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Cited by 218Antifungal resistance and susceptibilityFungal Infections and StudiesOcular Infections and Treatments

Bench-to-bedside review: Candida infections in the intensive care unit

Open access
Méan, Marie, Marchetti, Oscar, Calandra, Thierry·2008·Critical Care
DOI 10.1186/cc6212PMC PMC2374590
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Abstract

Invasive mycoses are life-threatening opportunistic infections and have emerged as a major cause of morbidity and mortality in critically ill patients. This review focuses on recent advances in our understanding of the epidemiology, diagnosis and management of invasive candidiasis, which is the predominant fungal infection in the intensive care unit setting. Candida spp. are the fourth most common cause of bloodstream infections in the USA, but they are a much less common cause of bloodstream infections in Europe. About one-third of episodes of candidaemia occur in the intensive care unit. Until recently, Candida albicans was by far the predominant species, causing up to two-thirds of all cases of invasive candidiasis. However, a shift toward non-albicans Candida spp., such as C. glabrata and C. krusei, with reduced susceptibility to commonly used antifungal agents, was recently observed. Unfortunately, risk factors and clinical manifestations of candidiasis are not specific, and conventional culture methods such as blood culture systems lack sensitivity. Recent studies have shown that detection of circulating beta-glucan, mannan and antimannan antibodies may contribute to diagnosis of invasive candidiasis. Early initiation of appropriate antifungal therapy is essential for reducing the morbidity and mortality of invasive fungal infections. For decades, amphotericin B deoxycholate has been the standard therapy, but it is often poorly tolerated and associated with infusion-related acute reactions and nephrotoxicity. Azoles such as fluconazole and itraconazole provided the first treatment alternatives to amphotericin B for candidiasis. In recent years, several new antifungal agents have become available, offering additional therapeutic options for the management of Candida infections. These include lipid formulations of amphotericin B, new azoles (voriconazole and posaconazole) and echinocandins (caspofungin, micafungin and anidulafungin).

Integrity signals

Registry

Crossref · 10.1186/cc6212

Cites

101 of 102 references verified1 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    A shift toward non-albicans Candida species, including C. glabrata and C. krusei, has been observed recently.

    “However, a shift toward non-albicans Candida spp., such as C. glabrata and C. krusei, with reduced susceptibility to commonly used antifungal agents, was recently observed.”
    • Also stated in: § Epidemiology · plain
      “During recent decades, several countries around the world have witnessed a change in the epidemiology of Candida infections, characterized by a progressive shift from a predominance of Candida albicans toward a predominance of non-albicans Candida spp. (including C. glabrata and C. krusei) [15].”
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  • Premisecitation

    Some non-albicans Candida species have reduced susceptibility to commonly used antifungals, observed in some North American and European centres.

    “Reduced susceptibility to commonly used antifungal agents has also been observed in some North American and European centres [18].”
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  • Premisenone given

    Opportunistic fungal pathogens, once mainly described in immunocompromised cancer patients, are now recognized as frequent causes of infection in surgical and critically ill patients.

    “Originally described in immunocompromised hosts, primarily cancer patients, opportunistic fungal pathogens have now been recognized as a frequent cause of infection in surgical and critically ill patients.”
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  • Premisecitation

    Many studies found no increase or a decrease in Candida sepsis incidence.

    “In contrast, numerous studies have revealed either no increase or sometimes even a decrease in the incidence of Candida sepsis [2-4].”
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    Candida albicans was formerly the predominant species, causing up to two-thirds of invasive candidiasis cases.

    “Until recently, Candida albicans was by far the predominant species, causing up to two-thirds of all cases of invasive candidiasis.”
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    Premisenone given

    Amphotericin B deoxycholate has been standard therapy for invasive fungal infections for decades.

    “For decades amphotericin B deoxycholate has been the standard therapy for invasive fungal infections.”
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    Premisecitation

    In Europe, Candida is a less common cause of bloodstream infections than in the USA, usually ranking sixth to tenth among nosocomial bloodstream infections.

    “but they are a much less common cause of bloodstream infections in Europe”
    • Also stated in: § Epidemiology · plain
      “In Europe, Candida is usually the sixth to the 10th cause of nosocomial bloodstream infections [4,12-14].”
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    Data from 790 ICUs in the US NNIS system from 1990 to 1999 showed Candida caused 5% to 10% of all bloodstream infections.

