Issues and Concerns in the Management of Systemic Candidiasis

  • I. W. Fong
Part of the Emerging Infectious Diseases of the 21st Century book series (EIDC)


Invasive candidiasis is the most common systemic fungal infection in hospitalized patients in the developed world, associated with a mortality of up to ≥40% even in patients treated with antifungals. It is a major cause of healthcare-associated or nosocomial infection induced by several Candida species; the most common species being Candida albicans, but the prevalence of the different species varies with geographical location and type of hospital practice. In some centers and countries there has been a shift in the frequency of non-C. albicans invasive disease with increased resistance to azoles such as fluconazole, the antifungal drug of choice in many countries and healthcare centers. Also there are increased reports of resistance to the newer class of antifungals, the echinocandins, which has replaced fluconazole as first choice in many guidelines and centers. Of major concern is the emergence of the novel multidrug resistant yeast, Candida auris, in the last 10 years that has been spreading globally with inter- and intra-hospital transmission. This chapter discusses the evidence to support guidelines recommendations for an echinocandin as initial therapy for invasive candidiasis over fluconazole.


Invasive candidiasis Candida species Candida albicans Candidemia Candida auris C. tropicalis C. glabrata Fluconazole Echinocandins Amphotericin Empiric treatment Intensive care unit 


  1. 1.
    Bongomin F, Gago S, Oladele RO, Denning DW (2017) Global and multi-national prevalence of fungal diseases—estimate precision. J Fungi (Basel) 3:57CrossRefGoogle Scholar
  2. 2.
    Cleveland AA, Harrison LH, Farley MM, Hollick R, Stein B, Chiller TM, Lockhart SR, Park BJ (2015) Declining incidence of candidemia and the shifting epidemiology of Candida resistance in two US metropolitan areas, 2008-2013: results from the population-based surveillance. PLoS One 10:e120452. Scholar
  3. 3.
    McCarty TP, Pappas PG (2016) Invasive candidiasis. J Infect Dis Clin North Am 30:103–124CrossRefGoogle Scholar
  4. 4.
    Perlroth J, Choi B, Spellberg B (2007) Nosocomial fungal infections: epidemiology, diagnosis, and treatment. Med Mycol 45:321–346PubMedCrossRefGoogle Scholar
  5. 5.
    Vincent JL, Rello J, Marshall J et al (2009) International study of the prevalence and outcomes of infection in intensive care units. JAMA 302:2323–2329PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Kulberg BJ, Arendrup MC (2015) Invasive candidiasis. N Engl J Med 373:1445–1456CrossRefGoogle Scholar
  7. 7.
    Koh AY, Kohler JR, Coggshall KT, Van Rooijen N, Pier GB (2008) Mucosal damage and neutrophils are required for Candida albicans dissemination. PLoS Pathog 4:e35. Scholar
  8. 8.
    Gazendam RP, van der Geer A, Roos D, van der Berg TK, Kuijpers TW (2016) How neutrophils kill fungi. Immunol Rev 273:299–311PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Duhring S, Germerodt S, Skerka C, Zipfel PF, Dandekar T, Schuster S (2015) Host-pathogen interaction between the human innate immune system and Candida albicans—understanding and modeling defense and evasion strategies. Front Microbiol.
  10. 10.
    Nash EE, Peters BM, Fidel PL, Noverr MC (2015) Morphology-independent virulence of Candida species during polymicrobial intra-abdominal infections with Staphylococcus aureus. Infect Immun 84:90–98PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Delano MJ, Ward PA (2016) Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest 126:23–31PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chin VK, Lee TV, Rusliza B, Chong PP (2016) Dissecting Candida albicans infection from the perspective of C. albicans virulence and omics approaches on host-pathogen interaction: a review. Int J Mol Sci 17:1643PubMedCentralCrossRefGoogle Scholar
  13. 13.
    Pappas PG, Lionakis MS, Arendrup MC, Ostrosky-Zeichner L, Kullberg BJ (2018) Invasive candidiasis. Nat Rev/Dis Primers 4:8026. Scholar
  14. 14.
