Pathogens in Severe Sepsis: New Paradigms for Fungi Treatment

  • Matteo BassettiEmail author
  • Malgorzata Mikulska


Candida is one of the most frequent pathogens in bloodstream infections, and is associated with significant morbidity and mortality. The epidemiology of the species responsible for candidemia, both at the local and worldwide levels, has been changing, shifting from C. albicans to non-albicans species, which can be resistant to fluconazole (C. krusei and C. glabrata) or difficult to eradicate because of biofilm production (C. parapsilosis). Numerous ICU patients have multiple risk factors for developing this infection, which include prolonged hospitalisation, use of broad-spectrum antibiotics, presence of intravascular catheters, parenteral nutrition, high APACHE score, etc. Moreover, delaying the specific therapy was shown to further increase morbidity and mortality. In order to minimise the impact of this infection, several management strategies have been developed, namely prophylaxis, empirical and pre-emptive therapy. Compared to prophylaxis, empirical and pre-emptive approaches allow reducing the exposure to antifungals by targeting only the patients at high risk of candidemia, without delaying therapy until the moment blood Candida is identified in blood cultures. The agents recommended for initial treatment of candidemia in critically ill patients include echinocandins and a lipid formulation of amphotericin B.


Intensive Care Unit Intensive Care Unit Patient Candida Species Bloodstream Infection Invasive Candidiasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Agvald-Ohman C, Klingspor L, Hjelmqvist H et al (2008) Invasive candidiasis in long-term patients at a multidisciplinary intensive care unit: Candida colonization index, risk factors, treatment and outcome. Scand J Infect Dis 40:145–153PubMedCrossRefGoogle Scholar
  2. Almirante B, Rodriguez D, Park BJ et al (2005) Epidemiology and predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, Barcelona, Spain, from 2002 to 2003. J Clin Microbiol 43:1829–1835PubMedCrossRefGoogle Scholar
  3. Alonso-Valle H, Acha O, Garcia-Palomo JD et al (2003) Candidemia in a tertiary care hospital: epidemiology and factors influencing mortality. Eur J Clin Microbiol Infect Dis 22:254–257PubMedGoogle Scholar
  4. Asmundsdottir LR, Erlendsdottir H, Haraldsson G et al (2008) Molecular epidemiology of candidemia: evidence of clusters of smoldering nosocomial infections. Clin Infect Dis 47:e17–e24PubMedCrossRefGoogle Scholar
  5. Bassetti M, Righi E, Costa A et al (2006) Epidemiological trends in nosocomial candidemia in intensive care. BMC Infect Dis 6:21PubMedCrossRefGoogle Scholar
  6. Bassetti M, Ansaldi F, Nicolini L et al (2009) Incidence of candidaemia and relationship with fluconazole use in an intensive care unit. J Antimicrob Chemother 64:625–629PubMedCrossRefGoogle Scholar
  7. Ben-Ami R, Weinberger M, Orni-Wasserlauff R et al (2008) Time to blood culture positivity as a marker for catheter-related candidemia. J Clin Microbiol 46:2222–2226PubMedCrossRefGoogle Scholar
  8. Bliss JM, Basavegowda KP, Watson WJ et al (2008) Vertical and horizontal transmission of Candida albicans in very low birth weight infants using DNA fingerprinting techniques. Pediatr Infect Dis J 27:231–235PubMedCrossRefGoogle Scholar
  9. Blumberg HM, Jarvis WR, Soucie JM et al (2001) Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis 33:177–186PubMedCrossRefGoogle Scholar
  10. Bouza E, Perez-Molina J, Munoz P (1999) Report of ESGNI01 and ESGNI02 studies. Bloodstream infections in Europe. Clin Microbiol Infect 5(2):S1–S12CrossRefGoogle Scholar
