Persistent Candidemia in adults: underlying causes and clinical significance in the antifungal stewardship era

  • Caroline AgnelliEmail author
  • Maricela Valerio
  • Emilio Bouza
  • Antonio Vena
  • Jesús Guinea
  • María del Carmen Martínez-Jiménez
  • Laura Judith Marcos-Zambrano
  • Pilar Escribano
  • Patricia Muñoz
  • on behalf of the COMIC Study Group (Collaborative Group on Mycosis)
Original Article


To investigate the causes and the clinical significance of persistent candidemia (PC) in adults diagnosed in a tertiary hospital with an active antifungal stewardship program. Retrospective cohort including all adults with candidemia from 2010 to 2018. PC was defined as any positive follow-up blood culture (BC) obtained ≥ 5 days from the first BCs yielding the same Candida species. PC was detected in 35/255 (13.7%) patients. There were no differences regarding antifungal adequacy in PC vs. non-PC (94.3% vs. 82.3%, p = 0.084) and primary source control (63.3% vs. 76.4%, p = 0.172) at the time of the follow-up BCs. The average time until source control (2 [0–37] vs. 2 days [0–44], p = 0.311) or adequate antifungal treatment (2 [0–26] vs. 2 days [− 2–10], p = 0.748) was similar. Patients with PC had more non-ocular complications (31.4% vs. 10.5%, p = 0.002). No impact on 30-day mortality was observed (31.4% vs. 22.3%, p = 0.238). The only independent factor associated with PC was to have a previously undetected site of infection [OR 4.28, 95%CI (1.77–10.34), p = 0.001]. Persistent candidemia was not associated with inadequate or delayed therapeutic management, nor higher 30-day mortality rates. Timely screening and control of unexpected infection sources are encouraged to shorten hospitalization and improve patient care.


Persistent candidemia Antifungal stewardship Mortality Candidemia 



We would like to thank all participants of the COMIC Study Group (Collaborative Group on Mycoses): F. Anaya, R. Bañares, E. Bouza, A. Bustinza, E. Chamorro, P. Escribano, A.Fernández-Cruz, J. Fernández-Quero, I. Frias, J. Gayoso, P. Gijón, J. Guinea, J. Hortal, M. C. Martínez, I. Márquez, M. C. Menárguez, P. Muñoz, M. Navarro, B. Padilla, J. Palomo, T. Peláez, J. Peral, B. Pinilla, D. Rincón, C. G. Rodríguez, M. Rodríguez, M Salcedo, M.Sánchez-Somolinos, M. Sanjurjo, M. Valerio, E. Verde, and E. Zamora.


This study was supported by Fondo de Investigación Sanitaria (FIS) - PM (PI13/01148) and LJMZ (PI14/00740); CA was supported by CAPES Foundation, Brazil/PDSE (88881.187981/2018-01); PE (CPI15/00115) and JG (CPII15/00006) are recipients of a Miguel Servet grant, and AV (CM15/00181) was supported by a Rio Hortega grant from Instituto de Salud Carlos III (ISCIII), also co-financed by the European Regional Development Fund (FEDER) “A way of making Europe.” Additional funding was received through the Plan Nacional de I+D+I 2013-2016, and PROgrama MULtidisciplinar para la Gestión de Antifúngicos y la Reducción de Candidiasis Invasora (PROMULGA) II Project.

Compliance with ethical standards

This study was approved by the institutional ethics committee (Comité Ético de Investigación Clínica del Hospital Gregorio Marañón [CEIC-A1], study code MICRO.HGUGM.2015–071). The need for an informed consent was waived owing to the non-interventional, retrospective design of the study.

