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Preventing invasive candida infections. Where could we do better?

Open AccessPublished:December 15, 2014DOI:https://doi.org/10.1016/j.jhin.2014.11.006

      Summary

      Invasive candidiasis is associated with high mortality rates, ranging from 35% to 60%, in the range reported for septic shock. The epidemiology and pathogenesis of invasive candidiasis differ according to the patient's immune status; the majority of cases in immunocompromised hosts are candidaemia, whereas non-candidaemic systemic candidiasis accounts for the majority of cases in critically ill patients. In contrast to candidaemia, non-candidaemic systemic candidiasis is difficult to prove, especially in critically ill patients. Up to 80% of these patients are colonized, but only 5–30% develop invasive infection. The differentiation of colonization and proven infection is challenging, and evolution from the former to the latter requires seven to 10 days. This continuum from colonization of mucosal surfaces to local invasion and then invasive infection makes it difficult to identify those critically ill patients likely to benefit most from antifungal prophylaxis or early empirical antifungal treatment. Early empirical treatment of non-candidaemic systemic candidiasis currently relies on the positive predictive value of risk assessment strategies, such as the colonization index, candida score, and predictive rules based on combinations of risk factors such as candida colonization, broad-spectrum antibiotics, and abdominal surgery. Although guidelines recently scored these strategies as being supported by limited evidence, they are widely used at bedside and have substantially decreased the incidence of invasive candidiasis.

      Keywords

      Introduction

      Candida spp. colonization develops in up to 80% of critically ill patients staying more than one week in intensive care, whereas invasive candidiasis is documented in only 5–10% of them.
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      • Garbino J.
      • Pittet D.
      Epidemiology of Candida species infections in critically ill non-immunosuppressed patients.
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      International study of the prevalence and outcomes of infection in intensive care units.
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      • Diekema D.
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      Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance®) registry, 2004–2008.
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      Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study.
      Early diagnosis of invasive candidiasis is difficult; it is generally late in the course of the infection before microbiological evidence is found.
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      Epidemiology of candidemia in Swiss tertiary care hospitals: secular trends, 1991–2000.
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      Diagnosis of invasive candidiasis in the ICU.
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      This may delay appropriate antifungal treatment and may be in part responsible for its high crude and attributable mortality rates, comparable to those reported for septic shock.
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      Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality.
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      Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study.
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      • et al.
      Systemic antifungal therapy in critically ill patients without invasive fungal infection.
      Indeed, extensive use of antifungals has promoted a shift to Candida spp. with reduced susceptibility.
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      Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001–2007): stable incidence but changing epidemiology of a still frequently lethal infection.
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      • et al.
      Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients.
      Recent guidelines resulting from expert consensus provided no high-level recommendations about antifungal prophylaxis and empirical antifungal treatment.
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      • Marchetti M.
      • Chakrabarti A.
      • et al.
      A research agenda on the management of intra-abdominal candidiasis: results from a consensus of multinational experts.
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      Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.
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      • Bassetti M.
      • Calandra T.
      • et al.
      ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      Despite limited evidence, antifungal prophylaxis and empirical treatment currently rely on the identification of patients with a high documented risk and on the positive predictive value of risk assessment strategies, such as the colonization index, candida score, and predictive rules based on combinations of risk factors.
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      • Garbino J.
      • Pittet D.
      Management of Candida species infections in critically ill patients.
      • Playford E.G.
      • Eggimann P.
      • Calandra T.
      Antifungals in the ICU.
      • Eggimann P.
      • Ostrosky-Zeichner L.
      Early antifungal intervention strategies in ICU patients.
      Identification of patients who could benefit from antifungal prophylaxis and empirical treatment may, however, be improved by taking into account some pathophysiological specificities of invasive candidiasis.
      • Montravers P.
      • Dupont H.
      • Eggimann P.
      Intra-abdominal candidiasis: the guidelines-forgotten non-candidemic invasive candidiasis.
      • Eggimann P.
      • Pittet D.
      Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later.

