Skip to main content
SpringerLink
Log in

Candida Biofilm: Clinical Implications of Recent Advances in Research

  • Current Management of Fungal Infections (L Ostrosky-Zeichner, Section Editor)
  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

Candida spp. are human commensals that can colonize devices and cause diseases associated with host tissue damage. In each lifestyle, Candida forms biofilms – communities of cells living within a protective extracellular matrix comprising proteins, polysaccharides, extracellular nucleic acids, and lipids. In vitro and in vivo models have defined basic steps in Candida biofilm formation as adhesion, initiation, maturation, and dispersal. Biofilms afford Candida cells resistance to antifungal agents, and host defenses and immune responses. In addition to “pathogenic” biofilm, Candida albicans also produces an alternative, permeable “sexual” biofilm that facilitates mating between cells. Treatment of biofilm infections consists of removing the infected device (if feasible) and antifungal therapy. Optimal antifungals are not defined, but echinocandins and lipid formulations of amphotericin B are most consistently active in model systems. Future research will shed light on how biofilm regulation allows Candida to adapt to diverse microenvironments relevant to commensalism and disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Casadevall A, Pirofski LA. Host-pathogen interactions: basic concepts of microbial commensalism, colonization, infection, and disease. Infect Immun. 2000;68(12):6511–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Chandra J et al. A rabbit model for evaluation of catheter-associated fungal biofilms. Virulence. 2011;2(5):466–74.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Pierce JV et al. Normal adaptation of Candida albicans to the murine gastrointestinal tract requires Efg1p-dependent regulation of metabolic and host defense genes. Eukaryot Cell. 2013;12(1):37–49.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Koh AY. Murine models of Candida gastrointestinal colonization and dissemination. Eukaryot Cell. 2013;12(11):1416–22.

    Article  CAS  PubMed  Google Scholar 

  5. Control, C.f.D. Candida bloodstream infectons: exploring the health impact of an underappreciated HAI. 03/06/20313 8/25/2013]; Available from: http://www.cdc.gov/hai/eip/pdf/Candida-factsheet.pdf.

  6. Kucharikova S et al. Detailed comparison of Candida albicans and Candida glabrata biofilms under different conditions and their susceptibility to caspofungin and anidulafungin. J Med Microbiol. 2011;60(Pt 9):1261–9.

    Article  CAS  PubMed  Google Scholar 

  7. Peters BM et al. Microbial interactions and differential protein expression in Staphylococcus aureus -Candida albicans dual-species biofilms. FEMS Immunol Med Microbiol. 2010;59(3):493–503.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Harriott MM, Noverr MC. Importance of Candida-bacterial polymicrobial biofilms in disease. Trends Microbiol. 2011;19(11):557–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Finkel JS, Mitchell AP. Genetic control of Candida albicans biofilm development. Nat Rev Microbiol. 2011;9(2):109–18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Harriott MM, Noverr MC. Ability of Candida albicans mutants to induce Staphylococcus aureus vancomycin resistance during polymicrobial biofilm formation. Antimicrob Agents Chemother. 2010;54(9):3746–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Xu H et al. Streptococcal co-infection augments Candida pathogenicity by amplifying the mucosal inflammatory response. Cell Microbiol. 2013. doi:10.1111/cmi.12216.

    PubMed  Google Scholar 

  12. Ramage G et al. Standardized method for in vitro antifungal susceptibility testing of Candida albicans biofilms. Antimicrob Agents Chemother. 2001;45(9):2475–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Frade JP, Arthington-Skaggs BA. Effect of serum and surface characteristics on Candida albicans biofilm formation. Mycoses. 2011;54(4):e154–62.

    Article  PubMed  Google Scholar 

  14. Cuellar-Cruz M et al. The effect of biomaterials and antifungals on biofilm formation by Candida species: a review. Eur J Clin Microbiol Infect Dis. 2012;31(10):2513–27.

