Review
Epidemiology of Candida species infections in critically ill non-immunosuppressed patients

https://doi.org/10.1016/S1473-3099(03)00801-6Get rights and content

Summary

A substantial proportion of patients become colonised with Candida spp during hospital stay, but only few subsequently develop severe infection. Clinical signs of severe infection manifest early but lack specificity until late in the course of the disease, thus representing a particular challenge for diagnosis. Mostly nosocomial, invasive candidaiasis occurs in only 1–8% of patients admitted to hospitals, but in around 10% of patients housed in intensive care units where it can represent up to 15% of all nosocomial infections. We review the epidemiology of invasive caandidiasis in non-immunocompromaised, critically ill patients with special emphasis on disease trends over time, pathophysiology, diagnostic approach, risk factors, and impact. Recent epidemiological data suggesting that the emergence of non-albicans candidaa strains with reduced susceptibility to azoles, previously linked to the use of new antifungals for empiric and prophylactic therapy in immunocompromised patients, may not have occurred in the critically ill. Management of invasive candidiasis in these patients will be addressed in the December issue of The Lancet Infectious Diseases.

Section snippets

Microbiology

Candida is a normal inhabitant of the human microbiological flora of skin, gastrointestinal, and genitourinary tracts, and may also be seen in the respiratory tract.14, 15 It is also recovered from the environment, particularly on surfaces.16 Candida albicans is the most abundant and significant species in human beings.

Clinical spectrum and definitions

The spectrum of diseases related to Candida spp is wide (table 3). Some entities are difficult to characterise, and there is no consensus on definitions in published work.2, 43 For immunocompromised patients such a consensus was reached by investigators from the Invasive Fungal Infections Cooperative Group (IFICG) of the European Organisation for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG) of the US National Institute of Allergy and Infectious Diseases (NIAID).46

Pathophysiology

Candida spp are part of the normal endogenous flora; temporary or permanent carriage in the gastrointestinal tract is documented among 40–50% of human beings. Mucocutaneous surface colonisation is rare under normal conditions.3 Colonisation is a prerequisite for the development of candidiasis;78, 121, 122, 123 it develops secondary to changes in the ecology of the endogenous flora that promote Candida spp overgrowth on mucosal and skin surfaces.124 Candida spp can also translocate across the

Diagnostic tools

The diagnosis of severe candidiasis remains a challenge.21, 41, 42, 43, 44, 45 Cultures other than blood or from normally sterile body sites are nonspecific and may become positive only late in the course of infection.121 Despite significant progress over the past decades and preliminary encouraging results, serology testing or molecular methods for the diagnosis of candidiasis are not currently used in clinical practice.166, 167, 168 The capacity to explore gene expression by microarray

Impact of candidiasis

Candidaemia is the only severe candidiasis for which the precise impact has been repeatedly established. Globally, the crude mortality rate is over 50% in most series with no decrease over several decades (table 9). There are large variations in the crude mortality rate, mainly reflecting the severity of the underlying diseases.

In the early 1980s, Miller and Wenzel175 suggested that the development of candidaemia predicted death. In a study of 1745 episodes of nosocomial bloodstream infections,

Search strategy and selection criteria

Data for this review were identified by searches of Medline, Current Contents, and references from relevant original articles published in English, French, and German between 1975 and 2003; many articles were identified through searches of the extensive files of the authors. Key word terms included “candidemia”, “candidiasis”, “invasive Candida infections”, “mycosis”, “fungal infections” and were combined with the “critically ill”, “epidemiology”, “risk factors”, “guidelines”, and “strategy”.

References (177)

  • AH Groll et al.

    Trends in the postmortem epidemiology of invasive fungal infections at a university hospital

    J Infect

    (1996)
  • VJ Krcmery et al.

    Longitudinal 10–year prospective survey of fungaemia in Slovak Republic: trends in etiology in 310 episodes

    Diagn Microbiol Infect Dis

    (2000)
  • EJ Anaissie et al.

    Predictors of adverse outcome in cancer patients with candidemia

    Am J Med

    (1998)
  • MA Pfaller et al.

    International surveillance of bloodstream infections due to Candida species in the European SENTRY Program: species distribution and antifungal susceptibility including the investigational triazole and echinocandin agents

    Diagn Microbiol Infect Dis

    (1999)
  • JA Karlowsky et al.

    Candidemia in a Canadian tertiary care hospital from 1976 to 1996

    Diagn Microbiol Infect Dis

    (1997)
  • D Armstrong

    Overview of invasive fungal infections and clinical presentation

    Baillière's Clin Infect Dis

    (1995)
  • WR Jarvis

    Epidemiology of nosocomial fungal infections, with emphasis on Candida species

    Clin Infect Dis

    (1995)
  • SB Wey et al.