    “Data from 790 ICUs reporting to the US National Nosocomial Infection Surveillance system between 1990 and 1999 [8,11] showed that Candida spp. were responsible for 5% to 10% of all bloodstream infections.”
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    Premisecitation

    Candida species rank fourth among causes of bloodstream infections in the USA.

    “Candida spp. are the fourth most common cause of bloodstream infections in the USA”
    • Also stated in: § Epidemiology · plain
      “Candida is now the fourth leading micro-organism responsible for bloodstream infections in the USA, outnumbering all Gram-negative bacilli [8-10].”
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    Candida and Aspergillus species are the most frequent causes of invasive fungal infections and carry high morbidity and mortality.

    “Candida and Aspergillus spp. are the most frequent causes of invasive fungal infections and are associated with high morbidity and mortality [3,5,6].”
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    Invasive aspergillosis now occurs in ICU patients, including mechanically ventilated patients and those with chronic lung disease receiving corticosteroids.

    “Invasive aspergillosis is now also occurring in intensive care unit (ICU) patients, including mechanically ventilated patients and patients with chronic lung diseases treated with corticosteroids [7].”
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    A US sepsis epidemiology survey found a threefold increase in fungal sepsis incidence between 1979 and 2000.

    “A survey of the epidemiology of sepsis conducted in the USA [1] revealed that the incidence of fungal sepsis increased threefold between 1979 and 2000.”
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    Premisecitation

    Blood culture systems have low sensitivity for invasive candidiasis, reported below 50%, and often become positive late.

    “conventional culture methods such as blood culture systems lack sensitivity”
    • Also stated in: § Diagnosis · plain
      “blood cultures lack sensitivity (reported to be <50%) [50] and usually become positive late [51].”
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    Premisecitation

    Invasive candidiasis incidence is 7 to 15 times higher than invasive aspergillosis.

    “The incidence of invasive candidiasis is sevenfold to 15-fold higher than that of invasive aspergillosis [3].”
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    Premisenone given

    Azoles such as fluconazole and itraconazole were the first alternatives to amphotericin B for candidiasis.

    “Azoles such as fluconazole and itraconazole provided the first treatment alternatives to amphotericin B for candidiasis.”
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    Premisenone given

    Amphotericin B deoxycholate is often poorly tolerated and causes infusion-related acute reactions and nephrotoxicity.

    “Unfortunately, amphotericin B deoxycholate is often poorly tolerated and associated with acute infusion-related reactions and nephrotoxicity.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    C. glabrata has progressively increased and now accounts for 15% to 20% of infections in most countries.

    “C. glabrata has progressively increased and now accounts for 15% to 20% of infections in most countries [16,17].”
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    In a Swiss survey from 1991 to 2000, ICUs and surgical wards accounted for about two-thirds of candidaemia episodes.

    “In a survey conducted by the Fungal Infection Network of Switzerland between 1991 and 2000 [4], ICUs and surgical wards accounted for about two-thirds of all episodes of candidaemia.”
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    Premisecitation

    Major risk factors for invasive Candida infection include surgery, especially abdominal surgery, total parenteral nutrition, acute renal failure, haemodialysis, immunosuppressive therapy, prolonged broad-spectrum antibiotics, and loss of skin or mucosal barrier integrity.

    “Together with colonization with Candida induced by profound alteration of the endogenous flora resulting from prolonged broad-spectrum antibiotic therapy and loss of integrity of skin and mucosal barriers, surgery (especially of the abdominal compartment), total parenteral nutrition, acute renal failure, haemodialysis and treatment with immunosuppressive agents are major risk factors for invasive”
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    Premisecitation

    In recent clinical trials of new antifungals, short-term mortality from candidaemia was 15% to 20% and long-term mortality 30% to 40%.

    “in the most recent clinical trials of new antifungal agents [30-35] the overall short-term (end of therapy) and long-term mortality (end of follow up) associated with candidaemia were found to be in the range of 15% to 20% and 30% to 40%, respectively (Figure 1).”
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    Premisecitation

    Invasive candidiasis is a leading cause of morbidity and mortality in immunocompetent and immunocompromised critically ill patients, with crude mortality over 40% to 60% and attributable mortality 20% to 40%.