  11. Bow EJ, Laverdiere M, Lussier N et al (2002) Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials. Cancer 94:3230–3246PubMedCrossRefGoogle Scholar
  12. Calandra T, Marchetti O (2004) Clinical trials of antifungal prophylaxis among patients undergoing surgery. Clin Infect Dis 39(Suppl 4):S185–S192PubMedCrossRefGoogle Scholar
  13. Choi HW, Shin JH, Jung SI et al (2007) Species-specific differences in the susceptibilities of biofilms formed by Candida bloodstream isolates to echinocandin antifungals. Antimicrob Agents Chemother 51:1520–1523PubMedCrossRefGoogle Scholar
  14. Chow JK, Golan Y, Ruthazer R et al (2008a) Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit. Clin Infect Dis 46:1206–1213PubMedCrossRefGoogle Scholar
  15. Chow JK, Golan Y, Ruthazer R et al (2008b) Risk factors for albicans and non-albicans candidemia in the intensive care unit. Crit Care Med 36:1993–1998PubMedCrossRefGoogle Scholar
  16. Cruciani M, de Lalla F, Mengoli C (2005) Prophylaxis of Candida infections in adult trauma and surgical intensive care patients: a systematic review and meta-analysis. Intensive Care Med 31:1479–1487PubMedCrossRefGoogle Scholar
  17. Davis SL, Vazquez JA, McKinnon PS (2007) Epidemiology, risk factors, and outcomes of Candida albicans versus non-albicans candidemia in nonneutropenic patients. Ann Pharmacother 41:568–573PubMedCrossRefGoogle Scholar
  18. De Waele JJ, Vogelaers D, Blot S et al (2003) Fungal infections in patients with severe acute pancreatitis and the use of prophylactic therapy. Clin Infect Dis 37:208–213PubMedCrossRefGoogle Scholar
  19. Diekema DJ, Messer SA, Brueggemann AB et al (2002) Epidemiology of candidemia: 3-year results from the emerging infections and the epidemiology of Iowa organisms study. J Clin Microbiol 40:1298–1302PubMedCrossRefGoogle Scholar
  20. Dimopoulos G, Ntziora F, Rachiotis G et al (2008) Candida albicans versus non-albicans intensive care unit-acquired bloodstream infections: differences in risk factors and outcome. Anesth Analg 106:523–529; table of contentsPubMedCrossRefGoogle Scholar
  21. DiNubile MJ, Lupinacci RJ, Strohmaier KM et al (2007) Invasive candidiasis treated in the intensive care unit: observations from a randomized clinical trial. J Crit Care 22:237–244PubMedCrossRefGoogle Scholar
  22. Eggimann P, Francioli P, Bille J et al (1999) Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients. Crit Care Med 27:1066–1072PubMedCrossRefGoogle Scholar
  23. Eggimann P, Garbino J, Pittet D (2003) Epidemiology of Candida species infections in critically ill non-immunosuppressed patients. Lancet Infect Dis 3:685–702PubMedCrossRefGoogle Scholar
  24. Filioti J, Spiroglou K, Panteliadis CP et al (2007) Invasive candidiasis in pediatric intensive care patients: epidemiology, risk factors, management, and outcome. Intensive Care Med 33:1272–1283PubMedCrossRefGoogle Scholar
  25. Forrest GN, Weekes E, Johnson JK (2008) Increasing incidence of Candida parapsilosis candidemia with caspofungin usage. J Infect 56:126–129PubMedCrossRefGoogle Scholar
  26. Fraser VJ, Jones M, Dunkel J et al (1992) Candidemia in a tertiary care hospital: epidemiology, risk factors, and predictors of mortality. Clin Infect Dis 15:414–421PubMedCrossRefGoogle Scholar
  27. Fridkin SK (2005) The changing face of fungal infections in health care settings. Clin Infect Dis 41:1455–1460PubMedCrossRefGoogle Scholar
  28. Fridkin SK, Kaufman D, Edwards JR et al (2006) Changing incidence of Candida bloodstream infections among NICU patients in the United States: 1995–2004. Pediatrics 117:1680–1687PubMedCrossRefGoogle Scholar