    Article  CAS  PubMed  Google Scholar 

  15. Sato M et al. Inhibitory effect of coated mannan against the adhesion of Candida biofilms to denture base resin. Dent Mater J. 2013;32(3):355–60.

    Article  CAS  PubMed  Google Scholar 

  16. Oncu S. In vitro effectiveness of antifungal lock solutions on catheters infected with Candida species. J Infect Chemother. 2011;17(5):634–9.

    Article  PubMed  Google Scholar 

  17. Chandra J, Mukherjee PK, Ghannoum MA. In vitro growth and analysis of Candida biofilms. Nat Protoc. 2008;3(12):1909–24.

    Article  CAS  PubMed  Google Scholar 

  18. Tournu H, Van Dijck P. Candida biofilms and the host: models and new concepts for eradication. Int J Microbiol. 2012;2012:845352.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Uppuluri P, Lopez-Ribot JL. An easy and economical in vitro method for the formation of Candida albicans biofilms under continuous conditions of flow. Virulence. 2010;1(6):483–7.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Bernhardt H, Knoke M, Bernhardt J. Efficacy of anidulafungin against biofilms of different Candida species in long-term trials of continuous flow cultivation. Mycoses. 2011;54(6):e821–7.

    Article  CAS  PubMed  Google Scholar 

  21. Costa AC et al. Methods for obtaining reliable and reproducible results in studies of Candida biofilms formed in vitro. Mycoses. 2013;56(6):614–22.

    Article  PubMed  Google Scholar 

  22. Martins M et al. Presence of extracellular DNA in the Candida albicans biofilm matrix and its contribution to biofilms. Mycopathologia. 2010;169(5):323–31.

    Article  CAS  PubMed  Google Scholar 

  23. Nett JE et al. Development and validation of an in vivo Candida albicans biofilm denture model. Infect Immun. 2010;78(9):3650–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Andes D et al. Development and characterization of an in vivo central venous catheter Candida albicans biofilm model. Infect Immun. 2004;72(10):6023–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Kucharikova S et al. Activities of systemically administered echinocandins against in vivo mature Candida albicans biofilms developed in a rat subcutaneous model. Antimicrob Agents Chemother. 2013;57(5):2365–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Dongari-Bagtzoglou A et al. Characterization of mucosal Candida albicans biofilms. PLoS One. 2009;4(11):e7967.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Harriott MM et al. Candida albicans forms biofilms on the vaginal mucosa. Microbiology. 2010;156(Pt 12):3635–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Bonhomme J, d’Enfert C. Candida albicans biofilms: building a heterogeneous, drug-tolerant environment. Curr Opin Microbiol. 2013;16(4):398–403.

    Article  CAS  PubMed  Google Scholar 

  29. Cuellar-Cruz M et al. Candida species: new insights into biofilm formation. Future Microbiol. 2012;7(6):755–71.

    Article  CAS  PubMed  Google Scholar 

  30. Sardi JC et al. Candida species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options. J Med Microbiol. 2013;62(Pt 1):10–24.

    Article  CAS  PubMed  Google Scholar 

  31. Flemming HC, Wingender J. The biofilm matrix. Nat Rev Microbiol. 2010;8(9):623–33.

    CAS  PubMed  Google Scholar 

  32. Douglas LJ. Candida biofilms and their role in infection. Trends Microbiol. 2003;11(1):30–6.

    Article  CAS  PubMed  Google Scholar 

  33. Paramonova E et al. Hyphal content determines the compression strength of Candida albicans biofilms. Microbiology. 2009;155(Pt 6):1997–2003.

    Article  CAS  PubMed  Google Scholar 

  34. Romanowski K et al. Candida albicans isolates from the gut of critically ill patients respond to phosphate limitation by expressing filaments and a lethal phenotype. PLoS One. 2012;7(1):e30119.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Ferreira AV et al. Candida albicans and non-C. albicans Candida species: comparison of biofilm production and metabolic activity in biofilms, and putative virulence properties of isolates from hospital environments and infections. Mycopathologia. 2013;175(3–4):265–72.