    “Invasive candidiasis is recognized as a leading cause of morbidity and mortality in both immunocompetent and immunocompromised critically ill patients, with reported crude and attributable mortality rates of more than 40% to 60% and 20% to 40%, respectively [13,23-29].”
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    Premisecitation

    In that Swiss survey, candidaemia incidence averaged 0.5 episodes per 10,000 patient-days per year, was stable over 10 years, and was five to 10 times higher in ICUs than other wards.

    “The incidence of candidaemia (on average 0.5 episodes/10,000 patient-days per year) was stable over this 10-year period and was five to 10 times higher in ICUs than in other wards.”
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    Premisecitation

    That prediction rule had sensitivity 34%, specificity 90%, positive predictive value 10%, and negative predictive value 97%.

    “This prediction rule exhibited a sensitivity of 34%, a specificity of 90%, a positive predictive value of 10% and a negative predictive value of 97%.”
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    Premisecitation

    Candidaemia is associated with longer mechanical ventilation, longer hospital stay, and higher healthcare costs.

    “Candidaemia is also associated with prolonged duration of mechanical ventilation and hospital stay, and increased health care costs [28,36-38].”
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    Premisecitation

    The EORTC/MSG criteria for invasive mycoses were developed in immunocompromised patients and may not apply to ICU patients.

    “Moreover, the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria for diagnosis of invasive mycoses [52], which are based on clinical, microbiological and radiological criteria, were developed in immunocompromised patients and may not apply to ICU patients.”
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    Premisecitation

    That estimate was based on a 2% fungal infection incidence and ranged from 9 in high-risk patients to 188 in low-risk patients.

    “This estimate, based on an incidence of fungal infection of 2%, ranged from 9 in high-risk patients to 188 in low-risk patients.”
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    Premisenone given

    Data on using risk assessment scores to guide patient management are not yet available, and their clinical utility remains to be established in prospective studies.

    “However, data on the use of these risk assessment scores for guiding patient management are not yet available and their clinical utility remains to be established in prospective clinical studies.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In that trial, fluconazole did not prevent severe Candida infections, the primary endpoint, but markedly reduced episodes of candidaemia.

    “Although it did not prevent the development of severe Candida infections, which was the primary study end-point, fluconazole prophylaxis markedly reduced the number of episodes of candidaemia.”
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    Premisenone given

    Little information has been published on beta-(1,3)-D-glucan tests in the ICU setting.

    “Unfortunately, little information has been published thus far on use of β-(1,3)-D-glucan tests in the ICU setting.”
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    Premisecitation

    Those guidelines suggested considering fluconazole prophylaxis in carefully selected patients, with an A1 recommendation.

    “However, it was suggested that fluconazole prophylaxis should be considered in carefully selected patients (a recommendation classified as A1, based on the strength of the evidence).”
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    Premisecitation

    Beta-(1,3)-D-glucan assays have shown sensitivities 69% to 97%, specificities 87% to 100%, positive predictive values 59% to 96%, and negative predictive values 75% to 97%.

    “Studies conducted with β-(1,3)-D-glucan assays have yielded sensitivities ranging from 69% to 97%, specificities ranging from 87% to 100%, and positive and negative predictive values ranging from 59% to 96% and 75% to 97%, respectively [56-59].”
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    Premisecitation

    For mannan, sensitivity was 40% and specificity 98%; for antimannan antibodies, sensitivity 53% and specificity 94%; combining both gave 80% to 90%.

    “Sensitivity and specificity (respectively) were 40% and 98% for mannan and 53% and 94% for anti-mannan antibodies, and 80% to 90% when combining the two tests [55].”
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    Premisecitation

    Voriconazole causes transient, fully reversible visual adverse events in 20% to 40% and liver function test abnormalities in 5% to 15% of treated patients.

    “Transient, fully reversible visual adverse events and abnormalities of liver function tests are observed in 20% to 40% and 5% to 15% of patients treated with voriconazole, respectively.”
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    Interpretationreasoning

    Recent studies indicate that echinocandins are effective and safe.