  29. Garbino J, Lew DP, Romand JA et al (2002) Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill patients: a randomized, double-blind, placebo-controlled trial in patients treated by selective digestive decontamination. Intensive Care Med 28:1708–1717PubMedCrossRefGoogle Scholar
  30. Garey KW, Rege M, Pai MP et al (2006) Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 43:25–31PubMedCrossRefGoogle Scholar
  31. Gudlaugsson O, Gillespie S, Lee K et al (2003) Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 37:1172–1177PubMedCrossRefGoogle Scholar
  32. Hachem R, Hanna H, Kontoyiannis D et al (2008) The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy. Cancer 112:2493–2499PubMedCrossRefGoogle Scholar
  33. Horn DL, Neofytos D, Anaissie EJ et al (2009) Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 48:1695–1703PubMedCrossRefGoogle Scholar
  34. Hughes WT, Armstrong D, Bodey GP et al (2002) 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730–751PubMedCrossRefGoogle Scholar
  35. Jarvis WR (1995) Epidemiology of nosocomial fungal infections, with emphasis on Candida species. Clin Infect Dis 20:1526–1530PubMedCrossRefGoogle Scholar
  36. Klingspor L, Tornqvist E, Johansson A et al (2004) A prospective epidemiological survey of candidaemia in Sweden. Scand J Infect Dis 36:52–55PubMedCrossRefGoogle Scholar
  37. Krcmery V, Barnes AJ (2002) Non-albicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect 50:243–260PubMedCrossRefGoogle Scholar
  38. Leon C, Ruiz-Santana S, Saavedra P et al (2006) A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med 34:730–737PubMedCrossRefGoogle Scholar
  39. Leroy O, Gangneux JP, Montravers P et al (2009) Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006). Crit Care Med 37:1612–1618PubMedCrossRefGoogle Scholar
  40. Lewis RE, Kontoyiannis DP, Darouiche RO et al (2002) Antifungal activity of amphotericin B, fluconazole, and voriconazole in an in vitro model of Candida catheter-related bloodstream infection. Antimicrob Agents Chemother 46:3499–3505PubMedCrossRefGoogle Scholar
  41. Lipsett PA (2004) Clinical trials of antifungal prophylaxis among patients in surgical intensive care units: concepts and considerations. Clin Infect Dis 39(Suppl 4):S193–S199PubMedCrossRefGoogle Scholar
  42. Macphail GL, Taylor GD, Buchanan-Chell M et al (2002) Epidemiology, treatment and outcome of candidemia: a five-year review at three Canadian hospitals. Mycoses 45:141–145PubMedCrossRefGoogle Scholar
  43. Maertens J, Theunissen K, Verhoef G et al (2005) Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 41:1242–1250PubMedCrossRefGoogle Scholar
  44. Magnason S, Kristinsson KG, Stefansson T et al (2008) Risk factors and outcome in ICU-acquired infections. Acta Anaesthesiol Scand 52:1238–1245PubMedCrossRefGoogle Scholar
  45. McKinnon PS, Goff DA, Kern JW et al (2001) Temporal assessment of Candida risk factors in the surgical intensive care unit. Arch Surg 136:1401–1408; discussion 1409PubMedCrossRefGoogle Scholar
  46. Morgan J, Meltzer MI, Plikaytis BD et al (2005) Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance. Infect Control Hosp Epidemiol 26:540–547PubMedCrossRefGoogle Scholar
  47. Morrell M, Fraser VJ, Kollef MH (2005) Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 49:3640–3645PubMedCrossRefGoogle Scholar
  48. Nolla-Salas J, Sitges-Serra A, Leon-Gil C et al (1997) Candidemia in non-neutropenic critically ill patients: analysis of prognostic factors and assessment of systemic antifungal therapy. Study Group of Fungal Infection in the ICU. Intensive Care Med 23:23–30PubMedCrossRefGoogle Scholar
  49. Ostrosky-Zeichner L (2004) Prophylaxis and treatment of invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis 23:739–744PubMedCrossRefGoogle Scholar