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Noyola DE, Fernandez M, Moylett EH, Baker CJ (2001) Ophthalmologic, visceral, and cardiac involvement in neonates with candidemia. Clin Infect Dis 32(7):1018–1023CrossRefGoogle Scholar
  2. 2.
    Fraser VJ, Jones M, Dunkel J, Storfer S, Medoff G, Dunagan WC (1992) Candidemia in a tertiary care hospital: epidemiology, risk factors, and predictors of mortality. Clin Infect Dis 15(3):414–421CrossRefGoogle Scholar
  3. 3.
    Luzzati R, Amalfitano G, Lazzarini L et al (2000) Nosocomial candidemia in non-neutropenic patients at an Italian tertiary care hospital. Eur J Clin Microbiol Infect Dis 19(8):602–607CrossRefGoogle Scholar
  4. 4.
    Zaoutis TE, Greves HM, Lautenbach E, Bilker WB, Coffin SE (2004) Risk factors for disseminated candidiasis in children with candidemia. Pediatr Infect Dis J 23(7):635–641CrossRefGoogle Scholar
  5. 5.
    Nucci M (2011) Persistent candidemia: causes and investigations. Curr Fungal Infect Rep 5(1):3–11CrossRefGoogle Scholar
  6. 6.
    Kang SJ, Kim SE, Kim UJ et al (2017) Clinical characteristics and risk factors for mortality in adult patients with persistent candidemia. J Infect Elsevier 75(3):246–253CrossRefGoogle Scholar
  7. 7.
    Vena A, Munoz P, Corisco R, et al. Efficacy of a “check-list” intervention bundle on the clinical evolution of patients with Candida bloodstream infections. 27th ECCMID. 2017. p. 24–25Google Scholar
  8. 8.
    Valerio M, Muñoz P, Rodríguez CG et al (2015) Antifungal stewardship in a tertiary-care institution: a bedside intervention. Clin Microbiol Infect 21(5):492.e1–492.e9CrossRefGoogle Scholar
  9. 9.
    Muñoz P, Valerio M, Vena A, Bouza E (2015) Antifungal stewardship in daily practice and health economic implications. Mycoses 58:14–25CrossRefGoogle Scholar
  10. 10.
    Vena A, Bouza E, Valerio M et al (2017) Candidemia in non-ICU surgical wards: comparison with medical wards. PLoS One Public Libr Sci 12(10):e0185339CrossRefGoogle Scholar
  11. 11.
    Mermel LA, Allon M, Bouza E et al (2009) Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 49(1):1–45CrossRefGoogle Scholar
  12. 12.
    Pappas PG, Kauffman CA, Andes DR et al (2016) Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis Oxford Univ Press 62(4):e1–e50Google Scholar
  13. 13.
    Arendrup MC, Cuenca-Estrella M, Lass-Flörl C, Hope W (2012) EUCAST-AFST. EUCAST technical note on the EUCAST definitive document EDef 7.2: method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for yeasts EDef 7.2 (EUCAST-AFST)*. Clin Microbiol Infect 18(7):E246–E247CrossRefGoogle Scholar
  14. 14.
    Marcos-Zambrano LJ, Escribano P, Bouza E, Guinea J (2014) Production of biofilm by Candida and non-Candida spp. isolates causing fungemia: comparison of biomass production and metabolic activity and development of cut-off points. Int J Med Microbiol 304(8):1192–1198CrossRefGoogle Scholar
  15. 15.
    Marcos-Zambrano LJ, Gómez-Perosanz M, Escribano P, Zaragoza O, Bouza E, Guinea J (2016) Biofilm production and antibiofilm activity of echinocandins and liposomal amphotericin B in echinocandin-resistant yeast species. Antimicrob Agents Chemother 60(6):3579–3586CrossRefGoogle Scholar
  16. 16.
    Nucci M, Perfect JR (2008) When primary antifungal therapy fails. Clin Infect Dis 46(9):1426–1433CrossRefGoogle Scholar
  17. 17.
    Baden LR, Bensinger W, Angarone M et al (2012) Prevention and treatment of cancer-related infections. J Natl Compr Cancer Netw 10(11):1412–1445CrossRefGoogle Scholar
  18. 18.
    Ruhnke M, Schwartz S (2016) Recent developments in the management of invasive fungal infections in patients with oncohematological diseases. Ther Adv Hematol SAGE Publ 7(6):345–359CrossRefGoogle Scholar
  19. 19.
    Clancy CJ, Nguyen MH (2013) Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis 56(9):1284–1292CrossRefGoogle Scholar
  20. 20.
    Li W-S, Chen Y-C, Kuo S-F, Chen F-J, Lee C-H (2018) The impact of biofilm formation on the persistence of candidemia. Front Microbiol 9:1196CrossRefGoogle Scholar
  21. 21.
    Monfredini PM, Souza ACR, Cavalheiro RP, Siqueira RA, Colombo AL (2017) Clinical impact of Candida spp. biofilm production in a cohort of patients with candidemia. Med Mycol 56(7):803–808CrossRefGoogle Scholar
  22. 22.
    Lin K-Y, Chen P-Y, Chuang Y-C et al (2018) Effectiveness of echinocandins versus fluconazole for treatment of persistent candidemia: a time-dependent analysis. J Inf Secur 77(3):242–248Google Scholar
  23. 23.