      Epidemiology and pathophysiology of invasive candidiasis

      Invasive candidiasis includes two closely related and often confused conditions: candidaemia and non-candidaemic systemic candidiasis. Candidaemia requires the growth of Candida spp. from the blood of a patient with temporally related signs of infection. In the intensive care unit (ICU), candidaemia ranges from five to 10 cases per 1000 admissions or three to 15 episodes per 10,000 patient days (five to 10 times the incidence on general hospital wards).
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      • Bille J.
      • Fluckiger U.
      • et al.
      Epidemiology of candidemia in Swiss tertiary care hospitals: secular trends, 1991–2000.
      • Zilberberg M.D.
      • Shorr A.F.
      • Kollef M.H.
      Secular trends in candidemia-related hospitalization in the United States, 2000–2005.
      • Leroy O.
      • Gangneux J.P.
      • Montravers P.
      • et al.
      Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006).
      Non-candidaemic systemic candidiasis corresponds to candida invasion, established by culture or histology, of normally sterile sites. Accordingly, the epidemiology of non-candidaemic systemic candidiasis is hard to determine. In a worldwide prevalence study performed in 1265 ICUs in May 2007, candida infection was reported in 17% (841/4947) of patients with microbiologically documented infection, but candidaemia was documented in only 99 cases.
      • Vincent J.L.
      • Rello J.
      • Marshall J.
      • et al.
      International study of the prevalence and outcomes of infection in intensive care units.
      • Kett D.H.
      • Azoulay E.
      • Echeverria P.M.
      • Vincent J.L.
      Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study.
      Invasive candidiasis is characterized by specific physiopathological characteristics (Table I).
      Table IPathophysiological characteristics of invasive candidiasis according to immune status
      Pathophysiological characteristicsImmunocompromised patientsCritically ill patients
      Immunity
       NeutrophilsDecreasedIncreased
       MacrophagesDecreasedIncreased
       T-cellsDecreasedNormal
      Ulcerations of mucosal surfaces
       Oropharyngeal++ to +++0 to +
       Upper digestive tract++ to +++0 to +
       Lower digestive tract++ to +++0 to +
       Typhlitis++ to +++0
      Digestive surgery0+ + to +++
      Antibiotic exposure++ to ++++ to ++
      Organ failure+ to ++++ to +++
      Candida colonization++ to +++++ to +++
      Invasive candidiasis
       Candidaemia++ to +++0 to +
       Non-candidaemic systemic candidiasis0 to +++ to +++
      Exogenous nosocomial transmission of candida has been reported, but studies using genotyping of candida strains showed that endogenous colonization is responsible for the large majority of severe candidiasis.
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      • Chandy R.
      • Metwali K.E.
      Candida albicans strain carriage in patients and nursing staff of an intensive care unit: a study of morphotypes and resistotypes.
      • Marco F.
      • Lockhart S.R.
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      • et al.
      Elucidating the origins of nosocomial infections with Candida albicans by DNA fingerprinting with the complex probe Ca3.
      • Nucci M.
      • Anaissie E.
      Revisiting the source of candidemia: skin or gut?.
      This explains why invasive candidiasis is characterized by seven- to 10-day delay between exposure to risk factors and development of infection.
      • Pittet D.
      • Monod M.
      • Filthuth I.
      • Frenk E.
      • Suter P.M.
      • Auckenthaler R.
      Contour-clamped homogeneous electric field gel electrophoresis as a powerful epidemiologic tool in yeast infections.
      • Pittet D.
      • Monod M.
      • Suter P.M.
      • Frenk E.
      • Auckenthaler R.
      Candida colonization and subsequent infections in critically ill surgical patients.
      • van de Veerdonk F.L.
      • Kullberg B.J.
      • Netea M.G.
      Pathogenesis of invasive candidiasis.
      The pathophysiology of invasive candidiasis differs markedly between immunocompromised and critically ill patients.
      • Montravers P.
      • Dupont H.
      • Eggimann P.
      Intra-abdominal candidiasis: the guidelines-forgotten non-candidemic invasive candidiasis.
      • Eggimann P.
      • Pittet D.
      Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later.
      In immunocompromised patients, prolonged neutropenia or functional impairment (transplanted patients), with eventual mucosal injuries resulting from chemotherapy combined with the selective pressure of frequent and repetitive exposure to antibacterial agents, results in high prevalence of invasive candidiasis with a large proportion of bloodstream infections.
      In critically ill patients, other factors explain the high prevalence of invasive candidiasis. Prolonged support of failing organs combined with the selective pressure of broad-spectrum antibiotics constitutes key risk factors for invasive candidiasis in non-surgical critically ill patients.
      • Eggimann P.
      • Garbino J.
      • Pittet D.
      Epidemiology of Candida species infections in critically ill non-immunosuppressed patients.
      • Kett D.H.
      • Azoulay E.
      • Echeverria P.M.
      • Vincent J.L.
      Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study.
      These factors may explain progressive colonization in a high proportion of patients after prolonged stay in the ICU. They may also explain a higher proportion of catheter-related infections in the absence of severe immune impairment.
      • Marchetti O.
      • Bille J.
      • Fluckiger U.
      • et al.
      Epidemiology of candidemia in Swiss tertiary care hospitals: secular trends, 1991–2000.
      • Charles P.E.
      • Doise J.M.
      • Quenot J.P.
      • et al.
      Candidemia in critically ill patients: difference of outcome between medical and surgical patients.
      • Charles P.E.
      • Dalle F.
      • Aube H.
      • et al.
      Candida spp. colonization significance in critically ill medical patients: a prospective study.
      • Eggimann P.
      • Calandra T.
      • Fluckiger U.
      • et al.
      Invasive candidiasis: comparison of management choices by infectious disease and critical care specialists.
      Additional factors play a specific role in patients after abdominal surgery.
      • Vincent J.L.
      • Anaissie E.
      • Bruining H.
      • et al.
      Epidemiology, diagnosis and treatment of systemic Candida infection in surgical patients under intensive care.
      Opening or perforation of the bowel results in contamination of the peritoneum by digestive flora. Surgical cleaning of the abdominal cavity combined with antibiotics is sufficient to allow full recovery in most cases, where the identification of Candida spp. has no clinical significance.
      • Montravers P.
      • Dupont H.
      • Eggimann P.
      Intra-abdominal candidiasis: the guidelines-forgotten non-candidemic invasive candidiasis.
      • Solomkin J.S.
      • Flohr A.B.
      • Quie P.G.
      • Simmons R.L.
      The role of Candida in intraperitoneal infections.
      Alternatively, colonization may progress to invasive candidiasis in recurrent peritonitis following anastomotic leakage.
      • Calandra T.
      • Bille J.
      • Schneider R.
      • Mosimann F.
      • Francioli P.
      Clinical significance of Candida isolated from peritoneum in surgical patients.
      • Eggimann P.
      • Francioli P.
      • Bille J.
      • et al.
      Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients.
      • Senn L.
      • Eggimann P.
      • Ksontini R.
      • et al.
      Caspofungin for prevention of intra-abdominal candidiasis in high-risk surgical patients.
      • Tissot F.
      • Lamoth F.
      • Hauser P.M.
      • et al.
      Beta-glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis.
      These factors may explain why candidaemia is not documented in most cases of invasive candidiasis in surgical patients until late in the disease, if at all.
      • Tissot F.
      • Lamoth F.
      • Hauser P.M.
      • et al.
      Beta-glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis.
      The interval between exposure to risk factors and development of invasive disease opens a window of about one week for a structured evaluation to identify patients who may truly benefit from antifungal prophylaxis or early empirical antifungal treatment according to the underlying condition and immune status.
      • Eggimann P.
      • Bille J.
      • Marchetti O.
      Diagnosis of invasive candidiasis in the ICU.
      • Eggimann P.
      • Garbino J.
      • Pittet D.
      Management of Candida species infections in critically ill patients.
      • Magill S.S.
      • Swoboda S.M.
      • Shields C.E.
      • et al.
      The epidemiology of Candida colonization and invasive candidiasis in a surgical intensive care unit where fluconazole prophylaxis is utilized: follow-up to a randomized clinical trial.