    “Thus, recent studies have shown that echinocandins are efficacious and safe, explaining why this new class of antifungal agents has assumed a prominent role in the management of patients with invasive candidiasis.”
    Quote in the paperSubstantial claim

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    Premisereasoning

    Lipid formulations of amphotericin B are better tolerated than amphotericin B deoxycholate and are used mainly in patients intolerant to conventional amphotericin B or with altered renal function.

    “Lipid formulations of amphotericin B (colloidal dispersion, lipid complex and liposomal) are better tolerated than amphotericin B deoxycholate and have been used mainly in patients who are intolerant to conventional amphotericin B or are unlikely to tolerate it because of altered renal function.”
    Quote in the paperNot a substantial claim

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    Premisenone given

    No comparative clinical trials in candidaemia have been performed with itraconazole or posaconazole, and their efficacy in that setting remains undetermined.

    “However, no comparative clinical trials in patients with candidaemia have been performed with these antifungal agents, and their efficacy in this clinical setting remains to be determined.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Premisecitation

    In invasive candidiasis, anidulafungin 100 mg daily after a 200 mg loading dose outperforms fluconazole 400 mg daily after an 800 mg loading dose.

    “In a randomized, double-blind study conducted in patients with invasive candidiasis [35], anidulafungin (100 mg/day after a 200 mg loading dose) was observed to be superior to fluconazole (400 mg/day after a 800 mg loading dose), but the study was reported to show noninferiority after removal of the centre that enrolled the largest number of patients.”
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    Interpretationnone given

    Cross-resistance could limit the utility of new azoles for infections caused by non-albicans Candida species.

    “One concern, however, might be the potential risk for development of cross-resistance, which could limit the utility of new azoles for therapy of infections due to non-albicans Candida spp.”
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    Premisecitation

    Voriconazole is active against all Candida species and is a new option for intravenous and oral therapy of Candida infections.

    “Voriconazole, a second-generation triazole that is active against all Candida spp., is a new option for intravenous and oral therapy of Candida infections [74].”
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    Premisecitation

    In a randomized open-label noninferiority trial in invasive Candida infections, voriconazole was at least as effective as and safer than amphotericin B deoxycholate followed by fluconazole.

    “In a randomized, open-label, comparative multicentre, noninferiority trial conducted in patients with invasive Candida infections [33], voriconazole (6 mg/kg per day after a 12 mg/kg loading dose on day 1) was shown to be at least as effective as and safer than amphotericin B deoxycholate (0.7 to 1 mg/kg per day) followed by intravenous or oral fluconazole (400 mg/day).”
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    Premisecitation

    Among 595 adults with candidemia or invasive candidiasis, micafungin at 100 or 150 mg daily was noninferior to caspofungin (70 mg loading, then 50 mg daily) for efficacy.

    “and caspofungin (70 mg loading dose and then 50 mg/day) in 595 adult patients with candidaemia or invasive candidiasis [30] reported noninferior efficacy of micafungin compared with that of caspofungin and similar safety profiles for the two compounds.”
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    Premisecitation

    In a multicentre study of non-neutropenic patients with candidaemia, fluconazole 400 mg/day was as efficacious as and better tolerated than amphotericin B deoxycholate 0.5 to 0.6 mg/kg/day.

    “In a multicentre study in non-neutropenic patients with candidaemia, fluconazole (400 mg/day) was found to be as efficacious as and better tolerated than amphotericin B deoxycholate (0.5 to 0.6 mg/kg per day) [31].”
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    Premisecitation

    A Japanese study found that early pre-emptive therapy with an azole or echinocandin based on multiple-site Candida colonization and a positive beta-(1,3)-D-glucan test prevented candidaemia but had no impact on mortality.

    “The findings indicated that early pre-emptive strategy prevented candidaemia but had no impact on mortality.”
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    Premisecitation

    Echinocandins are a newer class of intravenous antifungals that block the production of β-(1,3)-D-glucan in the fungal cell wall.

    “Echinocandins are a new class of parenteral antifungal agents that inhibit the synthesis of β-(1,3)-D-glucan in the fungal cell wall [82].”
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  • May combine two claims.

    Interpretationreasoning

    Promising recent developments include prevention aimed at high-risk patients, noninvasive diagnostics enabling earlier treatment, and an expanded drug arsenal; these may help defeat Candida infections.

