison between E-test and CLSI broth microdilution method for antifungal susceptibility testing of Candida albicans oral isolates. Rev Inst Med Trop Sao Paulo [cited 2019 7];50:7–10.
  3. 3.
    Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al (2015) Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis [cited 2019 2];62:civ933.
  4. 4.
    Fluconazole rationale for the EUCAST clinical breakpoints, version 2.0. 2013 [cited 2019 24].
  5. 5.
    European committee on antimicrobial susceptibility testing antifungal agents. Breakpoint tables for interpretation of MICs. Version 7.0. 2014;0–4Google Scholar
  6. 6.
    Clancy CJ, Yu VL, Morris AJ, Snydman DR, Nguyen MH (2005) Fluconazole MIC and the fluconazole dose/MIC ratio correlate with therapeutic response among patients with candidemia. Antimicrob Agents Chemother [cited 2018 19];49:3171–7.
  7. 7.
    Pai MP, Turpin RS, Garey KW (2007) Association of fluconazole area under the concentration-time curve/mic and dose/mic ratios with mortality in nonneutropenic patients with candidemia. Antimicrob Agents Chemother 1 [cited 2018 18];51:35–9.
  8. 8.
    Rodríguez-Tudela JL, Almirante B, Rodríguez-Pardo D, Laguna F, Donnelly JP, Mouton JW, et al (2007) Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia. Antimicrob Agents Chemother [cited 2018 19];51:3599–604.
  9. 9.
    Baddley JW, Patel M, Bhavnani SM, Moser SA, Andes DR (2008) Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother [cited 2018 19];52:3022–3028.
  10. 10.
    Brosh-Nissimov T, Ben-Ami R (2015) Differential association of fluconazole dose and dose/MIC ratio with mortality in patients with Candida albicans and non-albicans bloodstream infection. Clin Microbiol Infect [cited 2018 19]; 21:1011–1017.
  11. 11.
    Fernández-Ruiz M, Guinea J, Lora-Pablos D, Zaragoza Ó, Puig-Asensio M, Almirante B, et al (2017) Impact of fluconazole susceptibility on the outcome of patients with candidaemia: data from a population-based surveillance. Clin Microbiol Infect [cited 2018 19];23:672.e1–672.e11.
  12. 12.
    Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, et al (2017) Expressing the modification of diet in renal disease study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem [cited 2019 30];53:766–72.
  13. 13.
    Sobue S, Tan K, Layton G, Leclerc V, Weil A (2004) The effects of renal impairment on the pharmacokinetics and safety of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole. Br J Clin Pharmacol [cited 2019 30];57:773–784.
  14. 14.
    Siqueira RA, Doi AM, de Petrus Crossara PP, Koga PCM, Marques AG, Nunes FG, et al (2018) Evaluation of two commercial methods for the susceptibility testing of Candida species: Vitek 2® and Sensititre YeastOne®. Rev Iberoam Micol [cited 2019 7];35:83–7.
  15. 15.
    Pfaller MA, Diekema DJ, Sheehan DJ (2006) Interpretive breakpoints for fluconazole and Candida revisited: a blueprint for the future of antifungal susceptibility testing. Clin Microbiol Rev [cited 2019 9];19:435–47.
  16. 16.
    Kaur R, Dhakad M, Goyal R, Haque A, Mukhopadhyay G (2016) Identification and antifungal susceptibility testing of Candida species: a comparison of Vitek-2 system with conventional and molecular methods. J Glob Infect Dis [cited 2019 7];8:139.

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Nesrin Ghanem-Zoubi
    • 1
    Email author
  • Majd Qasum
    • 2
  • Johad Khoury
    • 3
  • Danny Zorbavel
    • 4
  • Merav Arnon
    • 4
  • Yuval Geffen
    • 5
  • Mical Paul
    • 1
  1. 1.Infectious Diseases InstituteRambam Health Care CampusHaifaIsrael
  2. 2.Internal Medicine Department DRambam Health Care CampusHaifaIsrael
  3. 3.Internal Medicine Department BRambam Health Care CampusHaifaIsrael
  4. 4.The Ruth and Bruce Rappaport Faculty of Medicine, TechnionIsrael Institute of TechnologyHaifaIsrael
  5. 5.Microbiology LaboratoryRambam Health Care CampusHaifaIsrael

Personalised recommendations