  50. Ostrosky-Zeichner L, Rex JH, Pappas PG et al (2003) Antifungal susceptibility survey of 2,000 bloodstream Candida isolates in the United States. Antimicrob Agents Chemother 47:3149–3154PubMedCrossRefGoogle Scholar
  51. Ostrosky-Zeichner L, Alexander BD, Kett DH et al (2005) Multicenter clinical evaluation of the (1–>3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 41:654–659PubMedCrossRefGoogle Scholar
  52. Ostrosky-Zeichner L, Sable C, Sobel J et al (2007) Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis 26:271–276PubMedCrossRefGoogle Scholar
  53. Pappas PG (2006) Invasive candidiasis. Infect Dis Clin North Am 20:485–506PubMedCrossRefGoogle Scholar
  54. Pappas PG, Kauffman CA, Andes D et al (2009) Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535PubMedCrossRefGoogle Scholar
  55. Parkins MD, Sabuda DM, Elsayed S et al (2007) Adequacy of empirical antifungal therapy and effect on outcome among patients with invasive Candida species infections. J Antimicrob Chemother 60:613–618PubMedCrossRefGoogle Scholar
  56. Passos XS, Costa CR, Araujo CR et al (2007) Species distribution and antifungal susceptibility patterns of Candida spp. bloodstream isolates from a Brazilian tertiary care hospital. Mycopathologia 163:145–151PubMedCrossRefGoogle Scholar
  57. Pelz RK, Hendrix CW, Swoboda SM et al (2001) Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg 233:542–548PubMedCrossRefGoogle Scholar
  58. Pereira GH, Muller PR, Szeszs MW et al (2010) Five-year evaluation of bloodstream yeast infections in a tertiary hospital: the predominance of non-C albicans Candida species. Med Mycol 48(6):839–842PubMedCrossRefGoogle Scholar
  59. Pfaller MA (1996) Nosocomial candidiasis: emerging species, reservoirs, and modes of transmission. Clin Infect Dis 22(Suppl 2):S89–S94PubMedCrossRefGoogle Scholar
  60. Pfaller MA, Diekema DJ (2010) Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36:1–53PubMedCrossRefGoogle Scholar
  61. Piarroux R, Grenouillet F, Balvay P et al (2004) Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical patients. Crit Care Med 32:2443–2449PubMedCrossRefGoogle Scholar
  62. Pittet D, Monod M, Suter PM et al (1994) Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg 220:751–758PubMedCrossRefGoogle Scholar
  63. Playford EG, Webster AC, Sorrell TC et al (2006) Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: systematic review and meta-analysis of randomized clinical trials. J Antimicrob Chemother 57:628–638PubMedCrossRefGoogle Scholar
  64. Presterl E, Parschalk B, Bauer E et al (2009) Invasive fungal infections and (1,3)-beta-D-glucan serum concentrations in long-term intensive care patients. Int J Infect Dis 13:707–712PubMedCrossRefGoogle Scholar
  65. Rangel-Frausto MS, Wiblin T, Blumberg HM et al (1999) National epidemiology of mycoses survey (NEMIS): variations in rates of bloodstream infections due to Candida species in seven surgical intensive care units and six neonatal intensive care units. Clin Infect Dis 29:253–258PubMedCrossRefGoogle Scholar
  66. Rex JH, Sobel JD (2001) Prophylactic antifungal therapy in the intensive care unit. Clin Infect Dis 32:1191–1200PubMedCrossRefGoogle Scholar
  67. Richards MJ, Edwards JR, Culver DH et al (2000) Nosocomial infections in combined medical-surgical intensive care units in the United States. Infect Control Hosp Epidemiol 21:510–515PubMedCrossRefGoogle Scholar
  68. Richet HM, Andremont A, Tancrede C et al (1991) Risk factors for candidemia in patients with acute lymphocytic leukemia. Rev Infect Dis 13:211–215PubMedCrossRefGoogle Scholar
  69. Ruan SY, Lee LN, Jerng JS et al (2008) Candida glabrata fungaemia in intensive care units. Clin Microbiol Infect 14:136–140PubMedCrossRefGoogle Scholar