    “Preventive strategies targeting patients with a high-risk profile, development of new noninvasive diagnostic tools that allow early diagnosis and therapy, and extension of the therapeutic armamentarium with new agents are encouraging recent advances that may allow us to overcome Candida infections.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    In that randomized double-blind candidemia trial, baseline characteristics were significantly imbalanced between arms; for example, APACHE II scores were lower in the combination group.

    “However, there were statistically significant differences in baseline covariates between the two groups, such as APACHE II score, which was lower in the combination treatment arm.”
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    Interpretationnone given

    Management of invasive candidiasis faces major difficulties: a shift toward non-albicans Candida species, vague risk factors and clinical signs, and delayed culture-based diagnosis.

    “Changing epidemiology with increased non-albicans Candida spp., nonspecific risk factors and clinical presentation, and late diagnosis with culture-based methods are major challenges in the management of invasive candidiasis.”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    Risk factors and clinical manifestations of candidiasis are not specific.

    “Unfortunately, risk factors and clinical manifestations of candidiasis are not specific”

  • The paper relies on this without support.

    Invasive candidiasis is the predominant fungal infection in critically ill patients.

    “which is the predominant fungal infection in the intensive care unit setting”
    “which is the predominant fungal infection occurring in critically ill patients”

  • The paper relies on this without support.

    In critically ill patients, Candida sepsis carries a poor outcome.

    “Given the poor prognosis of Candida sepsis in critically ill patients, clinicians have shown interest in using combinations of antifungal agents of different classes.”

  • The paper relies on this without support.

    Clinical evidence on combination antifungal treatment is scarce.

    “However, there is a dearth of information available from few clinical studies.”

  • The paper relies on this without support.

    Among critically ill patients, invasive candidiasis is the most frequent invasive fungal disease.

    “Invasive candidiasis is the most frequent invasive mycosis in critically ill patients.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Accurately diagnosing sepsis is challenging as sepsis can present in subtle ways, and some presentations that first appear to be sepsis turn out to be noninfectious conditions.

    “Accurately diagnosing sepsis is challenging as sepsis can present in subtle ways, and some presentations that first appear to be sepsis turn out to be noninfectious conditions (90, 93, 107, 108).”

    From Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. (2021) · cites this paper as [107]

    The Diagnosis section says invasive fungal infections are difficult to diagnose and often diagnosed late; the Conclusion notes their nonspecific clinical presentation. These passages support diagnostic difficulty for invasive candidiasis in ICU patients, but do not establish the broader claim about sepsis or say that apparent sepsis can turn out to be noninfectious. No page numbers are available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Sepsis and septic shock due to fungi are most commonly observed in ICUs and are associated with poor outcomes.

    “Sepsis and septic shock due to fungi are most commonly observed in ICUs and are associated with poor outcomes [166–170].”

    From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [169]

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Related

Authors
Méan, M., Marchetti, O., & Calandra, T.
Affiliations
Centre Hospitalier Universitaire Vaudois (CH)
Corresponding author
Calandra, Thierry
ORCID
Venue
Critical Care
Publisher
Springer Science and Business Media LLC
Published
2008
Volume
12
Issue
1
Pages
204
ISSN
1364-8535 (ISSN-L)
DOI
10.1186/cc6212
PMC
PMC2374590
OpenAlex
W2129688861
Semantic Scholar
c63f971ee43111d29cbda130e59003e92f73f75a
Cited by
217
References
102
Citations by year
2026: 6 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 4 · 2021: 14 · 2020: 8 · 2019: 8 · 2018: 14 · 2017: 7 · 2016: 18 · 2015: 10 · 2014: 21 · 2013: 21 · 2012: 10
FWCI
2.40
Type
journal article
Language
en
Open access
Locations
  • Critical Care (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Health Sciences › Medicine › Ophthalmology › Ocular Infections and Treatments
Keywords
invasive candidiasis, candidiasis, intensive care unit, candidemia, non-albicans Candida, Candida albicans, Candida glabrata, Candida krusei, antifungal resistance, β-glucan, amphotericin B deoxycholate, azoles, voriconazole, posaconazole, echinocandins, caspofungin, micafungin, anidulafungin, critically ill patients
MeSH terms
Antifungal Agents, Candidiasis, Humans, Intensive Care Units, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Hospital Mortality, Echinocandins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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