    Plantinga TS, Johnson MD, Scott WK et al (2012) Toll-like receptor polymorphisms increase susceptibility to candidemia. J Infect Dis 205:934–943PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Kumar V, Cheng S-C, Johnson MD et al (2014) Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidemia. Nat Commun 5:4675PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Johnson MD, Plantinga TS, van de Vosse E et al (2012) Cytokine gene polymorphisms and the outcome of invasive candidiasis: a prospective cohort study. Clin Infect Dis 54:502–510PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Yapar N (2014) Epidemiology and risk factors for invasive candidiasis. Ther Clin Risk Manag 10:95–105PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Richardson M, Lassa-Florl C (2008) Changing epidemiology of systemic fungal infections. Clin Microbiol Infect 14(Suppl 4):5–24PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Arendrup MC (2014) Update on antifungal resistance in Aspergillus and Candida. Clin Microbiol Infect 20(Suppl 6):42–48PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Arendrup M, HJorn T, Frimodt-Moller N (2002) In vivo pathogenicity of eight medically relevant Candida species. Infection 30:286–291PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Welsh RM, Sexton DJ, Forsberg K, Vallabhaneni S, Litvintseva A (2019) Insights into the unique nature of the East Asian clade of the emerging pathogenic yeast Candida auris. J Clin Microbiol 57:e00007–e00019. Scholar
  22. 22.
    Lee WG, Shin JH, Uh Y, Kang MG, Kim SH, Park KH, Ang HC (2011) First three reported cases of nosocomial fungemia caused by Candida auris. J Clin Microbiol 49:3139–3142PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Kwon YJ, Shin JH, Byeon SA et al (2019) Candida auris clinical isolates from South Korea: identification, antifungal susceptibility, and genotyping. J Clin Microbiol 57:e01624–e01618. Scholar
  24. 24.
    Tsay S, Kallen A, Jackson BR, Chiller TM, Vallabhaneni S (2018) Approach to the investigation and management of patients with Candida auris, an emerging multi-resistant yeast. Clin Infect Dis 66:306–311PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Forsberg K, Woodworth K, Walters M, Berkow EL, Jackson B, Chiller T, Vallbhaneni S (2019) Candida auris: the recent emergence of a multidrug-resistant fungal pathogen. Med Mycol 57:1–12PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Cadnum JL, Shaikh AA, Piedrahita CT et al (2018) Relative resistance of the emerging fungal pathogen Candida auris and other Candida species to killing by ultraviolet light. Infect Control Hosp Epidemiol 39:94–96PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Mayer F, Wilson D, Hube B (2013) Candida albicans pathogenicity mechanisms. Virulence 4:119–128PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Fakhim H, Vaezi A, Damaoui E et al (2018) Comparative virulence of Candida auris with Candida haelomuloni, Candida glabrata and Candida albicans in a murine model. Mycoses 61:377–382PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Rebolledo M, Sarria JC (2013) Intra-abdominal fungal infections. Curr Opin Infect Dis 26:441–446PubMedPubMedCentralGoogle Scholar
  30. 30.
    Hall AM, Poole LA, Renton B, Fisher M, Neal T, Halloran CM, Cox T, Hampshire PA (2013) Prediction of invasive candidiasis in critically ill patients with severe acute pancreatitis. Crit Care 17:R49. Scholar
  31. 31.
    Montavers P, Dupont H, Gauzit R et al (2006) Candida as a risk factor for mortality in peritonitis. Crit Care Med 34:646–652CrossRefGoogle Scholar
  32. 32.
    Bassetti M, Righti 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–i25PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Clancy CJ, Nguyen MH (2013) Finding the “missing 50%” of invasive candidiasis: how nonculture diagnosis will improve understanding of disease spectrum and transform patient care. Clin Infect Dis 56:1284–1292PubMedCrossRefGoogle Scholar
  34. 34.
    Vergidis P, Clancy CJ, Shields RK, Park SY, Wildfeuer BN, Simmons RL, Nguyen MH (2016) Intra-abdominal candidiasis: the importance of early source control and antifungal treatment. PLoS One 11:e0153247. Scholar
  35. 35.