  70. Saiman L, Ludington E, Dawson JD et al (2001) Risk factors for Candida species colonization of neonatal intensive care unit patients. Pediatr Infect Dis J 20:1119–1124PubMedCrossRefGoogle Scholar
  71. Savino JA, Agarwal N, Wry P et al (1994) Routine prophylactic antifungal agents (clotrimazole, ketoconazole, and nystatin) in nontransplant/nonburned critically ill surgical and trauma patients. J Trauma 36:20–25; discussion 25–26PubMedCrossRefGoogle Scholar
  72. Sendid B, Tabouret M, Poirot JL et al (1999) New enzyme immunoassays for sensitive detection of circulating Candida albicans mannan and antimannan antibodies: useful combined test for diagnosis of systemic candidiasis. J Clin Microbiol 37:1510–1517PubMedGoogle Scholar
  73. Shorr AF, Chung K, Jackson WL et al (2005) Fluconazole prophylaxis in critically ill surgical patients: a meta-analysis. Crit Care Med 33:1928–1935; quiz 1936PubMedCrossRefGoogle Scholar
  74. Shorr AF, Lazarus DR, Sherner JH et al (2007) Do clinical features allow for accurate prediction of fungal pathogenesis in bloodstream infections? Potential implications of the increasing prevalence of non-albicans candidemia. Crit Care Med 35:1077–1083PubMedCrossRefGoogle Scholar
  75. Singhi S, Rao DS, Chakrabarti A (2008) Candida colonization and candidemia in a pediatric intensive care unit. Pediatr Crit Care Med 9:91–95PubMedCrossRefGoogle Scholar
  76. Suljagic V, Cobeljic M, Jankovic S et al (2005) Nosocomial bloodstream infections in ICU and non-ICU patients. Am J Infect Control 33:333–340PubMedCrossRefGoogle Scholar
  77. Trick WE, Fridkin SK, Edwards JR et al (2002) Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989–1999. Clin Infect Dis 35:627–630PubMedCrossRefGoogle Scholar
  78. Tumbarello M, Posteraro B, Trecarichi EM et al (2007) Biofilm production by Candida species and inadequate antifungal therapy as predictors of mortality for patients with candidemia. J Clin Microbiol 45:1843–1850PubMedCrossRefGoogle Scholar
  79. Vaudry WL, Tierney AJ, Wenman WM (1988) Investigation of a cluster of systemic Candida albicans infections in a neonatal intensive care unit. J Infect Dis 158:1375–1379PubMedCrossRefGoogle Scholar
  80. Vincent JL, Bihari DJ, Suter PM et al (1995) The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC). Study EPIC International Advisory Committee. JAMA 274:639–644PubMedCrossRefGoogle Scholar
  81. Vincent JL, Rello J, Marshall J et al (2009) International study of the prevalence and outcomes of infection in intensive care units. JAMA 302:2323–2329PubMedCrossRefGoogle Scholar
  82. Viscoli C, Girmenia C, Marinus A et al (1999) Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis 28:1071–1079PubMedCrossRefGoogle Scholar
  83. Voss A, le Noble JL, Verduyn Lunel FM et al (1997) Candidemia in intensive care unit patients: risk factors for mortality. Infection 25:8–11PubMedCrossRefGoogle Scholar
  84. Wey SB, Mori M, Pfaller MA et al (1989) Risk factors for hospital-acquired candidemia. A matched case-control study. Arch Intern Med 149:2349–2353PubMedCrossRefGoogle Scholar
  85. Wisplinghoff H, Bischoff T, Tallent SM et al (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39:309–317PubMedCrossRefGoogle Scholar
  86. Zaoutis TE, Argon J, Chu J et al (2005) The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 41:1232–1239PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Infectious Diseases DivisionSanta Maria Della Misericordia University HospitalUdineItaly
  2. 2.Clinica Malattie InfettiveA.O.U. Santa Maria Della MisericordiaUdineItaly
  3. 3.Infectious Diseases DivisionSan Martino Hospital and University of Genoa School of MedicineGenoaItaly

Personalised recommendations