      Antifungal prophylaxis

      The bad prognosis of invasive candidiasis has stimulated the use of systematic antifungal prophylaxis in most immunocompromised patients over the past three decades.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America.
      This is considered to be responsible for the evolution of the epidemiology of candida infections, characterized by breakthrough invasive candidiasis and infections caused by candida strains resistant to the antifungal agent used for prophylaxis.
      • Sipsas N.V.
      • Lewis R.E.
      • Tarrand J.
      • et al.
      Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001–2007): stable incidence but changing epidemiology of a still frequently lethal infection.
      • Charlier C.
      • Hart E.
      • Lefort A.
      • et al.
      Fluconazole for the management of invasive candidiasis: where do we stand after 15 years?.
      • Maertens J.
      • Marchetti O.
      • Herbrecht R.
      • et al.
      European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3 – 2009 update.
      • Dannaoui E.
      • Desnos-Ollivier M.
      • Garcia-Hermoso D.
      • et al.
      Candida spp. with acquired echinocandin resistance, France, 2004–2010.
      The success of antifungal prophylaxis in bone marrow and solid organ transplant recipients has stimulated investigators to promote it in critically ill patients. Clinical results, however, should be interpreted with caution. Studies involving unselected critically ill patients at low risk (<10%) of invasive candidiasis failed to demonstrate any benefit of antifungal prophylaxis [number needed to treat (NNT): 20–50].
      • Sandven P.
      • Qvist H.
      • Skovlund E.
      • Giercksky K.E.
      Significance of Candida recovered from intraoperative specimens in patients with intra-abdominal perforations.
      • Schuster M.G.
      • Edwards Jr., J.E.
      • Sobel J.D.
      • et al.
      Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial.
      To avoid overuse of antifungals, we and others have emphasized that prophylaxis should target only critically ill patients in whom it has been shown useful.
      • Eggimann P.
      • Garbino J.
      • Pittet D.
      Management of Candida species infections in critically ill patients.
      • Eggimann P.
      • Francioli P.
      • Bille J.
      • et al.
      Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients.
      • Senn L.
      • Eggimann P.
      • Ksontini R.
      • et al.
      Caspofungin for prevention of intra-abdominal candidiasis in high-risk surgical patients.
      • Garbino J.
      • Lew D.P.
      • Romand J.A.
      • Hugonnet S.
      • Auckenthaler R.
      • Pittet D.
      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.
      • Pelz R.K.
      • Hendrix C.W.
      • Swoboda S.M.
      • et al.
      Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients.
      In these highly selected populations, representing only 1–3% of all ICU admissions, the NNT ranged from three to 10. This concept has been acknowledged and validated in guidelines for the management of invasive candidiasis in immunocompetent hosts.
      • Pappas P.G.
      • Kauffman C.A.
      • Andes D.
      • et al.
      Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.
      • Cornely O.A.
      • Bassetti M.
      • Calandra T.
      • et al.
      ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      Based on the available evidence, they state that institutions in which high rates of invasive candidiasis in adult ICU patients persist despite standard infection-control procedures should consider fluconazole prophylaxis only for highly selected ICU patients.
      • Pappas P.G.
      • Kauffman C.A.
      • Andes D.
      • et al.
      Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.
      • Cornely O.A.
      • Bassetti M.
      • Calandra T.
      • et al.
      ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      • Eggimann P.
      • Garbino J.
      • Pittet D.
      Management of Candida species infections in critically ill patients.
      Two small prospective studies, including one placebo-controlled, suggested that antifungal prophylaxis in patients presenting with anastomotic leakage after abdominal surgery may prevent the development of invasive candidiasis.
      • Cornely O.A.
      • Bassetti M.
      • Calandra T.
      • et al.
      ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      • Eggimann P.
      • Francioli P.
      • Bille J.
      • et al.
      Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients.
      • Senn L.
      • Eggimann P.
      • Ksontini R.
      • et al.
      Caspofungin for prevention of intra-abdominal candidiasis in high-risk surgical patients.
      Antifungal prophylaxis, however, should not be given to all ICU patients. In the absence of routinely available biomarkers to guide early empirical antifungal treatment, several risk-based strategies have been proposed to identify patients likely to benefit most.