    Bassetti M, Righi E, Ansaldi F et al (2015) A multicenter study of abdominal candidiasis: epidemiology, outcomes and predictors of mortality. Intensive Care Med 41:1601–1610PubMedCrossRefGoogle Scholar
  36. 36.
    Pfeiffer CD, Samsa GP, Schell WA, Reller LB, Perfect JR, Alexander BDF (2011) Quantitation of Candida CFU in the initial positive blood cultures. J Clin Microbiol 49:2879–2883PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Montravers P, Dupont H, Eggimann P (2013) Intra-abdominal candidiasis: the guidelines—forgotten non-candidemic invasive candidiasis. Intensive Care Med 39:2226–2230PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Dupont H, Bourichon A, Paugam-Burtz C, Mantz J, Desmonts J-M (2003) Can yeast isolation in peritoneal fluid be predicted in intensive care unit patients with peritonitis? Crit Care Med 31:752–757PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Calandra T, Bille J, Schneider R, Mosimann F, Francioli P (1989) Clinical significance of candida isolation from peritoneum in surgical patients. Lancet 334:1437–1440CrossRefGoogle Scholar
  40. 40.
    Clancy CJ, Nguyen MH (2018) Diagnosing invasive candidiasis. J Clin Microbiol 56:e01909–e01917PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Mylonakis E, Clancy CJ, Ostrosky-Zeichner L et al (2015) T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Infect Dis 60:892–899PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Clancy CJ, Pappas PG, Vazquez J et al (2018) Detecting infections rapidly and easily for candidemia trial, part 2 [DIRECT2]: a prospective, multicenter study of the T2Candida Panel. Clin Infect Dis 66:1678–1686PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Leon C, Ruiz-Santana S, Saaverdra P et al (2016) Contribution of Candida biomarkers and DNA detection for the diagnosis of invasive candidiasis in ICU patients with severe abdominal conditions. Crit Care 20:149PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Munoz P, Vena A, Machado M et al (2018) T2MR contributes to the very early diagnosis of complicated candidemia. A prospective study. J Antimicrob Chemother 73(Suppl 4):iv13–iv19PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    CLSI (2012) Reference method for broth dilution antifungal susceptibility testing of yeasts; fourth international supplement. CLSI document M27-S4. Clinical and Laboratory Standards Institute, WayneGoogle Scholar
  46. 46.
    Fothergill AW, Sutton DA, McCarthy DI, Wiederhold NP (2014) Impact of new antifungal breakpoints on antifungal resistance in Candida species. J Clin Microbiol 52:994–997PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Pfaller MA, Messer SA, Woosley LN, Jones RN, Castanheira M (2013) Echinocandins and triazole antifungal susceptibility profiles for clinical yeast and mold isolates collected from 2010 to 2011: application of new CLSI clinical breakpoints and epidemiological cutoff values for characterization of geographic and temporal trends of antifungal resistance. J Clin Microbiol 51:2571–2581PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Lee I, Zaoutis TE, Fishman NO, Morales KH, Nachamkin I, Lautenback E (2010) Risk factors for fluconazole resistance in patients with Candida glabrata bloodstream infection: potential impact of control group selection on characterizing the association between previous fluconazole use and fluconazole resistance. Am J Infect Control 38:456–460PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Whaley SG, Berkow EL, Rybak JM, Nishimoto AT, Barker KS, Rogers PD (2017) Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species. Front Microbiol.
  51. 51.
    Alexander BD, Johnson MD, Pfieffer CD et al (2013) Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 56:1724–1732PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Beyda ND, John J, Kilic A, Alam MJ, Lasco TM, Garey KW (2014) FKS mutant Candida glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis 59:819–825PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Shields RK, Nguyen MH, press EG, Updike CL, Clancy CJ (2013) Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure. Antimicrob Agents Chemother 57:3528–3535PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Vallabhaneni S, Cleveland AA, Farley MM et al (2015) Epidemiology and risk factors for echinocandin nonsusceptible Candida glabrata bloodstream infections: data from a large multisite population-based candidemia surveillance program, 2008-2014. Open Forum Infect Dis 2:ofv163. Scholar
  55. 55.