    Article  CAS  PubMed  Google Scholar 

  36. Yu LH et al. Possible inhibitory molecular mechanism of farnesol on the development of fluconazole resistance in Candida albicans biofilm. Antimicrob Agents Chemother. 2012;56(2):770–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Alem MA et al. Production of tyrosol by Candida albicans biofilms and its role in quorum sensing and biofilm development. Eukaryot Cell. 2006;5(10):1770–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Uppuluri P et al. Dispersion as an important step in the Candida albicans biofilm developmental cycle. PLoS Pathog. 2010;6(3):e1000828.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Katragkou A et al. Interactions between human phagocytes and Candida albicans biofilms alone and in combination with antifungal agents. J Infect Dis. 2010;201(12):1941–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Xie Z et al. Candida albicans biofilms do not trigger reactive oxygen species and evade neutrophil killing. J Infect Dis. 2012;206(12):1936–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Cottier F, Pavelka N. Complexity and dynamics of host-fungal interactions. Immunol Res. 2012;53(1–3):127–35.

    Article  CAS  PubMed  Google Scholar 

  42. Perlin DS. Current perspectives on echinocandin class drugs. Future Microbiol. 2011;6(4):441–57.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Shields RK et al. The presence of an FKS mutation rather than MIC is an independent risk factor for failure of echinocandin therapy among patients with invasive candidiasis due to Candida glabrata. Antimicrob Agents Chemother. 2012;56(9):4862–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Pappas PG et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503–35.

    Article  CAS  PubMed  Google Scholar 

  45. Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med. 2012;125(1 Suppl):S3–13.

    Article  CAS  PubMed  Google Scholar 

  46. Calderone RACCJ. Candida and candidiasis. Washington, DC: ASM Press; 2012.

    Google Scholar 

  47. Nweze EI et al. Development of a 96-well catheter-based microdilution method to test antifungal susceptibility of Candida biofilms. J Antimicrob Chemother. 2012;67(1):149–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Mathé L, Van Dijck P. Recent insights into Candida albicans biofilm resistance mechanisms. Curr Genet. 2013;59(4):251–64.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Tobudic S et al. Antifungal susceptibility of Candida albicans in biofilms. Mycoses. 2012;55(3):199–204.

    Article  PubMed  Google Scholar 

  50. Lu H et al. Rare case of septic arthritis caused by Candida krusei: case report and literature review. J Rheumatol. 2012;39(6):1308–9.

    Article  PubMed  Google Scholar 

  51. Nett JE et al. Role of Fks1p and matrix glucan in Candida albicans biofilm resistance to an echinocandin, pyrimidine, and polyene. Antimicrob Agents Chemother. 2010;54(8):3505–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. DiDone L, Oga D, Krysan DJ. A novel assay of biofilm antifungal activity reveals that amphotericin B and caspofungin lyse Candida albicans cells in biofilms. Yeast. 2011;28(8):561–8.

    Article  CAS  PubMed  Google Scholar 

  53. Simitsopoulou M et al. Species-specific and drug-specific differences in susceptibility of Candida biofilms to echinocandins: characterization of less common bloodstream isolates. Antimicrob Agents Chemother. 2013;57(6):2562–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Ramage G et al. Fungal biofilm resistance. Int J Microbiol. 2012;2012:528521.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Mitchell KF et al. Role of matrix beta-1,3 glucan in antifungal resistance of non-albicans Candida biofilms. Antimicrob Agents Chemother. 2013;57(4):1918–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Taff HT et al. A Candida biofilm-induced pathway for matrix glucan delivery: implications for drug resistance. PLoS Pathog. 2012;8(8):e1002848.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Bink A et al. Superoxide dismutases are involved in Candida albicans biofilm persistence against miconazole. Antimicrob Agents Chemother. 2011;55(9):4033–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Ramage G et al. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J Antimicrob Chemother. 2002;49(6):973–80.