      Risk-based strategies to guide empirical antifungal treatment

      Non-candidaemic systemic candidiasis represents the majority of invasive candidiasis cases occurring in critically ill patients, and early empirical antifungal treatment avoids delayed treatment of documented infection, which significantly worsens the outcome.
      • Morrell M.
      • Fraser V.J.
      • Kollef M.H.
      Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality.
      • Garey K.W.
      • Rege M.
      • Pai M.P.
      • et al.
      Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study.
      • Hsu D.I.
      • Nguyen M.
      • Nguyen L.
      • Law A.
      • Wong-Beringer A.
      A multicentre study to evaluate the impact of timing of caspofungin administration on outcomes of invasive candidiasis in non-immunocompromised adult patients.
      Unfortunately, the definition of microbiologically demonstrated infection is restrictive and cannot be used to guide antifungal initiation in clinical practice.
      • Eggimann P.
      • Garbino J.
      • Pittet D.
      Management of Candida species infections in critically ill patients.
      • Playford E.G.
      • Eggimann P.
      • Calandra T.
      Antifungals in the ICU.
      • Eggimann P.
      • Ostrosky-Zeichner L.
      Early antifungal intervention strategies in ICU patients.
      • Eggimann P.
      • Pittet D.
      Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later.
      • Zilberberg M.D.
      • Shorr A.F.
      • Kollef M.H.
      Secular trends in candidemia-related hospitalization in the United States, 2000–2005.
      Thus, early empirical treatment currently relies on the positive predictive value of risk assessment strategies, such as (1) colonization index, (2) candida score, and (3) predictive rules.
      • Eggimann P.
      • Garbino J.
      • Pittet D.
      Management of Candida species infections in critically ill patients.
      • Eggimann P.
      • Ostrosky-Zeichner L.
      Early antifungal intervention strategies in ICU patients.
      • Eggimann P.
      • Pittet D.
      Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later.
      • Pittet D.
      • Monod M.
      • Suter P.M.
      • Frenk E.
      • Auckenthaler R.
      Candida colonization and subsequent infections in critically ill surgical patients.
      • Leon C.
      • Ruiz-Santana S.
      • Saavedra P.
      • et al.
      A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization.
      • Paphitou N.I.
      • Ostrosky-Zeichner L.
      • Rex J.H.
      Rules for identifying patients at increased risk for candidal infections in the surgical intensive care unit: approach to developing practical criteria for systematic use in antifungal prophylaxis trials.
      • Ostrosky-Zeichner L.
      • Sable C.
      • Sobel J.
      • et al.
      Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting.
      • Ostrosky-Zeichner L.
      • Aranah L.
      • Eggimann P.
      • et al.
      Preliminary results of a multicenter, international, retrospective, study to validate a clinical prediction rule (CPR) to identify critically-ill patients at risk of invasive candidiasis (IC) for TReatment with Empirical Antifungal Therapy (TREAT Study). ICAAC 2008.
      These risk-based strategies share common characteristics: first, they are based on combinations of several risk factors, such as candida colonization, previous use of broad-spectrum antibiotics, and previous abdominal surgery; second, their positive predictive values (PPVs) are used for the early prediction of invasive candidiasis; third, their negative predictive values (NPVs) are much higher than their PPVs, for which they were developed (Table II).
      Table IIAccuracy of risk prediction models for invasive candidiasis in critically ill patients
      Adapted from Eggimann and Ostrosky-Zeichner.21
      ReferencePopulation, ICRisk-based prediction modelAccuracy of prediction
      Pittet et al.
      • Pittet D.
      • Monod M.
      • Suter P.M.
      • Frenk E.
      • Auckenthaler R.
      Candida colonization and subsequent infections in critically ill surgical patients.
      29 patients heavily colonized with Candida spp. (11 developed IC)Colonization index: threshold = 0.5PPV = 66%