    Tan TY, Hsu LY, Alejandria MM et al (2016) Antifungal susceptibility of invasive Candida bloodstream isolates from the Asia-Pacific region. Med Mycol 54:471–477PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Pfaller MA, Diekema DJ, Turnidge JD, Castanheira M, Jones RN (2019) Twenty years of the SENTRY antifungal surveillance program: results for Candida species from 1997-2016. Open Forum Infect Dis 6(Suppl 1):S79–S94PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Chowdhury A, Prakash A, Sharma C et al (2018) A multicenter study of antifungal susceptibility patterns among 350 Candida auris isolates [2009-17] in India: role of ERG11 and FKS genes in azole and echinocandin resistance. J Antimicrob Chemother 73:891–899CrossRefGoogle Scholar
  58. 58.
    Romera D, Aguilera-Corrrea JJ, Gadea I, Vinuela-Sandoval L, Garcia-Rodriguez J, Esteban J (2019) Candida auris: a comparison between planktonic and biofilm susceptibility to antifungal drugs. J Med Microbiol. Scholar
  59. 59.
    Pappas PG, Kauffmann 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 62:409–417PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Eschenauer GA, Nguyen M-H, Clancy CJ (2015) Is fluconazole or an echinocandin the agent of choice for candidemia. Ann Pharmacother 49:1068–1074PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Sobel JD, Revankar SG (2007) Echinocandins: first-choice or first-line therapy for invasive candidiasis? N Engl J Med 356:2525–2526PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Rex JH, Bennett JE, Sugar AM et al (1994) A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 331:1325–1330PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Reboli AC, Rotstein C, Pappas PG et al (2007) Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 356:2472–2482PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Andes DR, Safdar N, Badley JW et al (2012) Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis 54:1110–1122CrossRefGoogle Scholar
  65. 65.
    Puig-Asensio M, Peman J, Zaragoza R et al (2014) Impact of therapeutic strategies on the prognosis of candidemia in the ICU. Crit Care Med 42:1423–1432CrossRefGoogle Scholar
  66. 66.
    Bailey S, Leroy O, Azoulay E et al (2017) Impact of echinocandin on prognosis of proven invasive candidiasis in ICU: a post-hoc casual inference model using the AmarCAND2 study. J Infect 74:408–417CrossRefGoogle Scholar
  67. 67.
    Lopez-Cortez LE, Almirante B, Cuenca-Estrella M et al (2016) Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort. Clin Microbiol Infect:733.e1–8Google Scholar
  68. 68.
    Murri R, Scoppettuolo G, Ventura G et al (2016) Initial antifungal strategy does not correlate with mortality in patients with candidemia. Eur J Clin Microbiol Infect Dis 35:187–193PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Timsit JF, Azoulay E, Schwebel C et al (2016) Empiric micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure: the EMPIRICUS randomized clinical trial. JAMA 316:1555–1564PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Knitsch W, Vincent JL, Utzolino S et al (2015) A randomized, placebo-controlled trial of preemptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery for intra-abdominal infections. Clin Infect Dis 61:1671–1678PubMedPubMedCentralGoogle Scholar
  71. 71.
    Ostrosky-Zeichner L, Shoham S, Vasquez J et al (2014) MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk critical care setting. Clin Infect Dis 58:1219–1226PubMedCrossRefGoogle Scholar
  72. 72.
    Jensen RH, Johansen HK, Soes LM et al (2015) Post-treatment antifungal resistance among colonizing Candida isolates in candidemic patients: results from a systematic multicenter study. Antimicrob Agents Chemother 60:1500–1508PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Reboli AC, Shor AF, Rotstein C et al (2011) Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome. BMC Infect Dis 11:261PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Puig-Asensio M, Fernandez-Ruiz M, Aguado JM et al (2016) Propensity score analysis of the role of initial antifungal therapy in the outcome of Candida glabrata bloodstream infections. Antimicrob Agents Chemother 60:3291–3300PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Fernandez-Ruiz M, Guinea J, Lora-Pablos D et al (2017) Impact of fluconazole susceptibility on the outcome of patients with candidemia: data from a population-based surveillance. Clin Microbiol Infect 23:672PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • I. W. Fong
    • 1
  1. 1.St. Michael’s HospitalUniversity of TorontoTorontoCanada

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