    Muñoz P, Agnelli C, Guinea J et al (2018) Is biofilm production a prognostic marker in adults with candidaemia? Clin Microbiol Infect 24(9):1010–1015CrossRefGoogle Scholar
  24. 24.
    Hamdy RF, Zaoutis TE, Seo SK (2017) Antifungal stewardship considerations for adults and pediatrics. Virulence 8(6):658–672CrossRefGoogle Scholar
  25. 25.
    Nucci M, Anaissie E, Betts RFF et al (2010) Early removal of central venous catheter in patients with candidemia does not improve outcome: analysis of 842 patients from 2 randomized clinical trials. Clin Infect Dis 51(3):295–303CrossRefGoogle Scholar
  26. 26.
    Garnacho-Montero J, Diaz-Martin A, Garcia-Cabrera E, Ruiz Perez de Pipaon M, Hernandez-Caballero C, Lepe-Jimenez JA (2013) Impact on hospital mortality of catheter removal and adequate antifungal therapy in Candida spp. bloodstream infections. J Antimicrob Chemother 68(1):206–213CrossRefGoogle Scholar
  27. 27.
    Caccese R, Carfagna P, Pistilli N, Massetti AP, Falcone M, Venditti M (2012) Candidal thrombophlebitis of central veins: case report and review. Med Mycol 50(3):299–304CrossRefGoogle Scholar
  28. 28.
    Mahmood M, Kendi AT, Ajmal S, et al (2017) Meta-analysis of 18F-FDG PET/CT in the diagnosis of infective endocarditis. J Nucl Cardiol. Advance online publication.
  29. 29.
    Sharma P, Mukherjee A, Karunanithi S, Bal C, Kumar R (2014) Potential role of 18 F-FDG PET/CT in patients with fungal infections. Am J Roentgenol American Roentgen Ray Society 203(1):180–189CrossRefGoogle Scholar
  30. 30.
    Kauffman C (2015) Complications of candidemia in ICU patients: endophthalmitis, osteomyelitis, endocarditis. Semin Respir Crit Care Med. Thieme Medical Publishers 36(05):641–649CrossRefGoogle Scholar
  31. 31.
    Fernández-Cruz A, Cruz Menárguez M, Muñoz P et al (2015) The search for endocarditis in patients with candidemia: a systematic recommendation for echocardiography? A prospective cohort. Eur J Clin Microbiol Infect Dis 34(8):1543–1549CrossRefGoogle Scholar
  32. 32.
    Safdar A, Bannister TW, Safdar Z (2004) The predictors of outcome in immunocompetent patients with hematogenous candidasis. Int J Infect Dis 8(3):180–186CrossRefGoogle Scholar
  33. 33.
    Velasco E, Bigni R (2008) A prospective cohort study evaluating the prognostic impact of clinical characteristics and comorbid conditions of hospitalized adult and pediatric cancer patients with candidemia. Eur J Clin Microbiol Infect Dis 27(11):1071–1078CrossRefGoogle Scholar
  34. 34.
    Phillips P, Shafran S, Garber G et al (1997) Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients. Canadian Candidemia Study Group. Eur J Clin Microbiol Infect Dis 16(5):337–345CrossRefGoogle Scholar
  35. 35.
    Chen C-Y, Huang S-Y, Tsay W et al (2012) Clinical characteristics of candidaemia in adults with haematological malignancy, and antimicrobial susceptibilities of the isolates at a medical centre in Taiwan, 2001–2010. Int J Antimicrob Agents 40(6):533–538CrossRefGoogle Scholar
  36. 36.
    Bassetti M, Righi E, Montravers P, Cornely OA (2018) What has changed in the treatment of invasive candidiasis? A look at the past 10 years and ahead. J Antimicrob Chemother 73(suppl_1):i14–i25CrossRefGoogle Scholar
  37. 37.
    Puig-Asensio M, Padilla B, Garnacho-Montero J et al (2014) Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain. Clin Microbiol Infect 20(4):O245–O254CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Caroline Agnelli
    • 1
    • 2
    • 3
    Email author
  • Maricela Valerio
    • 1
    • 2
  • Emilio Bouza
    • 1
    • 2
    • 4
    • 5
  • Antonio Vena
    • 1
    • 2
    • 5
  • Jesús Guinea
    • 1
    • 2
    • 4
    • 5
  • María del Carmen Martínez-Jiménez
    • 1
    • 2
  • Laura Judith Marcos-Zambrano
    • 1
    • 2
    • 5
    • 6
  • Pilar Escribano
    • 1
    • 2
    • 5
  • Patricia Muñoz
    • 1
    • 2
    • 4
    • 5
  • on behalf of the COMIC Study Group (Collaborative Group on Mycosis)
  1. 1.Department of Clinical Microbiology and Infectious DiseasesHospital General Universitario Gregorio MarañónMadridSpain
  2. 2.Gregorio Marañón Sanitary Research InstituteMadridSpain
  3. 3.Department of Medicine, Division of Infectious Diseases, Escola Paulista de MedicinaUniversidade Federal de São PauloSão PauloBrazil
  4. 4.CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0058)MadridSpain
  5. 5.Department of Medicine, Faculty of MedicineUniversidad Complutense de MadridMadridSpain
  6. 6.Computational Biology Group, Precision Nutrition and Cancer Research ProgramIMDEA Food InstituteMadridSpain

Personalised recommendations