      NPV = 100%
      Paphitou et al.
      • Paphitou N.I.
      • Ostrosky-Zeichner L.
      • Rex J.H.
      Rules for identifying patients at increased risk for candidal infections in the surgical intensive care unit: approach to developing practical criteria for systematic use in antifungal prophylaxis trials.
      327 ICU patients staying ≥4 days [23 (11%) developed IC]Predictive rule – one of the following: diabetes, total parenteral nutrition, prior ICU stay, new onset haemodialysis, on broad-spectrum antibioticsCaptured 52% of IC

      Sensitivity = 83%

      Specificity = 50%

      PPV = 11%

      NPV = 98%
      Leon et al.
      • Leon C.
      • Ruiz-Santana S.
      • Saavedra P.
      • et al.
      A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization.
      1669 patients [97 (6%) with IC] staying ≥7 days in 73 mixed Spanish ICUsCandida score – to predict IC, sum of: severe sepsis (2 points), surgery (1), total parenteral nutrition (1), multifocal candida colonization (1). Threshold = 2.5 points.Captured 81% of IC

      Sensitivity = 81%

      Specificity = 74%

      PPV = 16%

      NPV = 98%
      Ostrosky-Zeichner et al.
      • Ostrosky-Zeichner L.
      • Sable C.
      • Sobel J.
      • et al.
      Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting.
      2890 patients [88 (3%) with proven or probable IC] staying ≥4 days in nine US/Brazilian ICUsPredictive rule – both systemic antibiotics and central venous catheter (day 1–3 of ICU stay); plus two of total parenteral nutrition (day 1–3 of ICU stay), dialysis (day 1–3 of ICU stay), major surgery (day –7 to 0 of ICU stay), pancreatitis (day –7 to 0 of ICU stay), steroids (day –7 to 3 of ICU stay), other immunosuppressive agents (day –7 to 0 of ICU stay)Captured 34% of IC

      Sensitivity = 34%

      Specificity = 90%

      PPV = 10%

      NPV = 97%
      Ostrosky-Zeichner et al.
      • Ostrosky-Zeichner L.
      • Aranah L.
      • Eggimann P.
      • et al.
      Preliminary results of a multicenter, international, retrospective, study to validate a clinical prediction rule (CPR) to identify critically-ill patients at risk of invasive candidiasis (IC) for TReatment with Empirical Antifungal Therapy (TREAT Study). ICAAC 2008.
      649 patients from mixed ICUs [12 (1.8%) developed IC]. Risk factors as above combined with the presence of Candida in specimens routinely collectedPredictive rule: all of: mechanical ventilation, broad-spectrum antibiotics and central venous catheter (day 1–3 of ICU stay); plus one of: total parenteral nutrition (day 1–3 of ICU stay), dialysis (day 1–3 of ICU stay), major surgery (day –7 to 0 of ICU stay), pancreatitis (day –7 to 0 of ICU stay), steroids (day –7 to 3 of ICU stay), other immunosuppressive agents (day –7 to 0 of ICU stay) plus presence of Candida spp. in any clinical specimenCaptured 66% of IC

      Sensitivity = 66%

      Specificity = 87%

      PPV = 9%

      NPV = 99%
      Charles et al.
      • Leon C.
      • Ruiz-Santana S.
      • Saavedra P.
      • et al.
      Usefulness of the “Candida score” for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients: a prospective multicenter study.
      136 ICU patients without bacterial infection staying ≥7 days in 36 mixed ICUs [20 (15%) developed IC]Candida score ≥3 points at day 7 [sum of: severe sepsis (2 points), surgery (1), total parenteral nutrition (1), multifocal candida colonization (1)] plus procalcitonin ≥0.3ng/mLCaptured 80% of IC