    Article  CAS  PubMed  Google Scholar 

  59. Badrane H et al. Rapid redistribution of phosphatidylinositol-(4,5)-bisphosphate and septins during the Candida albicans response to caspofungin. Antimicrob Agents Chemother. 2012;56(9):4614–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Lafleur MD, Qi Q, Lewis K. Patients with long-term oral carriage harbor high-persister mutants of Candida albicans. Antimicrob Agents Chemother. 2010;54(1):39–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Gao Y et al. Synergistic effect of doxycycline and fluconazole against Candida albicans biofilms and the impact of calcium channel blockers. FEMS Yeast Res. 2013;13(5):453–62.

    Article  CAS  PubMed  Google Scholar 

  62. Chatzimoschou A et al. Activities of triazole-echinocandin combinations against Candida species in biofilms and as planktonic cells. Antimicrob Agents Chemother. 2011;55(5):1968–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Bink A et al. The nonsteroidal antiinflammatory drug diclofenac potentiates the in vivo activity of caspofungin against Candida albicans biofilms. J Infect Dis. 2012;206(11):1790–7.

    Article  CAS  PubMed  Google Scholar 

  64. Delattin N, et al. Repurposing as a means to increase the activity of amphotericin B and caspofungin against Candida albicans biofilms. J Antimicrob Chemother. 2013. doi:10.1093/jac/dkt449.

  65. Blackwood RA et al. Ethanol locks therapy for resolution of fungal catheter infections. Pediatr Infect Dis J. 2011;30(12):1105–7.

    Article  PubMed  Google Scholar 

  66. Ko KS et al. In vitro evaluation of antibiotic lock technique for the treatment of Candida albicans, C. glabrata, and C. tropicalis biofilms. J Korean Med Sci. 2010;25(12):1722–6.

    Article  PubMed Central  PubMed  Google Scholar 

  67. Cateau E, Berjeaud JM, Imbert C. Possible role of azole and echinocandin lock solutions in the control of Candida biofilms associated with silicone. Int J Antimicrob Agents. 2011;37(4):380–4.

    Article  CAS  PubMed  Google Scholar 

  68. Walraven CJ, Lee SA. Antifungal lock therapy. Antimicrob Agents Chemother. 2013;57(1):1–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Onland W et al. Pediatric patients with intravascular devices: polymicrobial bloodstream infections and risk factors. J Pathog. 2011;2011:826169.

    Article  PubMed Central  PubMed  Google Scholar 

  70. Slobbe L et al. Prevention of catheter-related bacteremia with a daily ethanol lock in patients with tunnelled catheters: a randomized, placebo-controlled trial. PLoS One. 2010;5(5):e10840.

    Article  PubMed Central  PubMed  Google Scholar 

  71. Miceli MH et al. In vitro analyses of the effects of heparin and parabens on Candida albicans biofilms and planktonic cells. Antimicrob Agents Chemother. 2012;56(1):148–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Shanks RM et al. Catheter lock solutions influence staphylococcal biofilm formation on abiotic surfaces. Nephrol Dial Transplant. 2006;21(8):2247–55.

    Article  CAS  PubMed  Google Scholar 

  73. Zhou L et al. Parylene coating hinders Candida albicans adhesion to silicone elastomers and denture bases resin. Arch Oral Biol. 2010;55(6):401–9.

    Article  CAS  PubMed  Google Scholar 

  74. Monteiro DR et al. Silver colloidal nanoparticles: effect on matrix composition and structure of Candida albicans and Candida glabrata biofilms. J Appl Microbiol. 2013;114(4):1175–83.

    Article  CAS  PubMed  Google Scholar 

  75. Williams DL et al. Characterization of a novel active release coating to prevent biofilm implant-related infections. J Biomed Mater Res B Appl Biomater. 2013;101(6):1078–89.