    Hospital-acquired candidemia. The attributable mortality and excess length of stay

    Arch Intern Med

    (1988)
  • VJ Fraser et al.

    Candidemia in a tertiary care hospital: epidemiology, risk factors, and predictors of mortality

    Clin Infect Dis

    (1992)
  • CH Debusk et al.

    Candidemia: current epidemiologic characteristics and a long-term follow-up of the survivors

    Scand J Infect Dis

    (1994)
  • WT Hughes et al.

    2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer

    Clin Infect Dis

    (2002)
  • C Girmenia et al.

    Fluconazole and the changing epidemiology of candidemia

    Clin Infect Dis

    (1998)
  • D Abi-Said et al.

    The epidemiology of hematogenous candidiasis by different Candida species

    Clin Infect Dis

    (1997)
  • JR Wingard et al.

    Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole

    N Engl J Med

    (1991)
  • DB Louria

    Pathogenesis of candidiasis

    Antimicrob Agents Chemother

    (1965)
  • R Cohen et al.

    Fungal flora of the normal human small and large intestine

    N Engl J Med

    (1969)
  • SA Klotz et al.

    Factors governing adherence of Candida species to plastic surfaces

    Infect Immun

    (1985)
  • AM Freydiere et al.

    Yeast identification in the clinical microbiology laboratory: phenotypical methods

    Med Mycol

    (2001)
  • L Buchaille et al.

    Evaluation of six commercial systems for identification of medically important yeasts

    Eur J Clin Microbiol Infect Dis

    (1998)
  • JH Rex et al.

    Resistance of Candida species to fluconazole

    Antimicrob Agents Chemother

    (1995)
  • JH Rex et al.

    Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and candida infections

    Clin Infect Dis

    (1997)
  • JH Rex et al.

    Practice guidelines for the treatment of candidiasis

    Clin Infect Dis

    (2000)
  • DJ Diekema et al.

    Epidemiology of candidemia: 3–year results from the Emerging Infections and the Epidemiology of Iowa Organisms Study

    J Clin Microbiol

    (2002)
  • MA Pfaller et al.

    Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program, 2000

    Antimicrob Agents Chemother

    (2002)
  • D Sanglard et al.

    Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene

    Microbiology

    (1997)
  • H Vanden Bossche et al.

    Antifungal drug resistance in pathogenic fungi

    Med Mycol

    (1998)
  • KA Marr et al.

    Inducible azole resistance associated with a heterogeneous phenotype in Candida albicans.

    Antimicrob Agents Chemother

    (2001)
  • JH Rex et al.

    Antifungal susceptibility testing of isolates from a randomized, multicenter trial of fluconazole versus amphotericin B as treatment of nonneutropenic patients with candidemia

    Antimicrob Agents Chemother

    (1995)
  • JR Wingard et al.

    Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients

    Antimicrob Agents Chemother

    (1993)
  • CM Masia et al.

    Antifungal drug resistance to azoles and polyenes

    Lancet Infect Dis

    (2002)
  • MS Rangel-Frausto et al.

    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

    (1999)
  • MA Pfaller et al.

    International surveillance of bloodstream infections due to Candida species: frequency of occurrence and in vitro susceptibility to fluconazole, ravuconazole and voriconazole among isolates collected from 1997 through 1999 in the SENTRY Antimicrobial Surveillance Program

    J Clin Microbiol

    (2001)
  • MA Ghannoum et al.

    Susceptibility testing of fungi: current status of correlation of in vitro data with clinical outcome

    J Clin Microbiol

    (1996)
  • Reference method for broth dilution antifungal susceptibility testing of yeast: approved standard

    (1997)
  • MA Pfaller et al.

    Antifungal susceptibility testing: technical advances and potential clinical applications

    Clin Infect Dis

    (1997)
  • JH Rex et al.

    Antifungal susceptibility testing: practical aspects and current challenges

    Clin Microbiol Rev

    (2001)
  • E Chryssanthou

    Trends in antifungal susceptibility among Swedish Candida species bloodstream isolates from 1994 to 1998: comparison of the E-test and the sensititre yeast. One colorimetric antifungal panel with the NCCLS M27–A reference method

    J Clin Microbiol

    (2001)
  • G Morace et al.

    Multicenter comparative evaluation of six commercial systems and the National Committee for Clinical Laboratory Standards m27-A broth microdilution method for fluconazole susceptibility testing of Candida species

    J Clin Microbiol

    (2002)
  • E Chryssanthou et al.

    Comparison of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing proposed standard and the E-test with the NCCLS broth microdilution method for voriconazole and caspofungin susceptibility testing of yeast species

    J Clin Microbiol

    (2002)
  • Management of deep Candida infection in surgical and intensive care unit patients

    Intensive Care Med

    (1994)
  • Cited by (756)

    View all citing articles on Scopus
    View full text