      Sensitivity = 80%

      Specificity = 74%

      PPV = 59%

      NPV = 89%
      Ostrosky-Zeichner et al.
      • Posteraro B.
      • De Pascale G.
      • Tumbarello M.
      • et al.
      Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1→3)-beta-d-glucan assay, Candida score, and colonization index.
      597 ICU patients [22 (4%) with proven or probable IC] staying ≥4 days in six US ICUsPredictive rule: all of: mechanical ventilation, broad-spectrum antibiotics and central venous catheter (day 1–3 of ICU stay); plus one of: total parenteral nutrition (day 1–3 of ICU stay), dialysis (day 1–3 of ICU stay), major surgery (day –7 to 0 of ICU stay), pancreatitis (day –7 to 0 of ICU stay), steroids (day –7 to 3), other immunosuppressive agents (day –7 to 0 of ICU stay)Captured 90% of IC

      Sensitivity = 90%

      Specificity = 48%

      PPV = 6%

      NPV = 99%
      Hermsen et al.
      • Ostrosky-Zeichner L.
      • Shoham S.
      • Vazquez J.
      • et al.
      MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting.
      Matched case of IC (88) vs control (352) studyPredictive rule (Nebraska Medical Center rule) all of: broad-spectrum antibiotics and central venous catheter and total parenteral nutrition and steroids and abdominal surgery (day 1–3 of ICU stay)Captured 85% of IC

      Sensitivity = 84%

      Specificity = 60%

      PPV = 5%

      NPV = 99%
      IC, invasive candidiasis; ICU, intensive care unit; PPV, positive predictive value; NPV, negative predictive value.
      a Adapted from Eggimann and Ostrosky-Zeichner.
      • Eggimann P.
      • Ostrosky-Zeichner L.
      Early antifungal intervention strategies in ICU patients.

      Colonization index

      The documentation of increasing amounts of Candida spp. in semiquantitative cultures from multiple sites predicts the subsequent development of invasive candidiasis.
      • Eggimann P.
      • Garbino J.
      • Pittet D.
      Epidemiology of Candida species infections in critically ill non-immunosuppressed patients.
      The evaluation of colonization dynamics by periodic colonization index calculation accurately predicted the development of invasive candidiasis.
      • Charles P.E.
      • Dalle F.
      • Aube H.
      • et al.
      Candida spp. colonization significance in critically ill medical patients: a prospective study.
      • Vincent J.L.
      • Anaissie E.
      • Bruining H.
      • et al.
      Epidemiology, diagnosis and treatment of systemic Candida infection in surgical patients under intensive care.
      • Solomkin J.S.
      • Flohr A.B.
      • Quie P.G.
      • Simmons R.L.
      The role of Candida in intraperitoneal infections.
      In a prospective cohort study of critically ill surgical patients, Pittet et al. assessed the degree of colonization by daily colonization index defined as the ratio of the number of distinct non-blood body sites colonized by Candida spp. to the total number of body sites cultured.
      • Pittet D.
      • Monod M.
      • Suter P.M.
      • Frenk E.
      • Auckenthaler R.
      Candida colonization and subsequent infections in critically ill surgical patients.
      Only strains of Candida spp. with the same genetic identity were considered.
      • Pittet D.
      • Monod M.
      • Filthuth I.
      • Frenk E.
      • Suter P.M.
      • Auckenthaler R.
      Contour-clamped homogeneous electric field gel electrophoresis as a powerful epidemiologic tool in yeast infections.
      Eleven of 29 heavily colonized patients developed invasive candidiasis, which was independently predicted by the degree of colonization. Average candida colonization indices in colonized and infected patients were 0.47 and 0.7, respectively (P < 0.01). Furthermore, a colonization index threshold of ≥0.5 enabled the identification of all infected patients on average six days before the diagnosis of infection.
      A recent review on candida colonization index showed that it has been successfully used to characterize colonization dynamics, to assess the significance of candiduria, and to evaluate the impact of antifungal prophylaxis.
      • Eggimann P.
      • Pittet D.
      Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later.
      Despite limited bedside practicability, we concluded that the colonization index remains an important surrogate of the dynamics of colonization, which increases early in patients who develop invasive candidiasis.

      Candida score

      The candida score is a development of the colonization index.
      • Leon C.
      • Ruiz-Santana S.
      • Saavedra P.
      • et al.
      A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization.
      In a prospective cohort study of 1699 patients staying more than seven days in the ICU, Leon et al. found that surgery [odds ratio (OR): 2.71; 95% confidence interval (CI): 1.45–5.06], multifocal colonization (OR: 3.04; 95% CI: 1.45–6.39), total parenteral nutrition (OR: 2.48; 95% CI: 1.16–5.31), and severe sepsis (OR: 7.68; 95% CI: 4.14–14.22) predicted invasive candidiasis. When one point was attributed to each risk factor (but two for severe sepsis) and a cut-off value of 2.5 was used, the candida score showed 81% sensitivity and 74% specificity. We and others showed that the accuracy of a candida score ≥3 was greater than that of a colonization index ≥0.5.
      • Tissot F.
      • Lamoth F.
      • Hauser P.M.
      • et al.
      Beta-glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis.