    Article  PubMed  Google Scholar 

  76. Tran N et al. In vivo caprine model for osteomyelitis and evaluation of biofilm-resistant intramedullary nails. Biomed Res Int. 2013;2013:674378.

    Article  PubMed Central  PubMed  Google Scholar 

  77. Pereira CA et al. Susceptibility of Candida albicans, Staphylococcus aureus, and Streptococcus mutans biofilms to photodynamic inactivation: an in vitro study. Lasers Med Sci. 2011;26(3):341–8.

    Article  PubMed  Google Scholar 

  78. Bujdakova H et al. Participation of the Candida albicans surface antigen in adhesion, the first phase of biofilm development. FEMS Immunol Med Microbiol. 2010;59(3):485–92.

    CAS  PubMed  Google Scholar 

  79. Hornby JM et al. Quorum sensing in the dimorphic fungus Candida albicans is mediated by farnesol. Appl Environ Microbiol. 2001;67(7):2982–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Hamblin MR, Hasan T. Photodynamic therapy: a new antimicrobial approach to infectious disease? Photochem Photobiol Sci. 2004;3(5):436–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Dovigo LN et al. Investigation of the photodynamic effects of curcumin against Candida albicans. Photochem Photobiol. 2011;87(4):895–903.

    Article  CAS  PubMed  Google Scholar 

  82. Costa AC et al. Effect of erythrosine- and LED-mediated photodynamic therapy on buccal candidiasis infection of immunosuppressed mice and Candida albicans adherence to buccal epithelial cells. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114(1):67–74.

    Article  PubMed  Google Scholar 

  83. Soll DR. The evolution of alternative biofilms in an opportunistic fungal pathogen: an explanation for how new signal transduction pathways may evolve. Infect Genet Evol. 2013. doi:10.1016/j.meegid.2013.07.013.

    PubMed  Google Scholar 

  84. Srikantha T et al. Identification of genes upregulated by the transcription factor Bcr1 that are involved in impermeability, impenetrability, and drug resistance of Candida albicans a/alpha biofilms. Eukaryot Cell. 2013;12(6):875–88.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Daniels KJ et al. Opaque cells signal white cells to form biofilms in Candida albicans. EMBO J. 2006;25(10):2240–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Yi S et al. Alternative mating type configurations (a/alpha versus a/a or alpha/alpha) of Candida albicans result in alternative biofilms regulated by different pathways. PLoS Biol. 2011;9(8):e1001117.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Pierce CG et al. A simple and reproducible 96-well plate-based method for the formation of fungal biofilms and its application to antifungal susceptibility testing. Nat Protoc. 2008;3(9):1494–500.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Uppuluri P, Chaturvedi AK, Lopez-Ribot JL. Design of a simple model of Candida albicans biofilms formed under conditions of flow: development, architecture, and drug resistance. Mycopathologia. 2009;168(3):101–9.

    Article  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

EG Press has no conflicts.

RK Shields has received investigator-initiated research funding from Merck and Astellas.

CJ Clancy has received research funding from Pfizer and Merck.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. University of Pittsburgh, Scaife Hall, Suite 871, 3550 Terrace Street, Pittsburgh, PA, 15261, USA

    Ellen G. Press, Ryan K. Shields & Cornelius J. Clancy

  2. Pittsburgh VA Healthcare System, Pittsburgh, PA, USA

    Cornelius J. Clancy

Authors
  1. Ellen G. Press
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryan K. Shields
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cornelius J. Clancy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cornelius J. Clancy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Press, E.G., Shields, R.K. & Clancy, C.J. Candida Biofilm: Clinical Implications of Recent Advances in Research. Curr Fungal Infect Rep 8, 72–80 (2014). https://doi.org/10.1007/s12281-014-0176-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12281-014-0176-z

Keywords

Search

Navigation