      Vincent JL. When to start antifungals in abdominal infections: Let us be INTENSE. 34th International Symposium on Intensive Care and Emergency Medicine, Brussels, Belgium, 2014. Oral presentation.

      • Montravers P.
      • Mira J.P.
      • Gangneux J.P.
      • Leroy O.
      • Lortholary O.
      AmarCand Study Group. A multicentre study of antifungal strategies and outcome of Candida spp. peritonitis in intensive-care units.
      The usefulness of this score in ruling out the risk of invasive candidiasis has also been demonstrated.

      Vincent JL. When to start antifungals in abdominal infections: Let us be INTENSE. 34th International Symposium on Intensive Care and Emergency Medicine, Brussels, Belgium, 2014. Oral presentation.

      In a multicentre cohort of 1007 patients staying more than seven days in ICU, only 13/565 (2.3%) patients with candida scores <3 developed candidiasis, corresponding to an NPV of 98%. However, the usefulness of the candida score to guide empirical antifungal treatment has not been tested in prospective clinical studies.

      Predictive rules

      Up to five risk factors associated with invasive candidiasis in retrospective analyses of cohorts of critically ill patients were combined to develop predictive rules for the early identification of critically ill patients at high risk of developing invasive candidiasis.
      • Eggimann P.
      • Ostrosky-Zeichner L.
      Early antifungal intervention strategies in ICU patients.
      Despite progressive improvement in the accuracy of these rules, three industry-sponsored studies failed to demonstrate their clinical usefulness in guiding the early initiation of empirical antifungal treatment in critically ill patients. A predictive rule was used in a multicentre, randomized, double-blind, placebo-controlled trial comparing caspofungin with placebo as antifungal prophylaxis in 222 critically ill patients with ICU stays of three or more days who were ventilated, received antibiotics, had a central line catheter, and had one of the following additional risk factors: parenteral nutrition, dialysis, surgery, pancreatitis, systemic steroids, or other immunosuppressants.
      • Ostrosky-Zeichner L.
      • Pappas P.G.
      • Shoham S.
      • et al.
      Improvement of a clinical prediction rule for clinical trials on prophylaxis for invasive candidiasis in the intensive care unit.
      The incidence of invasive candidiasis was 16.7% (14/84) in patients receiving placebo and 9.8% (10/102) in patients receiving caspofungin (P = 0.14). Treatment safety, length of stay, antifungal use, and mortality did not differ between groups. The authors concluded that caspofungin prophylaxis was safe, with a non-significant tendency to reduce invasive candidiasis. Two currently unpublished studies demonstrated no clinical usefulness of predictive rules based on clinical factors in guiding empirical antifungal treatment. The first, entitled ‘Pilot feasibility study with patients who are at high risk for developing invasive candidiasis in a critical care setting’ (ClinicalTrials.gov identifier: NCT01045798), was terminated due to a low recruitment rate after the inclusion of only 15 patients. The second study, entitled ‘An exploratory study to compare the efficacy and safety of micafungin as a pre-emptive treatment of invasive candidiasis versus placebo in high risk surgical subjects – a multicentre, randomized, double-blind study’ (ClinicalTrials.gov identifier: NCT01122368), included only surgical critically ill patients. Preliminary results showed a high proportion of invasive candidiasis cases at study entry. The overall rate of infection did not differ between patients receiving pre-emptive antifungal treatment (11.1%) and those receiving placebo (8.9%), but the number of patients excluded from the analysis resulted in insufficient statistical power.
      • Charles P.E.
      • Castro C.
      • Ruiz-Santana S.
      • Leon C.
      • Saavedra P.
      • Martin E.
      Serum procalcitonin levels in critically ill patients colonized with Candida spp: new clues for the early recognition of invasive candidiasis?.
      These three studies strongly suggest that despite better positive predictive value than colonization index and candida score, predictive rules may not be feasible at the bedside.

      The clinical paradox arising from the use of risk-based strategies

      The laborious nature of the clinical use and the limited availability of solid clinical data explain the low level of evidence attributed by experts to these risk-based strategies in consensus guidelines. Nevertheless, they are widely used at bedside and have succeeded in decreasing the incidence of invasive candidiasis.
      • Azoulay E.
      • Dupont H.
      • Tabah A.
      • et al.
      Systemic antifungal therapy in critically ill patients without invasive fungal infection.
      • Pappas P.G.
      • Kauffman C.A.
      • Andes D.
      • et al.
      Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.
      • Cornely O.A.
      • Bassetti M.
      • Calandra T.
      • et al.
      ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      • Leroy O.
      • Gangneux J.P.
      • Montravers P.
      • et al.
      Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006).
      • Hermsen E.D.
      • Zapapas M.K.
      • Maiefski M.
      • Rupp M.E.
      • Freifeld A.G.
      • Kalil A.C.
      Validation and comparison of clinical prediction rules for invasive candidiasis in intensive care unit patients: a matched case–control study.
      This picture reflects opposing strategies: clinicians concerned by the worse prognosis of delayed treatment start antifungals early, even in low-risk patients; whereas experts, more concerned by the negative ecological impact and cost of antifungals, recommend delayed prescription, which risks failing to identify patients requiring early treatment.

      New insight into risk-based strategies

      We have emphasized that these diagnostic risk-based strategies result in the following paradigm: the most sensitive method (colonization index) increases the number of patients receiving useless treatment, whereas the most specific method (predictive rules) increases the number of patients not receiving early antifungals and developing invasive candidiasis.
      • Eggimann P.
      • Bille J.
      • Marchetti O.
      Diagnosis of invasive candidiasis in the ICU.
      • Eggimann P.
      • Ostrosky-Zeichner L.
      Early antifungal intervention strategies in ICU patients.
      • Eggimann P.
      • Pittet D.
      Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later.
      Objective analysis of the accuracy of the risk-based strategies shows that the NPVs of these strategies are much higher than their PPVs, for which they were developed (Table II).
      • Pittet D.
      • Monod M.
      • Suter P.M.
      • Frenk E.
      • Auckenthaler R.
      Candida colonization and subsequent infections in critically ill surgical patients.
      • Leon C.
      • Ruiz-Santana S.
      • Saavedra P.
      • et al.
      A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization.
      • Paphitou N.I.
      • Ostrosky-Zeichner L.
      • Rex J.H.
      Rules for identifying patients at increased risk for candidal infections in the surgical intensive care unit: approach to developing practical criteria for systematic use in antifungal prophylaxis trials.
      • Ostrosky-Zeichner L.
      • Sable C.
      • Sobel J.
      • et al.
      Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting.
      • Ostrosky-Zeichner L.
      • Aranah L.
      • Eggimann P.
      • et al.
      Preliminary results of a multicenter, international, retrospective, study to validate a clinical prediction rule (CPR) to identify critically-ill patients at risk of invasive candidiasis (IC) for TReatment with Empirical Antifungal Therapy (TREAT Study). ICAAC 2008.
      • Posteraro B.
      • De Pascale G.
      • Tumbarello M.
      • et al.
      Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1→3)-beta-d-glucan assay, Candida score, and colonization index.
      Among them, only the NPV of the candida score has been validated in a multicentre prospective clinical trial.
      • Leon C.
      • Ruiz-Santana S.
      • Saavedra P.
      • et al.
      Usefulness of the “Candida score” for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients: a prospective multicenter study.

      A practical approach for antifungal treatment in critically ill patients

      In patients perceived to be at risk of invasive candidiasis, we propose to evaluate the appropriateness of early empirical antifungal treatment by using both the PPVs and NPVs of the risk assessment strategies (Figure 1). We suggest restricting antifungal prophylaxis to surgical patients presenting with anastomotic leakage after abdominal surgery or reopening of the digestive tract during the same hospitalization to prevent the development of invasive candidiasis.
      • Cornely O.A.
      • Bassetti M.
      • Calandra T.
      • et al.
      ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.
      • Eggimann P.
      • Francioli P.
      • Bille J.
      • et al.
      Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients.
      • Senn L.
      • Eggimann P.
      • Ksontini R.
      • et al.
      Caspofungin for prevention of intra-abdominal candidiasis in high-risk surgical patients.
      For patients in whom invasive candidiasis is suspected, early empirical antifungal treatment should be considered when the candida score is ≥ 3. In these cases, a colonization index calculated using the available microbiological data of ≥0.5 strengthens the evidence of a very high risk of invasive candidiasis. Early empirical antifungal treatment should not be started in patients identified to be at low risk by a candida score <3. In these situations, a colonization index calculated using the available microbiological data of <0.5 strengthens the case for avoiding empirical antifungal treatment; further exposure or additional risk factors are required for the development of invasive candidiasis, and these will be captured by an increase in candida score or colonization index.
      Figure thumbnail gr1
      Figure 1Risk assessment strategies for antifungal treatment.

      Conflict of interest statement

      P.E. received research grants, educational grants, speaker's honoraria or consultant's honoraria from: Astellas, Merck, Sharp & Dohme-Chibret, and Pfizer. Y.A.Q., P.P.R. and J.L.P. declare no potential conflicts of interest.

      Funding sources

      None.

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